1 00:00:09,007 --> 00:00:11,210 WELCOME TO THE CLINICAL CENTER GRAND ROUNDS, 2 00:00:11,210 --> 00:00:15,013 A WEEKLY SERIES OF EDUCATIONAL LECTURES FOR PHYSICIANS AND 3 00:00:15,013 --> 00:00:17,649 HEALTH CARE PROFESSIONALS BROADCAST FROM THE CLINICAL 4 00:00:17,649 --> 00:00:20,619 CENTER AT THE NATIONAL INSTITUTES OF HEALTH IN 5 00:00:20,619 --> 00:00:22,421 BETHESDA, MD. 6 00:00:22,421 --> 00:00:25,958 THE NIH CLINICAL CENTER IS THE WORLD'S LARGEST HOSPITAL TOTALLY 7 00:00:25,958 --> 00:00:29,661 DEDICATED TO INVESTIGATIONAL RESEARCH AND LEADS THE GLOBAL 8 00:00:29,661 --> 00:00:32,598 EFFORT IN TRAINING TODAY'S INVESTIGATORS AND DISCOVERING 9 00:00:32,598 --> 00:00:34,767 TOMORROW'S CURES. 10 00:00:34,767 --> 00:00:44,263 LEARN MORE BY VISITING US ONLINE AT HTTP://CLINICALCENTER.NIH.GOV 11 00:00:44,263 --> 00:00:45,731 GOOD AFTERNOON, EVERYONE, AND 12 00:00:45,731 --> 00:00:47,366 WELCOME TO TODAY'S CLINICAL 13 00:00:47,366 --> 00:00:48,801 CENTER GRAND ROUNDS. 14 00:00:48,801 --> 00:00:51,637 THE HOPKINS CLOUD CME ACTIVITY 15 00:00:51,637 --> 00:00:55,908 CODE FOR TODAY'S GRAND ROUNDS IS 16 00:00:55,908 --> 00:00:56,108 57883. 17 00:00:56,108 --> 00:00:58,010 PLEASE TEXT THIS CODE TO JOHNS 18 00:00:58,010 --> 00:00:59,612 HOPKINS CME PHONE NUMBER ON THE 19 00:00:59,612 --> 00:01:01,480 SLIDE TO RECEIVE CME CREDIT FOR 20 00:01:01,480 --> 00:01:02,681 THE LECTURE. 21 00:01:02,681 --> 00:01:03,983 WE ALSO KINDLY INVITE YOU TO 22 00:01:03,983 --> 00:01:05,284 PROVIDE FEEDBACK ON TODAY'S 23 00:01:05,284 --> 00:01:07,052 LECTURE BY SCANNING THE QR CODE 24 00:01:07,052 --> 00:01:08,587 SHOWN ON THE CME SLIDE. 25 00:01:08,587 --> 00:01:10,322 FOR THOSE WHO ARE APPLYING FOR 26 00:01:10,322 --> 00:01:12,291 CME, YOU'LL RECEIVE THE FEEDBACK 27 00:01:12,291 --> 00:01:15,027 SURVEY VIA A LINK BY EMAIL. 28 00:01:15,027 --> 00:01:15,928 THE SURVEY WILL BE USED TO 29 00:01:15,928 --> 00:01:17,129 PROVIDE US WITH ANY IMPORTANT 30 00:01:17,129 --> 00:01:18,564 FEEDBACK ABOUT THIS 31 00:01:18,564 --> 00:01:19,832 PRESENTATION, AND ALLOWS YOU TO 32 00:01:19,832 --> 00:01:21,600 SUBMIT ANY SUGGESTIONS FOR 33 00:01:21,600 --> 00:01:24,770 FUTURE GRAND ROUNDS TOPICS. 34 00:01:24,770 --> 00:01:25,971 FOLLOWING THE PRESENTATION, 35 00:01:25,971 --> 00:01:28,174 QUESTIONS FOR THE SPEAKER WILL 36 00:01:28,174 --> 00:01:29,575 BE TAKEN FROM THE MICROPHONES IN 37 00:01:29,575 --> 00:01:30,242 THE AISLES. 38 00:01:30,242 --> 00:01:31,877 THOSE VIEWING ON VIDEOCAST CAN 39 00:01:31,877 --> 00:01:32,945 SUBMIT QUESTIONS AT ANY TIME 40 00:01:32,945 --> 00:01:34,280 DURING THE LECTURE BY SCROLLING 41 00:01:34,280 --> 00:01:35,548 DOWN AND CLICKING THE LIVE 42 00:01:35,548 --> 00:01:37,116 FEEDBACK BUTTON LOCATED ON THE 43 00:01:37,116 --> 00:01:38,450 VIDEOCAST WEBSITE. 44 00:01:38,450 --> 00:01:39,652 QUESTIONS WILL BE ANSWERED AS 45 00:01:39,652 --> 00:01:41,153 TIME PERMITS AT THE CONCLUSION 46 00:01:41,153 --> 00:01:44,223 OF THE PRESENTATION. 47 00:01:44,223 --> 00:01:45,658 NOW ON TO TODAY'S TALK. 48 00:01:45,658 --> 00:01:47,860 THE CONTEMPORARY CLINICAL 49 00:01:47,860 --> 00:01:48,828 MEDICINE GREAT TEACHERS GRAND 50 00:01:48,828 --> 00:01:49,929 ROUNDS IS A SPECIAL SERIES 51 00:01:49,929 --> 00:01:51,564 WITHIN THE CLINICAL CENTER GRAND 52 00:01:51,564 --> 00:01:52,131 ROUNDS PROGRAM. 53 00:01:52,131 --> 00:01:53,766 AS CONCEIVED BY THE FIRST 54 00:01:53,766 --> 00:01:54,967 COMMITTEE CHAIR OF THE GREAT 55 00:01:54,967 --> 00:01:58,470 TEACHERS COMMITTEE, DR. PAUL 56 00:01:58,470 --> 00:02:00,906 PLATZ, DISTINGUISHED SCIENTIST 57 00:02:00,906 --> 00:02:06,645 EEMERITUS OF NIAMS, TO PRESENT N 58 00:02:06,645 --> 00:02:07,746 TOPICS AND IDEAS ABOUT WHICH 59 00:02:07,746 --> 00:02:12,351 THEY ARE PASSIONATE TO SHARE 60 00:02:12,351 --> 00:02:13,752 THEIR REFLECTIONS WITH US AND TO 61 00:02:13,752 --> 00:02:14,620 INSPIRE YOUNG INVESTIGATORS IN 62 00:02:14,620 --> 00:02:17,156 THE PURSUIT OF CAREERS IN THE 63 00:02:17,156 --> 00:02:19,325 FIELD OF BIOMEDICAL RESEARCH. 64 00:02:19,325 --> 00:02:22,094 OUR SPEAKER TODAY IS 65 00:02:22,094 --> 00:02:27,366 DR. ELIZABETH PARKS, SCHOOL OF 66 00:02:27,366 --> 00:02:28,200 MEDICINE AT THE UNIVERSITY OF 67 00:02:28,200 --> 00:02:28,968 MISSOURI. 68 00:02:28,968 --> 00:02:30,936 SHE'S ALSO THE ASSOCIATE 69 00:02:30,936 --> 00:02:32,371 DIRECTOR OF THE CLINICAL 70 00:02:32,371 --> 00:02:33,472 TRANSLATIONAL SCIENCE UNIT AND 71 00:02:33,472 --> 00:02:35,741 AN INVESTIGATOR IN THE 72 00:02:35,741 --> 00:02:36,575 UNIVERSITY'S NEXT GEN PRECISION 73 00:02:36,575 --> 00:02:40,246 HEALTH INITIATIVE. 74 00:02:40,246 --> 00:02:43,782 DR. PARKS RECEIVES HER BACHELOR 75 00:02:43,782 --> 00:02:44,950 OF SCIENCE AT THE UNIVERSITY OF 76 00:02:44,950 --> 00:02:45,918 WISCONSIN-MADISON AND EARNED HER 77 00:02:45,918 --> 00:02:48,220 PH.D. IN NUTRITIONAL 78 00:02:48,220 --> 00:02:49,154 BIOCHEMISTRY AT THE UNIVERSITY 79 00:02:49,154 --> 00:02:50,556 OF CALIFORNIA DAVIS. 80 00:02:50,556 --> 00:02:52,491 SHORTLY AFTER, SHE COMPLETED HER 81 00:02:52,491 --> 00:02:53,926 POSTDOCTORAL FELLOWSHIP AT UC 82 00:02:53,926 --> 00:02:56,629 BERKELEY AND UC SAN FRANCISCO. 83 00:02:56,629 --> 00:02:57,763 IN 2013, SHE MOVED TO THE 84 00:02:57,763 --> 00:03:00,232 UNIVERSITY OF MISSOURI. 85 00:03:00,232 --> 00:03:01,901 DR. PARKS' RESEARCH FOCUSES ON 86 00:03:01,901 --> 00:03:03,435 HOW UNDERSTANDING HOW THE FOOD 87 00:03:03,435 --> 00:03:05,938 WE EAT IS PROCESSED IN THE BODY 88 00:03:05,938 --> 00:03:08,007 TO BENEFIT HEALTH, AND HOW FOOD 89 00:03:08,007 --> 00:03:10,209 CAN ALSO CONTRIBUTE TO THE 90 00:03:10,209 --> 00:03:12,945 PROGRESSION OF DISEASES SUCH AS 91 00:03:12,945 --> 00:03:13,512 OBESITY, PREDIABETES AND 92 00:03:13,512 --> 00:03:14,046 DIABETES. 93 00:03:14,046 --> 00:03:15,547 THE MAJOR RESEARCH CONTRIBUTIONS 94 00:03:15,547 --> 00:03:17,182 OF THE PARKS LAB EMANATE FROM 95 00:03:17,182 --> 00:03:18,951 THE DEVELOPMENT OF NOVEL 96 00:03:18,951 --> 00:03:20,319 TECHNIQUES TO MEASURE THE 97 00:03:20,319 --> 00:03:22,021 ABSORPTION AND DISPOSAL OF 98 00:03:22,021 --> 00:03:24,423 DIETARY FATS, CARBOHYDRATES AND 99 00:03:24,423 --> 00:03:26,191 PROTEINS IN BOTH HUMANS AND IN 100 00:03:26,191 --> 00:03:27,493 ANIMAL MODELS. 101 00:03:27,493 --> 00:03:29,561 OVER THE PAST 24 YEARS, 102 00:03:29,561 --> 00:03:31,297 DR. PARKS HAS DEVELOPED METHODS 103 00:03:31,297 --> 00:03:32,831 USING COMBINATIONS OF MULTIPLE 104 00:03:32,831 --> 00:03:35,501 STABLE ISOTOPES, COUPLED WITH 105 00:03:35,501 --> 00:03:36,568 MATHEMATICAL MODELING TO 106 00:03:36,568 --> 00:03:39,071 ESTABLISH A NON-STEADY STATE 107 00:03:39,071 --> 00:03:40,606 MODEL OF POST MEAL METABOLISM. 108 00:03:40,606 --> 00:03:41,907 USING THIS MODEL, SHE'S SHOWN 109 00:03:41,907 --> 00:03:44,109 THAT IN CONTRAST TO RODENTS, A 110 00:03:44,109 --> 00:03:45,978 SIGNIFICANT AMOUNT OF MEAL FAT 111 00:03:45,978 --> 00:03:47,513 CAN CYCLE THROUGH THE LIVER IN 112 00:03:47,513 --> 00:03:48,914 HEALTHY HUMANS. 113 00:03:48,914 --> 00:03:50,349 HER LAB'S SEMINAL CONTRIBUTIONS 114 00:03:50,349 --> 00:03:52,217 HAVE INCLUDED UNDERSTANDING HOW 115 00:03:52,217 --> 00:03:53,452 DIETARY SUGARS, WHICH CAN BE 116 00:03:53,452 --> 00:03:56,155 MADE INTO FAT IN THE LIVER, 117 00:03:56,155 --> 00:03:57,790 SIGNIFICANTLY CONTRIBUTE TO 118 00:03:57,790 --> 00:04:01,727 METABOLIC DYSFUNCTION ASSOCIATED 119 00:04:01,727 --> 00:04:03,996 STEATOHEPATITIS OR MASH. 120 00:04:03,996 --> 00:04:05,230 DR. PARKS HAS HELD LEADERSHIP 121 00:04:05,230 --> 00:04:06,966 POSITIONS IN THE AMERICAN 122 00:04:06,966 --> 00:04:08,067 SOCIETY FOR NUTRITION AND WAS 123 00:04:08,067 --> 00:04:09,802 PRESIDENT OF THE OBESITY SOCIETY 124 00:04:09,802 --> 00:04:11,236 IN 2 2023. 125 00:04:11,236 --> 00:04:13,005 SHE'S A FELLOW OF THE AMERICAN 126 00:04:13,005 --> 00:04:13,872 HEART ASSOCIATION AND THE 127 00:04:13,872 --> 00:04:15,708 OBESITY SOCIETY, AND HAS BEEN A 128 00:04:15,708 --> 00:04:17,242 STANDING MEMBER OF NIH GRANT 129 00:04:17,242 --> 00:04:19,111 REVIEW COMMITTEES FOCUSING ON 130 00:04:19,111 --> 00:04:20,546 METABOLISM, DIABETES AND 131 00:04:20,546 --> 00:04:20,779 OBESITY. 132 00:04:20,779 --> 00:04:22,614 SHE'S ALSO AN AD HOC MEMBER AND 133 00:04:22,614 --> 00:04:25,884 CHAIR OF NUMEROUS NIH REVIEW 134 00:04:25,884 --> 00:04:26,885 COMMITTEES. 135 00:04:26,885 --> 00:04:29,722 THE TITLE OF DR. PARKS' 136 00:04:29,722 --> 00:04:38,063 PRESENTATION TODAY IS -- PLEASE 137 00:04:38,063 --> 00:04:40,666 JOIN ME IN WELCOMING TODAY'S 138 00:04:40,666 --> 00:04:42,668 GRAND ROUND SPEAKER, 139 00:04:42,668 --> 00:04:43,102 DR. ELIZABETH PARKS. 140 00:04:43,102 --> 00:04:44,203 >> THANK YOU VERY MUCH AND IT'S 141 00:04:44,203 --> 00:04:44,903 GOOD TO BE HERE. 142 00:04:44,903 --> 00:04:46,772 I HAVE LEARNED A LOT TODAY. 143 00:04:46,772 --> 00:04:52,845 I'D LIKE TO SHARE WITH YOU SOME 144 00:04:52,845 --> 00:04:57,049 THOSE I HAVE ON DEPOSITS OF 145 00:04:57,049 --> 00:04:57,983 FATTY LIVER DISEASE. 146 00:04:57,983 --> 00:04:59,651 MY EMAIL IS IN THE UPPER 147 00:04:59,651 --> 00:05:02,921 RIGHT-HAND CORNER AND CONFLICT 148 00:05:02,921 --> 00:05:04,123 OF INTEREST IS IMPORTANT FOR ME 149 00:05:04,123 --> 00:05:04,890 TO DISCLOSE. 150 00:05:04,890 --> 00:05:06,525 I CONSULT WITH BOTH THE 151 00:05:06,525 --> 00:05:07,292 PHARMACEUTICAL INDUSTRY AND ALSO 152 00:05:07,292 --> 00:05:08,761 THE FOOD INDUSTRY, NONE OF THE 153 00:05:08,761 --> 00:05:09,962 INFORMATION I'M GOING TO GIVE 154 00:05:09,962 --> 00:05:13,832 TODAY RELATES TO THAT. 155 00:05:13,832 --> 00:05:17,336 SOY WASO I WANT TO START WITH AE 156 00:05:17,336 --> 00:05:20,205 FROM A NOBLE LAUREATE 120 YEARS 157 00:05:20,205 --> 00:05:20,472 AGO. 158 00:05:20,472 --> 00:05:22,174 IT IS NOT ACCIDENTAL THAT ALL 159 00:05:22,174 --> 00:05:23,675 PHENOMENON OF HUMAN LIFE ARE 160 00:05:23,675 --> 00:05:25,677 DOMINATED BY THE SEARCH FOR 161 00:05:25,677 --> 00:05:26,545 DAILY BREAD. 162 00:05:26,545 --> 00:05:27,346 PRECISE KNOWLEDGE OF WHAT 163 00:05:27,346 --> 00:05:29,481 HAPPENS TO FOOD ENTERING THE 164 00:05:29,481 --> 00:05:31,250 ORGANISM MUST BE THE SUBJECT OF 165 00:05:31,250 --> 00:05:33,085 IDEAL PHYSIOLOGY, THE PHYSIOLOGY 166 00:05:33,085 --> 00:05:35,054 OF THE FUTURE. 167 00:05:35,054 --> 00:05:37,056 AND IT STILL IS WHY WE CHOOSE TO 168 00:05:37,056 --> 00:05:39,992 EAT AND WHAT WE EAT IS STILL THE 169 00:05:39,992 --> 00:05:45,831 PHYSIOLOGY OF THE FUTURE. 170 00:05:45,831 --> 00:05:48,133 I STUDY THE NON-EQUILIBRIUM 171 00:05:48,133 --> 00:05:49,168 STEADY STATE. 172 00:05:49,168 --> 00:05:50,369 RICHARD FINEMAN SAID THIS IS 173 00:05:50,369 --> 00:05:52,371 WHEN ALL THE FAST THINGS HAVE 174 00:05:52,371 --> 00:05:53,338 HAPPENED BUT THE SLOW THINGS 175 00:05:53,338 --> 00:05:54,106 HAVE NOT. 176 00:05:54,106 --> 00:05:55,741 AND WHAT HE MEANS BY THAT IS 177 00:05:55,741 --> 00:05:57,543 EVEN WHEN HE HUMANS ARE FASTING, 178 00:05:57,543 --> 00:05:58,944 WE ARE ADAPTING. 179 00:05:58,944 --> 00:06:00,979 WE ARE CONTINUALLY ADAPTING TO 180 00:06:00,979 --> 00:06:07,386 EVERY HOUR THAT WE DO NOT EAT. 181 00:06:07,386 --> 00:06:09,421 AND HUMANS ARE SYSTEMS 182 00:06:09,421 --> 00:06:10,289 ANALYZERS, SO I'M GOING TO TALK 183 00:06:10,289 --> 00:06:11,857 TODAY ABOUT LOOKING AT SYSTEMS 184 00:06:11,857 --> 00:06:16,895 AS THEY CHANGE. 185 00:06:16,895 --> 00:06:17,930 WE WATCH THE WEATHER REPORT ON 186 00:06:17,930 --> 00:06:19,198 THE NEWS AND WE ARE NOT 187 00:06:19,198 --> 00:06:19,865 CHALLENGED BY THE PRESENTATION 188 00:06:19,865 --> 00:06:20,732 OF THAT COMPLEXITY. 189 00:06:20,732 --> 00:06:22,034 THERE'S LOTS OF VARIABILITY 190 00:06:22,034 --> 00:06:24,036 THERE ON THE WEATHER, THERE'S 191 00:06:24,036 --> 00:06:26,405 LOTS OF DATA, AND THE WEATHER 192 00:06:26,405 --> 00:06:27,406 MODEL HELPS US PREDICT THE 193 00:06:27,406 --> 00:06:31,110 FUTURE. 194 00:06:31,110 --> 00:06:31,877 INDIVIDUALS ANALYSES OF THE 195 00:06:31,877 --> 00:06:33,412 COMPLEXITY IN THE WORLD AROUND 196 00:06:33,412 --> 00:06:35,514 US SHOULD THEN COME NATURALLY, 197 00:06:35,514 --> 00:06:37,015 BECAUSE WE ARE SYSTEMS 198 00:06:37,015 --> 00:06:38,217 ANALYZERS, BUT SOMEHOW IN 199 00:06:38,217 --> 00:06:39,885 BIOLOGY, MODELING OF SYSTEMS HAS 200 00:06:39,885 --> 00:06:42,254 NOT BEEN UNIVERSALLY ACCEPTED, 201 00:06:42,254 --> 00:06:44,223 RATHER THE CULTURE CONTINUES TO 202 00:06:44,223 --> 00:06:45,991 FOCUS ON BREAKING DOWN SYSTEMS 203 00:06:45,991 --> 00:06:50,362 TO A SINGLE MEASURABLE UNIT. 204 00:06:50,362 --> 00:06:52,331 THIS IS BECAUSE MOST OF OUR 205 00:06:52,331 --> 00:06:53,765 MEASURING TOOLS DO NOT CAPTURE 206 00:06:53,765 --> 00:06:56,034 THE FLUX OF MOLECULES IN THE 207 00:06:56,034 --> 00:06:56,702 BODY. 208 00:06:56,702 --> 00:06:59,004 WE MEASURE CONCENTRATION REALLY, 209 00:06:59,004 --> 00:07:02,508 REALLY WELL, BUT NOT MOVEMENT OF 210 00:07:02,508 --> 00:07:02,908 MOLECULES. 211 00:07:02,908 --> 00:07:04,610 SOME PIECES OF DATA ARE HARDER 212 00:07:04,610 --> 00:07:07,112 TO OBTAIN THAN OTHERS, AND WE 213 00:07:07,112 --> 00:07:09,281 NEED TO EXPAND OUR METHODS TO BE 214 00:07:09,281 --> 00:07:10,716 ABLE TO COLLECT THESE RIGHT 215 00:07:10,716 --> 00:07:11,817 PIECES OF INFORMATION AT THE 216 00:07:11,817 --> 00:07:12,818 RIGHT TIME. 217 00:07:12,818 --> 00:07:15,220 AND THIS IS WHAT I'M GOING TO 218 00:07:15,220 --> 00:07:15,721 DESCRIBE TODAY. 219 00:07:15,721 --> 00:07:17,189 SOME OF OUR METHODS THAT WE'VE 220 00:07:17,189 --> 00:07:18,824 WORKED ON OVER THE LAST 25 YEARS 221 00:07:18,824 --> 00:07:22,494 TO BE ABLE TO CAPTURE THE VIDEO 222 00:07:22,494 --> 00:07:24,363 OF THE BODY'S METABOLISM AS 223 00:07:24,363 --> 00:07:28,100 OPPOSED TO A SNAPSHOT. 224 00:07:28,100 --> 00:07:31,270 WE NEED BOTH DYNAMIC MODELS AND 225 00:07:31,270 --> 00:07:32,471 ADAPTIVE BEHAVIORAL MODELS AS 226 00:07:32,471 --> 00:07:35,407 WELL. 227 00:07:35,407 --> 00:07:37,943 AND LASTLY, IN THE END, AS THE 228 00:07:37,943 --> 00:07:39,144 MODELING PROCESS HAS HELPED US 229 00:07:39,144 --> 00:07:41,780 PUT OUT TO THE COMMUNITY 230 00:07:41,780 --> 00:07:43,215 TESTABLE PREDICTIONS, AND I'VE 231 00:07:43,215 --> 00:07:44,283 OVER THE YEARS HAD LOTS OF 232 00:07:44,283 --> 00:07:45,717 PEOPLE COME UP TO ME AT 233 00:07:45,717 --> 00:07:48,120 CONFERENCES AND SAY, WE STUDIED 234 00:07:48,120 --> 00:07:50,155 THIS BECAUSE IT WAS SUGGESTED IN 235 00:07:50,155 --> 00:07:51,490 THE PAPER THAT YOU PUBLISHED AND 236 00:07:51,490 --> 00:07:53,058 THAT'S EXACTLY WHAT WE WANT TO 237 00:07:53,058 --> 00:07:56,562 DO. 238 00:07:56,562 --> 00:07:57,763 SO IN THE PRESENTATION OUTLINE, 239 00:07:57,763 --> 00:07:59,398 WE'RE GOING TO FOCUS FIRST ON 240 00:07:59,398 --> 00:08:00,265 LIPID THAT'S MADE IN THE LIVER, 241 00:08:00,265 --> 00:08:02,868 AND THIS IS CALLED DE NOVO 242 00:08:02,868 --> 00:08:04,970 LIPOGENESIS, AND HOW IT CONTROLS 243 00:08:04,970 --> 00:08:06,038 LIVER LIPID STORAGE. 244 00:08:06,038 --> 00:08:08,240 I'M GOING TO THEN SHOW YOU SOME 245 00:08:08,240 --> 00:08:12,077 DATA FROM INDIVIDUAL RESPONSES 246 00:08:12,077 --> 00:08:13,812 OF OVEREATING, AND THEN TALK A 247 00:08:13,812 --> 00:08:16,348 LITTLE BIT ABOUT HOW DE NOVO 248 00:08:16,348 --> 00:08:17,015 LIPOGENESIS CONTRIBUTES TO LIVER 249 00:08:17,015 --> 00:08:20,052 DISEASE. 250 00:08:20,052 --> 00:08:21,587 THEN WE'LL SWITCH TO THE 251 00:08:21,587 --> 00:08:27,392 PERIPHERY, ADIPOSE FATTY ACID 252 00:08:27,392 --> 00:08:28,460 FLUX. 253 00:08:28,460 --> 00:08:29,628 WE USE THIS MODEL TO DETERMINE 254 00:08:29,628 --> 00:08:31,897 THE ROLE OF INSULIN UPTAKE OF 255 00:08:31,897 --> 00:08:33,298 FREE FATTY ACIDS IN THE 256 00:08:33,298 --> 00:08:36,368 PERIPHERY. 257 00:08:36,368 --> 00:08:38,003 AND THEN I'LL SHOW YOU SOME 258 00:08:38,003 --> 00:08:38,971 TREATMENTS TO IMPROVE FATTY 259 00:08:38,971 --> 00:08:39,538 LIVER DISEASE. 260 00:08:39,538 --> 00:08:40,739 I'M GOING TO TALK ABOUT ENERGY 261 00:08:40,739 --> 00:08:42,241 RESTRICTION ALONE, DIET, AND 262 00:08:42,241 --> 00:08:44,776 THEN DIET PLUS EXERCISE. 263 00:08:44,776 --> 00:08:46,745 SO LET'S GET STARTED. 264 00:08:46,745 --> 00:08:48,580 THIS IS A SLIDE WITH THE LIVER 265 00:08:48,580 --> 00:08:49,581 AT THE CENTER. 266 00:08:49,581 --> 00:08:52,284 THE ADIPOSE TISSUE IS DOWN THERE 267 00:08:52,284 --> 00:08:53,752 ON THE RIGHT. 268 00:08:53,752 --> 00:08:55,387 AND THE INTESTINE UP ON THE LEFT 269 00:08:55,387 --> 00:08:57,022 AND THE MUSCLE, AND I APOLOGIZE 270 00:08:57,022 --> 00:08:59,091 TO THOSE OF YOU WHO STUDY THE 271 00:08:59,091 --> 00:09:00,626 BRAIN, THERE ISN'T A BRAIN ON 272 00:09:00,626 --> 00:09:00,959 HERE. 273 00:09:00,959 --> 00:09:02,261 WE'RE GOING TO TALK ABOUT FLUX 274 00:09:02,261 --> 00:09:04,263 OF NUTRIENTS BETWEEN THESE FOUR 275 00:09:04,263 --> 00:09:05,564 ORGANS. 276 00:09:05,564 --> 00:09:07,432 WHEN WILL I FIRST STARTED TO 277 00:09:07,432 --> 00:09:09,268 DEVELOP THIS MODEL, I WANTED TO 278 00:09:09,268 --> 00:09:11,136 KNOW WHERE DID HEPATIC LIPID 279 00:09:11,136 --> 00:09:15,407 DROPLETS COME FROM. 280 00:09:15,407 --> 00:09:17,242 THEY'RE ELEVATED IN OBESITY, IN 281 00:09:17,242 --> 00:09:17,576 DIABETES. 282 00:09:17,576 --> 00:09:19,344 WHY DO THEY BUILD UP AND WHERE 283 00:09:19,344 --> 00:09:20,646 DOES THAT FAT COME FROM BECAUSE 284 00:09:20,646 --> 00:09:21,947 IF WE COULD FIGURE THAT OUT, 285 00:09:21,947 --> 00:09:25,584 THEN WE COULD MOVE TO A 286 00:09:25,584 --> 00:09:26,885 TREATMENT. 287 00:09:26,885 --> 00:09:28,420 AND ONE OF THE FIRST PLACES WE 288 00:09:28,420 --> 00:09:29,521 DISCOVERED WAS THAT NEW FAT MADE 289 00:09:29,521 --> 00:09:32,791 FROM DIETARY SUGARS CONTRIBUTED 290 00:09:32,791 --> 00:09:37,195 SIGNIFICANTLY TO THIS POOL. 291 00:09:37,195 --> 00:09:38,597 SECOND, WE ASKED WHETHER DIETARY 292 00:09:38,597 --> 00:09:40,232 FAT COULD CAUSE FATTY LIVER AS 293 00:09:40,232 --> 00:09:41,800 WELL, AND THEN THIRD, THE ONE 294 00:09:41,800 --> 00:09:43,602 THAT'S BEEN DOWN THERE IN THE 295 00:09:43,602 --> 00:09:45,470 RIGHT-HAND CORNER IS THE 296 00:09:45,470 --> 00:09:46,471 ADIPOSE. 297 00:09:46,471 --> 00:09:48,206 AND MANY SCIENTISTS BELIEVE THAT 298 00:09:48,206 --> 00:09:50,542 FATTY LIVER IS CAUSED BY TOO 299 00:09:50,542 --> 00:09:53,011 MUCH BODY FAT, AND AS I'LL SHOW 300 00:09:53,011 --> 00:09:55,414 YOU, ADIPOSE FATTY ACID FLUX TO 301 00:09:55,414 --> 00:09:58,050 THE LIVER IS A DOMINANT SOURCE, 302 00:09:58,050 --> 00:10:00,485 BUT IT IS NOT EXACTLY THE 303 00:10:00,485 --> 00:10:01,620 CONTROLLING SOURCE OF WHETHER OR 304 00:10:01,620 --> 00:10:03,555 NOT THE FAT GETS STORED IN THE 305 00:10:03,555 --> 00:10:07,559 LIVER. 306 00:10:07,559 --> 00:10:12,064 I'M ALSO GOING TO SHOW YOU THE 307 00:10:12,064 --> 00:10:13,265 INEFA MODEL WILL DEMONSTRATE 308 00:10:13,265 --> 00:10:14,966 THIS PATHWAY OF FREE FATTY ACIDS 309 00:10:14,966 --> 00:10:16,802 FROM THE ADIPOSE BEING TAKEN UP 310 00:10:16,802 --> 00:10:18,003 INTO THE PERIPHERY, THAT GREEN 311 00:10:18,003 --> 00:10:19,037 LINE THERE. 312 00:10:19,037 --> 00:10:23,108 SO WHAT IS DE NOVO LIPOGENESIS? 313 00:10:23,108 --> 00:10:24,643 DE NOVO LIPOGENESIS IS WHEN WE 314 00:10:24,643 --> 00:10:25,944 FIND A NEW FAT IN THE LIVER THAT 315 00:10:25,944 --> 00:10:29,748 DIDN'T COME TO THE LUFER AS A LA 316 00:10:29,748 --> 00:10:30,215 FAT ALREADY. 317 00:10:30,215 --> 00:10:32,484 IF I EAT BUTTER, A FAT, I COULD 318 00:10:32,484 --> 00:10:34,920 GET THAT FAT STORED IN MY LIVER. 319 00:10:34,920 --> 00:10:36,655 THAT'S ONE WAY YOU COULD DO 320 00:10:36,655 --> 00:10:37,689 THIS. 321 00:10:37,689 --> 00:10:39,591 BUT DE NOVO LIPOGENESIS IS THAT 322 00:10:39,591 --> 00:10:41,360 WHEN ONE CONSUMES SUGARS, THEY 323 00:10:41,360 --> 00:10:44,629 GO DOWN GLYCOLYSIS AND THEIR 324 00:10:44,629 --> 00:10:46,064 BUILDING BLOCKS ARE TAKEN APART 325 00:10:46,064 --> 00:10:47,699 AND PUT BACK TOGETHER AS A NEW 326 00:10:47,699 --> 00:10:52,671 FATTY ACID. 327 00:10:52,671 --> 00:10:54,606 WHEN WE FIRST STARTED THIS WORK, 328 00:10:54,606 --> 00:10:57,342 I WAS FOCUSING ON THIS STEADY 329 00:10:57,342 --> 00:10:59,711 STATE, SO I WANTED TO SET UP A 330 00:10:59,711 --> 00:11:02,247 SITUATION WHERE SUBJECTS WERE 331 00:11:02,247 --> 00:11:04,549 CONTINUOUSLY FED FOR NINE HOURS. 332 00:11:04,549 --> 00:11:06,084 IT WAS 11 HOURS ACTUALLY. 333 00:11:06,084 --> 00:11:08,253 AND SO WE PUT AN I.V. LINE IN 334 00:11:08,253 --> 00:11:09,788 AND DREW BLOOD ALL NIGHT, AND 335 00:11:09,788 --> 00:11:11,423 THEN WE FED THEM THROUGH A 336 00:11:11,423 --> 00:11:14,593 REALLY TINY TUBE, DUODENAL TUBE, 337 00:11:14,593 --> 00:11:17,429 NOT AN NG TUBE, INTO THE UPPER 338 00:11:17,429 --> 00:11:20,399 INTESTINE, AND I HAD BEEN 339 00:11:20,399 --> 00:11:20,866 LABELING LIPOGENESIS. 340 00:11:20,866 --> 00:11:23,201 AND SO WHAT YOU SEE HERE ON THE 341 00:11:23,201 --> 00:11:25,003 LEFT-HAND SIDE IS THE PERCENT OF 342 00:11:25,003 --> 00:11:26,805 FATTY ACIDS COMING OUT OF THE 343 00:11:26,805 --> 00:11:28,774 LIVER THAT WERE MADE FROM SUGAR. 344 00:11:28,774 --> 00:11:31,176 AND THE FIRST TIME I SAW THIS, I 345 00:11:31,176 --> 00:11:32,778 THOUGHT, THERE'S A LOT HERE. 346 00:11:32,778 --> 00:11:34,579 EACH ONE OF THESE LINES IS A 347 00:11:34,579 --> 00:11:36,548 PERSON, AND YOU CAN SEE THE HUGE 348 00:11:36,548 --> 00:11:39,050 VARIABILITY IN THIS PATHWAY 349 00:11:39,050 --> 00:11:39,718 BETWEEN PEOPLE. 350 00:11:39,718 --> 00:11:42,454 YOU CAN GET A SENSE THAT 351 00:11:42,454 --> 00:11:44,089 LIPOGENESIS IS SUPPRESSED WITH 352 00:11:44,089 --> 00:11:46,158 FASTING ALL NIGHT LONG. 353 00:11:46,158 --> 00:11:47,726 THE THIRD POINT IS THAT IT'S 354 00:11:47,726 --> 00:11:49,461 HIGHEST AT ABOUT 1:00 IN THE 355 00:11:49,461 --> 00:11:51,897 MORNING. 356 00:11:51,897 --> 00:11:53,365 SO WE'RE MAKING THE MOST FAT OUT 357 00:11:53,365 --> 00:11:54,466 OF SUGAR IN THE MIDDLE OF THE 358 00:11:54,466 --> 00:11:55,567 NIGHT WHILE WE'RE SLEEPING. 359 00:11:55,567 --> 00:11:57,869 THEN WE TURNED ON THE FEEDING 360 00:11:57,869 --> 00:11:59,738 TUBE, AND SOME OF THESE 361 00:11:59,738 --> 00:12:01,573 INDIVIDUALS TURNED ON THIS 362 00:12:01,573 --> 00:12:02,774 PATHWAY JUST -- IT SHOT UP LIKE 363 00:12:02,774 --> 00:12:05,744 A ROCKET, AND OTHER SUBJECTS, 364 00:12:05,744 --> 00:12:06,945 THAT GREEN LINE THERE ON THE 365 00:12:06,945 --> 00:12:08,914 VERY BOTTOM, THAT PERSON'S LIVER 366 00:12:08,914 --> 00:12:10,982 HARDLY TOOK ANY SUGAR AND MADE 367 00:12:10,982 --> 00:12:13,852 FAT OUT OF IT. 368 00:12:13,852 --> 00:12:15,253 SO WHAT PREDICTS THIS? 369 00:12:15,253 --> 00:12:16,254 IT'S NOT AGE. 370 00:12:16,254 --> 00:12:18,323 THERE WAS A 35-YEAR-OLD AT THE 371 00:12:18,323 --> 00:12:20,358 TOP UP THERE AND A 38-YEAR-OLD 372 00:12:20,358 --> 00:12:22,027 AT THE VERY BOTTOM. 373 00:12:22,027 --> 00:12:23,695 THIS WAS THE FIRST TIME THERE'S 374 00:12:23,695 --> 00:12:25,630 ANY KIND OF STUDY LIKE THIS HAD 375 00:12:25,630 --> 00:12:27,732 EVER BEEN DONE, AND I THOUGHT 376 00:12:27,732 --> 00:12:31,036 MAYBE BODY FAT WOULD CAUSE THAT 377 00:12:31,036 --> 00:12:32,070 LIPOGENESIS TO BE HIGHER AND 378 00:12:32,070 --> 00:12:34,506 THAT WAS NOT THE CASE. 379 00:12:34,506 --> 00:12:35,507 RIGHT IN THE MIDDLE THERE, YOU 380 00:12:35,507 --> 00:12:38,009 CAN SEE THIS 23-YEAR-OLD WHO'S 381 00:12:38,009 --> 00:12:39,211 GOT 7% BODY FAT. 382 00:12:39,211 --> 00:12:40,479 I WILL NEVER FORGET HIM. 383 00:12:40,479 --> 00:12:43,582 HE WAS A COLLEGIATELY RANKED 384 00:12:43,582 --> 00:12:44,683 INTERNATIONALLY KNOWN SOCCER 385 00:12:44,683 --> 00:12:45,984 REFEREE. 386 00:12:45,984 --> 00:12:47,819 THIS GUY RAN ALL WEEK LONG AND 387 00:12:47,819 --> 00:12:49,588 YOU CAN SEE IF YOU CAN LOOK AT 388 00:12:49,588 --> 00:12:51,556 THE PINK LINE, HE STARTS VERY 389 00:12:51,556 --> 00:12:54,426 HIGH AT MIDNIGHT AND WITH 390 00:12:54,426 --> 00:12:56,495 FASTING, HE SUPPRESSES THIS 391 00:12:56,495 --> 00:12:57,596 PATHWAY ALMOST DOWN TO REALLY 392 00:12:57,596 --> 00:12:59,231 LOW LEVELS, AND THEN THE MINUTE 393 00:12:59,231 --> 00:13:00,765 WE STARTED TO FEED HIM, HE 394 00:13:00,765 --> 00:13:06,238 STARTED TO MAKE FAT FROM SUGAR. 395 00:13:06,238 --> 00:13:08,440 SO LET'S LOOK AT LIPOGENESIS 396 00:13:08,440 --> 00:13:11,042 PATTERNS IN HEALTHY INDIVIDUALS. 397 00:13:11,042 --> 00:13:13,345 WE DID A STUDY WHERE WE FED AN 398 00:13:13,345 --> 00:13:15,080 ORAL GLUCOSE TOLERANCE TEST AND 399 00:13:15,080 --> 00:13:17,048 MY SENSE WAS THAT FRUCTOSE WOULD 400 00:13:17,048 --> 00:13:19,684 BE MORE LIPOGENIC THAN GLUCOSE. 401 00:13:19,684 --> 00:13:21,419 SO I STARTED TO REPLACE THE 402 00:13:21,419 --> 00:13:22,754 GLUCOSE WITH FRUCTOSE. 403 00:13:22,754 --> 00:13:25,490 SO THE PINK DATA ARE HALF 404 00:13:25,490 --> 00:13:26,791 FRUCTOSE, HALF GLUCOSE, AND THE 405 00:13:26,791 --> 00:13:29,261 BLUE ARE 75% FRUCTOSE. 406 00:13:29,261 --> 00:13:31,162 AND THESE ARE THE GLUCOSE 407 00:13:31,162 --> 00:13:31,863 CONCENTRATIONS. 408 00:13:31,863 --> 00:13:33,598 WE GAVE THESE CARBOHYDRATE 409 00:13:33,598 --> 00:13:35,233 BOLUSES AT BREAKFAST AND THEN WE 410 00:13:35,233 --> 00:13:36,968 FED THE STANDARDIZED LUNCH EVERY 411 00:13:36,968 --> 00:13:38,803 TIME THEY CAME BACK, THEY GOT 412 00:13:38,803 --> 00:13:41,006 EXACTLY THE SAME LUNCH. 413 00:13:41,006 --> 00:13:42,774 THERE ARE THE INSULIN RESPONSES 414 00:13:42,774 --> 00:13:44,509 AND OF COURSE INSULIN IS HIGHEST 415 00:13:44,509 --> 00:13:46,678 WHEN JUST GLUCOSE WAS FED. 416 00:13:46,678 --> 00:13:49,414 AND THEN HERE ARE THE LIPOGENIC 417 00:13:49,414 --> 00:13:51,950 DATA, AND THE GLUCOSE IN AN ORAL 418 00:13:51,950 --> 00:13:53,151 GLUCOSE TOLERANCE TEST, THE 419 00:13:53,151 --> 00:13:54,786 BLACK CIRCLES ON THE BOTTOM 420 00:13:54,786 --> 00:13:55,987 HARDLY STIMULATED THIS PATHWAY 421 00:13:55,987 --> 00:13:56,888 AT ALL. 422 00:13:56,888 --> 00:13:59,758 BUT YOU CAN START TO APPRECIATE 423 00:13:59,758 --> 00:14:00,792 THE LIPOGENIC POTENTIAL OF 424 00:14:00,792 --> 00:14:06,598 FRUCTOSE. 425 00:14:06,598 --> 00:14:07,799 HERE ARE SOME OTHER DATA WHERE 426 00:14:07,799 --> 00:14:09,234 WE FED TWO MEALS, IDENTICAL 427 00:14:09,234 --> 00:14:10,869 MEALS AT 7:00 IN THE MORNING AND 428 00:14:10,869 --> 00:14:13,171 THEN AGAIN AROUND NOONTIME. 429 00:14:13,171 --> 00:14:15,574 YOU'RE GOING TO SEE IN THESE 430 00:14:15,574 --> 00:14:16,241 INDIVIDUALS LIPOGENESIS BEING 431 00:14:16,241 --> 00:14:18,944 VERY LOW AT MIDNIGHT IN SOME OF 432 00:14:18,944 --> 00:14:20,078 THEM, ALMOST NOTHING UP IN 433 00:14:20,078 --> 00:14:21,379 SUBJECT NUMBER TWO UP THERE, 434 00:14:21,379 --> 00:14:22,781 ALMOST NOT MEASURABLE. 435 00:14:22,781 --> 00:14:25,617 YOU'LL ALSO SEE THE PATTERN RISE 436 00:14:25,617 --> 00:14:27,519 AND IS HIGHER IN MANY 437 00:14:27,519 --> 00:14:28,587 INDIVIDUALS, IT'S HIGHER AFTER 438 00:14:28,587 --> 00:14:31,222 THE SECOND MEAL OF THE DAY, 439 00:14:31,222 --> 00:14:32,190 HIGHER AGAIN AFTER DINNER AND 440 00:14:32,190 --> 00:14:35,260 THEN PEAKING AT NIGHTTIME. 441 00:14:35,260 --> 00:14:37,429 SO HERE ARE THE INSULIN VALUES. 442 00:14:37,429 --> 00:14:39,631 ACROSS THE BOARD, INSULIN IS 443 00:14:39,631 --> 00:14:41,800 HIGHER IN INDIVIDUALS THAT HAVE 444 00:14:41,800 --> 00:14:46,972 JAI AHIGH LIPOGENIC RATES BUT IT 445 00:14:46,972 --> 00:14:48,607 REALLY ISN'T A VERY GOOD 446 00:14:48,607 --> 00:14:49,040 PREDICTOR. 447 00:14:49,040 --> 00:14:51,076 SO LET'S LOOK AT THIS PATHWAY 448 00:14:51,076 --> 00:14:52,877 WHEN IT'S IN THE SETTING OF 449 00:14:52,877 --> 00:14:55,180 OVEREATING. 450 00:14:55,180 --> 00:14:57,248 THIS STUDY IS CALLED THE 451 00:14:57,248 --> 00:14:58,450 TAILGATE STUDY, AS YOU WILL SEE 452 00:14:58,450 --> 00:15:02,487 WHY IN A MINUTE. 453 00:15:02,487 --> 00:15:04,356 WE RECRUITED 18 OVERWEIGHT 454 00:15:04,356 --> 00:15:06,091 SUBJECTS, BMI OF 32, AND THEY 455 00:15:06,091 --> 00:15:07,425 WERE STUDIED ONLY ON ONE 456 00:15:07,425 --> 00:15:07,892 OCCASION. 457 00:15:07,892 --> 00:15:10,695 THIS IS NOT A WELL CONTROLLED 458 00:15:10,695 --> 00:15:14,766 BLINDED STUDY, AS YOU CAN 459 00:15:14,766 --> 00:15:15,500 IMAGINE. 460 00:15:15,500 --> 00:15:16,701 THEY CAME INTO THE CLINICAL 461 00:15:16,701 --> 00:15:19,337 RESEARCH CENTER, THEY HAD AN 462 00:15:19,337 --> 00:15:20,639 MRIMRS TO MEASURE LIVER FAT. 463 00:15:20,639 --> 00:15:23,608 WE PLACED AN I.V. LINE, AND THEN 464 00:15:23,608 --> 00:15:25,210 THE TREATMENT OCCURRED, AND THAT 465 00:15:25,210 --> 00:15:26,277 WAS A TAILGATE WITH ALCOHOL. 466 00:15:26,277 --> 00:15:28,546 AT THE END OF THE DAY, WE PUT 467 00:15:28,546 --> 00:15:29,981 THEM BACK IN THE SCANNER AND 468 00:15:29,981 --> 00:15:32,450 THEN BECAUSE THEY HAD ALCOHOL IN 469 00:15:32,450 --> 00:15:33,818 THEM, THEY SLEPT OVERNIGHT AT 470 00:15:33,818 --> 00:15:35,320 THE CLINICAL RESEARCH CENTER AND 471 00:15:35,320 --> 00:15:36,388 WE DREW BLOOD THE NEXT MORNING 472 00:15:36,388 --> 00:15:38,923 TO SHOW THAT THEY WERE NO LONGER 473 00:15:38,923 --> 00:15:39,257 DRUNK. 474 00:15:39,257 --> 00:15:42,193 THIS IS WHAT WE FED THEM. 475 00:15:42,193 --> 00:15:43,395 THEY WERE ENCOURAGED TO EAT, 476 00:15:43,395 --> 00:15:45,163 THEY WERE WATCHING SPORTS ON TV, 477 00:15:45,163 --> 00:15:48,433 THEY WERE -- WE DID THIS IN 478 00:15:48,433 --> 00:15:50,335 PAIRS, AND WE REFRESHED THE 479 00:15:50,335 --> 00:15:53,371 BUFFET TO MAKE IT ENTICING. 480 00:15:53,371 --> 00:15:55,006 THREE DAYS BEFORE WE STUDIED THE 481 00:15:55,006 --> 00:15:56,307 SUBJECT, THEY CONSUMED HEAVY 482 00:15:56,307 --> 00:16:00,779 WATER TO MEASURE LIPOGENESIS, SO 483 00:16:00,779 --> 00:16:03,748 THIS IS A DEUTERIUM LABELED 484 00:16:03,748 --> 00:16:05,183 WATER, PEOPLE DRINK IT, IT'S 485 00:16:05,183 --> 00:16:06,384 RELATIVELY EASY TO USE, AND WHEN 486 00:16:06,384 --> 00:16:08,219 FATTY ACIDS ARE BEING MADE FROM 487 00:16:08,219 --> 00:16:09,854 SUGARS, THE PATHWAY GETS LABELED 488 00:16:09,854 --> 00:16:12,490 WITH WATER. 489 00:16:12,490 --> 00:16:16,428 SO HERE IS THE SUBJECT 490 00:16:16,428 --> 00:16:18,496 SUBJECTIVE INTOXICATION DATA, 491 00:16:18,496 --> 00:16:20,699 WITH ZERO BEING NOT DRUNK AT ALL 492 00:16:20,699 --> 00:16:21,900 AND 10 BEING MORE DRUNK THAN 493 00:16:21,900 --> 00:16:22,867 I'VE EVER BEEN IN MY LIFE. 494 00:16:22,867 --> 00:16:24,069 AND YOU CAN SEE THESE PEOPLE 495 00:16:24,069 --> 00:16:25,336 WERE HAPPY, THIS WAS NOT A 496 00:16:25,336 --> 00:16:26,071 SLOPPY STUDY. 497 00:16:26,071 --> 00:16:29,441 THESE WERE PEOPLE WHO DRANK 498 00:16:29,441 --> 00:16:31,309 ALCOHOL HABITUALLY. 499 00:16:31,309 --> 00:16:33,044 HERE'S THE BREATH ALCOHOL. 500 00:16:33,044 --> 00:16:35,013 OUR GOAL WAS TO KEEP THEM RIGHT 501 00:16:35,013 --> 00:16:37,415 AT THE LEGAL LIMIT IN MISSOURI 502 00:16:37,415 --> 00:16:39,084 ALL AFTERNOON, AND WE DID 503 00:16:39,084 --> 00:16:40,785 ACHIEVE THAT. 504 00:16:40,785 --> 00:16:42,353 IF THEIR BLOOD ALCOHOL ROSE A 505 00:16:42,353 --> 00:16:43,655 LITTLE TOO HIGH, WE SAID WHY 506 00:16:43,655 --> 00:16:44,923 DON'T YOU WAIT A LITTLE BIT, IF 507 00:16:44,923 --> 00:16:46,624 IT WAS TOO LOW, WE ASKED THEM, 508 00:16:46,624 --> 00:16:48,359 WOULD YOU HAVE ANOTHER DRINK. 509 00:16:48,359 --> 00:16:49,661 THEY WEREN'T REQUIRED TO DRINK, 510 00:16:49,661 --> 00:16:51,629 BUT OUR GOAL WAS TO KEEP THEM IN 511 00:16:51,629 --> 00:16:54,399 THAT TARGET RANGE IF POSSIBLE. 512 00:16:54,399 --> 00:16:55,800 AND THEN I'LL REMIND YOU THEY 513 00:16:55,800 --> 00:16:58,403 HAD THE LIVER MRI BEFORE AND 514 00:16:58,403 --> 00:16:59,537 AFTER, AND WHEN I FIRST SAW 515 00:16:59,537 --> 00:17:00,739 THESE DATA FROM THE GRAD 516 00:17:00,739 --> 00:17:02,607 STUDENT, I WAS DUMBFOUNDED. 517 00:17:02,607 --> 00:17:05,744 I THOUGHT FOR SURE WE WOULD 518 00:17:05,744 --> 00:17:06,845 INCREASE LIVER FAT WITH ALL OF 519 00:17:06,845 --> 00:17:09,280 THAT FOOD AND ALCOHOL. 520 00:17:09,280 --> 00:17:11,116 SO I ASKED HIM TO GO BACK AND 521 00:17:11,116 --> 00:17:12,217 LOOK AT THE INDIVIDUAL DATA, AND 522 00:17:12,217 --> 00:17:15,186 THIS IS A SMALL STUDY, BUT HE 523 00:17:15,186 --> 00:17:16,354 SIMPLY CRUDELY PLOTTED ALL THE 524 00:17:16,354 --> 00:17:18,656 RESULTS ON A GRAPH, AND THE 525 00:17:18,656 --> 00:17:20,291 INDIVIDUALS ON THE LEFT HAD AN 526 00:17:20,291 --> 00:17:22,160 INCREASE IN LIVER FAT AND THOSE 527 00:17:22,160 --> 00:17:24,996 ON THE RIGHT HAD A REDUCTION IN 528 00:17:24,996 --> 00:17:26,097 LIVER FAT. 529 00:17:26,097 --> 00:17:27,632 SO I SAID WELL, WHAT DID THEY 530 00:17:27,632 --> 00:17:28,333 EAT? 531 00:17:28,333 --> 00:17:30,268 WELL, THEY ATE CLOSE TO 532 00:17:30,268 --> 00:17:31,336 5,000-CALORIES ALL AFTERNOON, 533 00:17:31,336 --> 00:17:33,338 AND THIS INCLUDES THE ALCOHOL. 534 00:17:33,338 --> 00:17:37,809 SO WE DIVIDED THIS INTO THE 535 00:17:37,809 --> 00:17:38,943 INDIVIDUALS WHO GAINED LIVER FAT 536 00:17:38,943 --> 00:17:40,211 ON THE LEFT THERE, AND YOU CAN 537 00:17:40,211 --> 00:17:41,513 SEE THEIR ALCOHOL INTAKE WAS 538 00:17:41,513 --> 00:17:42,514 ACTUALLY LESS THAN THE 539 00:17:42,514 --> 00:17:44,249 INDIVIDUALS WHO LOST LIVER FAT, 540 00:17:44,249 --> 00:17:48,653 AND THEY CONSUMED MORE 541 00:17:48,653 --> 00:17:50,455 CARBOHYDRATE ADD LIBITUM. 542 00:17:50,455 --> 00:17:52,457 THIS IS DE NOVO LIPOGENESIS 543 00:17:52,457 --> 00:17:53,992 MEASURED WITH LABELED WATER FROM 544 00:17:53,992 --> 00:17:57,695 NOON TO 5:00 P.M., AND WITHIN 545 00:17:57,695 --> 00:17:58,596 THE TRIGLYCERIDE IN THE BLOOD, 546 00:17:58,596 --> 00:17:59,597 YOU CAN SEE THE SIGNAL COMING 547 00:17:59,597 --> 00:18:00,932 OUT OF THE LIVER, AND THOSE 548 00:18:00,932 --> 00:18:02,634 INDIVIDUALS WHO INCREASED LIVER 549 00:18:02,634 --> 00:18:05,069 FAT DURING OVEREATING TURNED ON 550 00:18:05,069 --> 00:18:07,138 THIS PATHWAY FROM THE SUGARS AND 551 00:18:07,138 --> 00:18:09,641 THE ALCOHOL THEY CONSUMED. 552 00:18:09,641 --> 00:18:13,444 AND THE CHANGE IN LIVER FAT 553 00:18:13,444 --> 00:18:16,247 SYNTHESIS, AS MEASURED BY DE 554 00:18:16,247 --> 00:18:17,182 NOVO LIPOGENESIS, CORRELATED 555 00:18:17,182 --> 00:18:18,716 WITH THE PERCENT CHANGE WITH 556 00:18:18,716 --> 00:18:18,883 MRI. 557 00:18:18,883 --> 00:18:20,251 SO I THINK IT'S REAL. 558 00:18:20,251 --> 00:18:22,187 YOU SEE VARIABILITY THERE. 559 00:18:22,187 --> 00:18:23,521 BUT THOSE INDIVIDUALS THAT 560 00:18:23,521 --> 00:18:25,723 TURNED ON DE NOVO LIPOGENESIS 561 00:18:25,723 --> 00:18:27,025 WHILE OVEREATING WERE THE SAME 562 00:18:27,025 --> 00:18:28,126 INDIVIDUALS THAT GAINED LIVER 563 00:18:28,126 --> 00:18:32,497 FAT. 564 00:18:32,497 --> 00:18:34,132 SO I SHOW THIS DATA BECAUSE THIS 565 00:18:34,132 --> 00:18:35,433 REALLY GOT ME THINKING, I 566 00:18:35,433 --> 00:18:37,302 THOUGHT I KNEW WHAT WAS GOING TO 567 00:18:37,302 --> 00:18:37,635 HAPPEN. 568 00:18:37,635 --> 00:18:38,736 I'VE THOUGHT FOR SURE I WOULD 569 00:18:38,736 --> 00:18:40,905 HAVE GONE TO VEGAS ON THIS, AND 570 00:18:40,905 --> 00:18:41,806 I WAS WRONG. 571 00:18:41,806 --> 00:18:45,076 YOU CAN'T REALLY KNOW SOMEONE'S 572 00:18:45,076 --> 00:18:46,377 SENSITIVITY TO EXCESS FOOD 573 00:18:46,377 --> 00:18:47,812 INTAKE UNTIL YOU DO THE 574 00:18:47,812 --> 00:18:51,616 MEASUREMENTS. 575 00:18:51,616 --> 00:18:53,051 ALL RIGHT. 576 00:18:53,051 --> 00:18:55,019 SO DE NOVO LIPOGENESIS 577 00:18:55,019 --> 00:18:58,089 CONTRIBUTES TO 578 00:18:58,089 --> 00:18:59,624 METABOLIC-ASSOCIATED 579 00:18:59,624 --> 00:19:00,925 STIATOHEPATITIS, SO I WANTED TO 580 00:19:00,925 --> 00:19:02,894 KNOW IF REDUCING IT WAS 581 00:19:02,894 --> 00:19:06,865 SUFFICIENT TO LEAD TO HASH 582 00:19:06,865 --> 00:19:07,198 REGRESSION. 583 00:19:07,198 --> 00:19:11,436 SO THIS CONCEPT, I BRING THIS UP 584 00:19:11,436 --> 00:19:13,504 NOW, I'M NOT GOING TO SHOW YOU 585 00:19:13,504 --> 00:19:15,139 THE REDUCTION DATA YET BUT THIS 586 00:19:15,139 --> 00:19:16,608 IS AN ACTIVE FIELD OF RESEARCH 587 00:19:16,608 --> 00:19:18,009 AND THE REASON IS, BECAUSE FOR 588 00:19:18,009 --> 00:19:19,210 THE MAJORITY OF MY CAREER, 589 00:19:19,210 --> 00:19:21,512 PEOPLE TOLD ME THAT DE NOVO 590 00:19:21,512 --> 00:19:23,248 LIPOGENESIS IS JUST MAKING FAT, 591 00:19:23,248 --> 00:19:27,418 AND THAT IS INERT. 592 00:19:27,418 --> 00:19:31,990 IN THE HEPATOLOGY FIELD, IT'S 593 00:19:31,990 --> 00:19:34,292 CALLED SIMPLE STIATOSIS. 594 00:19:34,292 --> 00:19:35,693 I DON'T THINK IT'S SIMPLE AT 595 00:19:35,693 --> 00:19:35,927 ALL. 596 00:19:35,927 --> 00:19:37,362 I THINK EXCESS FAT IN THE LIVER 597 00:19:37,362 --> 00:19:39,097 IS A BIG FLAG TO THE BODY, 598 00:19:39,097 --> 00:19:40,531 OVERFED, TOO MANY CALORIES, 599 00:19:40,531 --> 00:19:42,166 STRUGGLING WITH ENERGY BALANCE. 600 00:19:42,166 --> 00:19:44,235 AND THAT THOSE FATTY ASITS CAN 601 00:19:44,235 --> 00:19:49,507 BE TOXIC IN THEMSELVES. 602 00:19:49,507 --> 00:19:50,808 WHY DO I THINK THAT THIS IS MORE 603 00:19:50,808 --> 00:19:52,777 THAN JUST FAT SYNTHESIS? 604 00:19:52,777 --> 00:19:54,512 IT'S BECAUSE NEWLY MADE FATTY 605 00:19:54,512 --> 00:19:55,847 ACIDS IN THE LIVER ARE HANDLED 606 00:19:55,847 --> 00:19:57,048 DIFFERENTLY THAN FATTY ACIDS 607 00:19:57,048 --> 00:19:58,283 THAT COME IN FROM OUTSIDE THE 608 00:19:58,283 --> 00:19:58,816 LIVER. 609 00:19:58,816 --> 00:20:00,985 WE KNOW THEY'RE PROCESSED 610 00:20:00,985 --> 00:20:02,420 DIFFERENTLY IN DROPLETS, THEY'RE 611 00:20:02,420 --> 00:20:03,621 USED DIFFERENTLY FOR FAT 612 00:20:03,621 --> 00:20:05,490 OXIDATION. 613 00:20:05,490 --> 00:20:09,627 INCREASED TE DE NOVO LIPOGENESIS 614 00:20:09,627 --> 00:20:11,496 ADDS FATTY ACIDS TO THE 615 00:20:11,496 --> 00:20:14,866 LIPOPARTICLE THAT'S LEAVING. 616 00:20:14,866 --> 00:20:16,501 FRUCTOSE AND -- THEY MAKE THE 617 00:20:16,501 --> 00:20:18,469 PARTICLE BIGGER AND INCREASE 618 00:20:18,469 --> 00:20:20,138 TRIGLYCERIDES IN THE BLOOD. 619 00:20:20,138 --> 00:20:22,440 WHEREAS RESTRICTING DE NOVO 620 00:20:22,440 --> 00:20:23,741 LIPOGENESIS, RESTRICTING SUGARS 621 00:20:23,741 --> 00:20:26,577 REDUCES THE PARTICLE SIZE. 622 00:20:26,577 --> 00:20:28,980 SO DNL ALSO CONTRIBUTES TO 623 00:20:28,980 --> 00:20:29,981 HYPERLIPIDEMIA. 624 00:20:29,981 --> 00:20:31,282 REDUCING FREE FATTY ACID FLUX 625 00:20:31,282 --> 00:20:33,685 FROM THE ADIPOSE TISSUE, WITH 626 00:20:33,685 --> 00:20:35,420 THINGS LIKE INSULIN OR NIACIN, 627 00:20:35,420 --> 00:20:37,422 REDUCES THE PARTICLE NUMBER. 628 00:20:37,422 --> 00:20:40,091 SO FREE FATTY ACIDS COME INTO 629 00:20:40,091 --> 00:20:42,026 THE LIVER AND THEY ARE PROCESSED 630 00:20:42,026 --> 00:20:43,094 DIFFERENTLY THAN THE ONES THAT 631 00:20:43,094 --> 00:20:46,898 ARE MADE LOCALLY. 632 00:20:46,898 --> 00:20:51,936 DE NOVO LIPOGENESIS CONTRIBUTES 633 00:20:51,936 --> 00:20:54,005 PULMITATE, A SATURATED FATTY 634 00:20:54,005 --> 00:20:56,607 ACID, AND SATURATED FATTY ACIDS 635 00:20:56,607 --> 00:20:58,676 IN CELL CULTURE INCREASE 636 00:20:58,676 --> 00:21:00,912 HEPATOCYTE OXIDATIVE STRESS, ER 637 00:21:00,912 --> 00:21:04,082 STRESS, INFLAMMATION, AND 638 00:21:04,082 --> 00:21:05,917 APOPTOSIS. 639 00:21:05,917 --> 00:21:07,352 SUCROSE-DRIVEN DE NOVO 640 00:21:07,352 --> 00:21:08,753 LIPOGENESIS EXACERBATES THE 641 00:21:08,753 --> 00:21:11,055 HEPATIC TOXICITY OF DIETARY 642 00:21:11,055 --> 00:21:12,256 SATURATED FAT. 643 00:21:12,256 --> 00:21:14,125 SO WHEN YOU TURN THIS 644 00:21:14,125 --> 00:21:18,062 BIOCHEMICAL PATHWAY ON, IT IS 645 00:21:18,062 --> 00:21:19,263 GOVERNING THE FATES OF FATTY 646 00:21:19,263 --> 00:21:23,334 ACIDS FROM OTHER SOURCES. 647 00:21:23,334 --> 00:21:24,502 IF I GET UP IN THE MORNING AND 648 00:21:24,502 --> 00:21:28,339 I'M FASTING AND I EAT A PAT OF 649 00:21:28,339 --> 00:21:31,976 BUTTER, I WILL BURN THAT BUTTER. 650 00:21:31,976 --> 00:21:34,946 IF I EAT A PAT OF BUTTER AND EAT 651 00:21:34,946 --> 00:21:35,813 A GENTLEMANLY BEAN WITH IT, I 652 00:21:35,813 --> 00:21:36,681 WILL NOT BURN THE BUTTER. 653 00:21:36,681 --> 00:21:38,683 WHEN YOU TURN ON FATTY ACID 654 00:21:38,683 --> 00:21:40,318 SYNTHESIS, YOU ROUTE OTHER FATTY 655 00:21:40,318 --> 00:21:44,489 ACIDS TO STORAGE AND AWAY FROM 656 00:21:44,489 --> 00:21:44,889 OXIDATION. 657 00:21:44,889 --> 00:21:46,324 THIS HAS BEEN SHOWN IN NUMEROUS 658 00:21:46,324 --> 00:21:51,129 RODENT MODELS AND IN HUMANS. 659 00:21:51,129 --> 00:21:52,363 SO THE QUESTION IS WHAT ELSE IS 660 00:21:52,363 --> 00:21:53,498 CONNECTED TO THIS PATHWAY, AND 661 00:21:53,498 --> 00:22:03,908 WE KNOW THAT MURI IS 662 00:22:07,278 --> 00:22:08,446 THEY'RE ALSO USED TO TARGET 663 00:22:08,446 --> 00:22:09,647 PROTEINS TO VARIOUS LOCATIONS IN 664 00:22:09,647 --> 00:22:10,882 THE CELL AND I HAVE A QUESTION 665 00:22:10,882 --> 00:22:12,884 AS TO WHETHER FATTY ACID 666 00:22:12,884 --> 00:22:14,118 SYNTHESIS, WHEN IT'S TURNED ON, 667 00:22:14,118 --> 00:22:16,621 IS CONTRIBUTING TO CELLULAR 668 00:22:16,621 --> 00:22:21,659 SIGNALING IN THAT MANNER CH SO 669 00:22:21,659 --> 00:22:23,694 IF DE NOVO LIPOGENESIS IS HIGH, 670 00:22:23,694 --> 00:22:25,797 AND THIS IS AN OLD TERM, IN 671 00:22:25,797 --> 00:22:26,798 NON-ALCOHOLIC FATTY LIVER 672 00:22:26,798 --> 00:22:28,900 DISEASE, DOES IT CONTRIBUTE TO 673 00:22:28,900 --> 00:22:30,301 GRADED INCREASES ACROSS THE 674 00:22:30,301 --> 00:22:33,071 SPECTRUM OF DISEASE? 675 00:22:33,071 --> 00:22:34,372 DOES IT ONLY CONTRIBUTE FAT AND 676 00:22:34,372 --> 00:22:37,975 STOPS THERE? 677 00:22:37,975 --> 00:22:39,310 OR DOES IT CONTRIBUTE AS PEOPLE 678 00:22:39,310 --> 00:22:42,146 GET SICKER? 679 00:22:42,146 --> 00:22:46,217 SO MAJID SYED PROPOSED STUDYING 680 00:22:46,217 --> 00:22:48,052 49 PATIENTS HEADED FOR BARIATRIC 681 00:22:48,052 --> 00:22:48,786 SURGERY. 682 00:22:48,786 --> 00:22:50,354 HE GAVE THEM LABELED WATER 683 00:22:50,354 --> 00:22:51,322 BEFORE THE SURGERY AND THEN 684 00:22:51,322 --> 00:22:52,123 WAITED FOR THE SURGEON TO BE 685 00:22:52,123 --> 00:22:54,292 ABLE TO SAMPLE A LITTLE WEDGE 686 00:22:54,292 --> 00:22:57,328 PIECE OF THE LIVER, WHICH WAS 687 00:22:57,328 --> 00:22:58,563 COMMON AT OUR INSTITUTION, TO 688 00:22:58,563 --> 00:23:00,298 MAKE SURE THAT INDIVIDUALS WITH 689 00:23:00,298 --> 00:23:02,033 OBESITY GOING TO BARIATRIC 690 00:23:02,033 --> 00:23:03,468 SURGERY TO DOCUMENT WHAT THEIR 691 00:23:03,468 --> 00:23:07,605 LIVER CONDITIONS WERE. 692 00:23:07,605 --> 00:23:09,574 AND THEN HE TOOK THAT SAMPLE AND 693 00:23:09,574 --> 00:23:11,142 WENT BACK TO THE LAB AND 694 00:23:11,142 --> 00:23:12,343 ANALYZED IT. 695 00:23:12,343 --> 00:23:13,845 HE LOOKED AT THE HISTOLOGY AND 696 00:23:13,845 --> 00:23:14,712 DIVIDED THESE PATIENTS BETWEEN 697 00:23:14,712 --> 00:23:17,815 HAVING NO DISEASE AT ALL, 698 00:23:17,815 --> 00:23:22,386 NON-ALCOHOLIC FATTY LIVER, PORE, 699 00:23:22,386 --> 00:23:29,827 BORDERLINE STEATOHEPATITIS AND 700 00:23:29,827 --> 00:23:32,563 AUTISM OUT STEATOHEPATITIS AND 701 00:23:32,563 --> 00:23:33,664 ANALYZED THE SAMPLES. 702 00:23:33,664 --> 00:23:37,034 SO I'LL SHOW YOU SOME PROOF OF 703 00:23:37,034 --> 00:23:39,137 CONCEPT HERE. 704 00:23:39,137 --> 00:23:40,638 AS ONE LIPID GOES UP, THE OTHER 705 00:23:40,638 --> 00:23:41,272 DOES. 706 00:23:41,272 --> 00:23:44,475 AND THEY'RE BOTH HIGHER IN THE 707 00:23:44,475 --> 00:23:45,576 WORST LIVER CASES. 708 00:23:45,576 --> 00:23:48,079 THIS IS LIVER DE NOVO 709 00:23:48,079 --> 00:23:51,249 LIPOGENESIS AND TRIGLYCERIDE DE 710 00:23:51,249 --> 00:23:51,949 NOVO LIPOJEP CYST. 711 00:23:51,949 --> 00:23:53,684 SO THESE NEW FATTY ACIDS REALLY 712 00:23:53,684 --> 00:23:56,287 DO NOT GO EVERYWHERE. 713 00:23:56,287 --> 00:23:57,822 THEY'RE SELECTIVELY PUT IN 714 00:23:57,822 --> 00:24:00,224 TRIGLYCERIDE. 715 00:24:00,224 --> 00:24:03,895 THIS IS THE FATTY ACID SYNTHASE 716 00:24:03,895 --> 00:24:05,062 PROTEIN THAT'S SUPPOSED TO BE 717 00:24:05,062 --> 00:24:06,531 CARRYING OUT THIS REACTION AND 718 00:24:06,531 --> 00:24:07,665 IT CORRELATES VERY, VERY WELL 719 00:24:07,665 --> 00:24:09,200 WITH THE ACTIVITY THAT'S GOING 720 00:24:09,200 --> 00:24:12,703 ON AS MEASURED BY LABEL. 721 00:24:12,703 --> 00:24:14,572 AND THEN LASTLY THE FRACTIONAL 722 00:24:14,572 --> 00:24:16,107 LIPOGENESIS IN THE LIVER 723 00:24:16,107 --> 00:24:17,608 CORRELATES VERY, VERY NICELY 724 00:24:17,608 --> 00:24:20,244 WITH WHAT'S OUT IN THE BLOOD IN 725 00:24:20,244 --> 00:24:20,678 VLDL. 726 00:24:20,678 --> 00:24:22,113 SO THESE DATA SHOW THAT I DON'T 727 00:24:22,113 --> 00:24:23,848 HAVE TO DO A LIVER BIOPSY TO 728 00:24:23,848 --> 00:24:24,949 FIGURE OUT WHAT'S GOING ON IN 729 00:24:24,949 --> 00:24:25,383 THAT ORGAN. 730 00:24:25,383 --> 00:24:27,151 I CAN LOOK AT THE LIPIDS THAT 731 00:24:27,151 --> 00:24:29,754 ARE BEING SECRETED AND 732 00:24:29,754 --> 00:24:32,924 UNDERSTAND THE CONTROL OF THIS 733 00:24:32,924 --> 00:24:36,093 PATHWAY. 734 00:24:36,093 --> 00:24:37,228 SO IF YOU LOOK AT THEIR LEVELS 735 00:24:37,228 --> 00:24:40,031 OF DISEASE, DE NOVO LIPOGENESIS 736 00:24:40,031 --> 00:24:43,000 INCREASES ACROSS ALL OF THEM. 737 00:24:43,000 --> 00:24:44,535 IT IS NOT DIFFERENT BETWEEN THE 738 00:24:44,535 --> 00:24:46,504 BORDERLINE NASH AND THE NASH, 739 00:24:46,504 --> 00:24:48,206 BUT IT'S DEFINITELY ELEVATED IN 740 00:24:48,206 --> 00:24:50,775 INDIVIDUALS WITH HEPATOCELLULAR 741 00:24:50,775 --> 00:24:54,612 BALLOONING AND INFLAMMATION. 742 00:24:54,612 --> 00:24:56,013 SO I ASKED LET'S LOOK AT IT A 743 00:24:56,013 --> 00:24:56,681 DIFFERENT WAY. 744 00:24:56,681 --> 00:24:58,416 SOME PEOPLE THINK OF THIS 745 00:24:58,416 --> 00:25:01,586 DISEASE AS FIRST STEATOSIS, THEN 746 00:25:01,586 --> 00:25:02,687 INFLAMMATION, AND YOU KEEP 747 00:25:02,687 --> 00:25:08,326 ADDING RISK TO GET TO CIRRHOSIS. 748 00:25:08,326 --> 00:25:11,495 SO HE DIVIDED INTO THOSE WITH A 749 00:25:11,495 --> 00:25:14,532 HEALTHY LIVER, THOSE WITH 750 00:25:14,532 --> 00:25:16,801 STEATOSIS, HE ADDED BALLOONING 751 00:25:16,801 --> 00:25:17,368 AND FIBROSIS AS WELL. 752 00:25:17,368 --> 00:25:19,370 WHAT YOU SEE IS THE PATHWAY IS 753 00:25:19,370 --> 00:25:20,671 INCREASED IN EVERY SUBJECT WHO'S 754 00:25:20,671 --> 00:25:22,540 SICKER AND GOT WORSE LIVER 755 00:25:22,540 --> 00:25:24,075 DISEASE UNTIL YOU GET TO THE 756 00:25:24,075 --> 00:25:26,377 END, AND WE REALLY BELIEVE THAT 757 00:25:26,377 --> 00:25:29,513 THOSE INDIVIDUALS WITH GU FIBRO, 758 00:25:29,513 --> 00:25:30,348 GENERALLY GLOBALLY THEIR LIVER 759 00:25:30,348 --> 00:25:34,151 IS FAILING. 760 00:25:34,151 --> 00:25:35,886 PROTEIN SYNTHESIS IS PROBABLY 761 00:25:35,886 --> 00:25:36,854 AFFECTED, LIPID SYNTHESIS IS 762 00:25:36,854 --> 00:25:43,728 AFFECTED. 763 00:25:43,728 --> 00:25:45,162 SO THAT'S MAKING FAT IN THE 764 00:25:45,162 --> 00:25:45,363 LIVER. 765 00:25:45,363 --> 00:25:46,664 I WANT TO SHOW YOU HOW WE CAN 766 00:25:46,664 --> 00:25:49,200 LACK AT OTHER FATTY ACIDS COMING 767 00:25:49,200 --> 00:25:50,301 INTO THE LIVER GET STORED THERE. 768 00:25:50,301 --> 00:25:52,370 THIS IS CALLED THE INEFA MODEL. 769 00:25:52,370 --> 00:25:54,071 SO NOW WE'RE TALKING ABOUT THE 770 00:25:54,071 --> 00:25:57,942 RIGHT-HAND SIDE, THE LOWER RIGHT 771 00:25:57,942 --> 00:25:58,743 HERE. 772 00:25:58,743 --> 00:26:00,344 WHEN ONE EATS A MEAL, INSULIN 773 00:26:00,344 --> 00:26:03,981 SHOULD TURN OFF FREE FATTY ACID 774 00:26:03,981 --> 00:26:05,616 RELEASED FROM ADIPOSE TISSUE. 775 00:26:05,616 --> 00:26:06,917 IT DOESN'T COMPLETELY TURN IT 776 00:26:06,917 --> 00:26:07,251 OFF. 777 00:26:07,251 --> 00:26:10,321 SOME FATTY ACIDS STILL ARE 778 00:26:10,321 --> 00:26:12,723 COMING OUT OF LIPOLYSIS, AND 779 00:26:12,723 --> 00:26:16,827 ALSO AFTER A MEAL, DIETARY FAT 780 00:26:16,827 --> 00:26:19,397 IN THE CHYLOMICRON IS BEING 781 00:26:19,397 --> 00:26:20,665 BROKEN DOWN AND FATTY ACIDS ARE 782 00:26:20,665 --> 00:26:22,433 BEING TAKEN UP INTO THE ADIPOSE 783 00:26:22,433 --> 00:26:23,234 AND THE MUSCLE. 784 00:26:23,234 --> 00:26:24,735 SO I ASKED THE QUESTION, IF 785 00:26:24,735 --> 00:26:27,138 INSULIN INCREASES GLUCOSE UPTAKE 786 00:26:27,138 --> 00:26:30,041 INTO CELLS, DOES IT ALSO 787 00:26:30,041 --> 00:26:32,510 INCREASE FATTY ACID UPTAKE INTO 788 00:26:32,510 --> 00:26:33,177 CELLS? 789 00:26:33,177 --> 00:26:34,912 THE STORY WITH INSULIN AND 790 00:26:34,912 --> 00:26:38,983 ADIPOSE IS THAT RED CROSS THERE. 791 00:26:38,983 --> 00:26:40,851 IN MY FIELD, YOU LEARN INSULIN 792 00:26:40,851 --> 00:26:42,787 TURNS OFF ADIPOSE LIPOLYSIS, AND 793 00:26:42,787 --> 00:26:44,221 THERE HAS BEEN MUCH, MUCH LESS 794 00:26:44,221 --> 00:26:47,191 FOCUS ON WHAT ELSE IN INSULIN IS 795 00:26:47,191 --> 00:26:47,825 DOING TO LIPIDS. 796 00:26:47,825 --> 00:26:49,894 SO I WENT TO THE LITERATURE, AND 797 00:26:49,894 --> 00:26:51,329 THIS IS A FRACTIONAL CATABOLIC 798 00:26:51,329 --> 00:26:52,296 RATE ON THE Y AXIS. 799 00:26:52,296 --> 00:26:54,932 THIS IS THE SPEED AT WHICH FATTY 800 00:26:54,932 --> 00:26:56,667 ACIDS ARE LEAVING THE PLASMA, 801 00:26:56,667 --> 00:26:58,769 AND THESE DATA WEREN'T EXACTLY 802 00:26:58,769 --> 00:26:59,970 IN EVERY ONE OF THESE PAPERS, 803 00:26:59,970 --> 00:27:01,505 BUT YOU COULD CALCULATE THEM 804 00:27:01,505 --> 00:27:03,574 BASED ON THE DATA PRESENTED. 805 00:27:03,574 --> 00:27:05,209 AND WHEN YOU LOOK ACROSS WHAT'S 806 00:27:05,209 --> 00:27:07,011 IN THE LITERATURE, IT APPEARS 807 00:27:07,011 --> 00:27:09,246 THAT THE HIGHER LEVEL OF 808 00:27:09,246 --> 00:27:10,247 INSULIN, THE GREATER THE UPTAKE 809 00:27:10,247 --> 00:27:17,822 OF FATTY ACIDS INTO CELLS. 810 00:27:17,822 --> 00:27:20,958 SO WE BEGAN TO QUANTIFY INSULIN 811 00:27:20,958 --> 00:27:25,129 MEDIATED NEFA UPTAKE, AND WE DID 812 00:27:25,129 --> 00:27:27,131 TWO RESEARCH TESTS IN A SINGLE 813 00:27:27,131 --> 00:27:27,732 SUBJECT. 814 00:27:27,732 --> 00:27:30,568 THE FIRST WAS AN INTRAVENOUS 815 00:27:30,568 --> 00:27:31,335 GLUCOSE TOLERANCE TEST AND THEN 816 00:27:31,335 --> 00:27:33,003 WE DID A MEAL STUDY AND MEASURED 817 00:27:33,003 --> 00:27:34,739 THE FATTY ACID FLUX USING 818 00:27:34,739 --> 00:27:36,574 ISOTOPES. 819 00:27:36,574 --> 00:27:39,877 THE MEAL WAS LABELED WITH 13C 820 00:27:39,877 --> 00:27:42,813 HEAVY PALMITATE MIXED IN TO 821 00:27:42,813 --> 00:27:44,682 FETTUCINE SAUCE ON PASTA, AND 822 00:27:44,682 --> 00:27:46,083 THEN WE DREW BLOOD ALL NIGHT AND 823 00:27:46,083 --> 00:27:49,487 WE STARTED INFUSING A PALMITATE 824 00:27:49,487 --> 00:27:53,958 LABEL INTO THE BLOOD AT MIDNI 825 00:27:53,958 --> 00:27:55,693 MIDNIGHT. 826 00:27:55,693 --> 00:27:57,962 ALL THOSE TINY LITTLE BLOOD 827 00:27:57,962 --> 00:28:00,931 DRAWS, THIS IS STILL HALF OF AN 828 00:28:00,931 --> 00:28:04,635 AMERICAN RED CROSS BLOOD DRAW. 829 00:28:04,635 --> 00:28:06,637 AT LUNCH WE FED A SECOND MEAL, 830 00:28:06,637 --> 00:28:07,805 WHICH WAS EXACTLY THE SAME MEAL 831 00:28:07,805 --> 00:28:09,907 AS THE FIRST BUT WE PUT A 832 00:28:09,907 --> 00:28:11,742 DIFFERENT ISOTOPE IN SO WE COULD 833 00:28:11,742 --> 00:28:12,510 TRACK LUNCH AS WELL. 834 00:28:12,510 --> 00:28:16,914 SO THIS IS MY SIMPLE SCHEME THAT 835 00:28:16,914 --> 00:28:19,316 BOB FEHR, MY GOOD COLLEAGUE, AND 836 00:28:19,316 --> 00:28:20,117 I DEVELOPED. 837 00:28:20,117 --> 00:28:20,951 ON THE LEFT-HAND SIDE WE'RE JUST 838 00:28:20,951 --> 00:28:24,021 GOING TO CALL THIS SWIM LANE AN 839 00:28:24,021 --> 00:28:25,222 ADIPOSE TISSUE, BECAUSE THAT'S 840 00:28:25,222 --> 00:28:26,724 WHERE MOST OF THE FATTY ACIDS IN 841 00:28:26,724 --> 00:28:28,159 THE BLOOD PLASMA ARE COMING 842 00:28:28,159 --> 00:28:29,927 FROM, AND WE KNOW WELL THAT 843 00:28:29,927 --> 00:28:31,328 INSULIN TURNS OFF THE RELEASE OF 844 00:28:31,328 --> 00:28:33,197 ADIPOSE TISSUE. 845 00:28:33,197 --> 00:28:37,368 YOU'VE GOT VLDL TRIGLYCERIDE AND 846 00:28:37,368 --> 00:28:38,869 ALSO CHYLOMICRON TRIGLYCERIDES 847 00:28:38,869 --> 00:28:41,172 AND WE HYPOTHESIZED THAT INSULIN 848 00:28:41,172 --> 00:28:41,972 WOULD INCREASE THEIR BREAK DOWN 849 00:28:41,972 --> 00:28:43,674 AND SOME OF THOSE FATTY ACIDS 850 00:28:43,674 --> 00:28:44,775 WOULD BE RELEASED RIGHT THERE IN 851 00:28:44,775 --> 00:28:45,876 THE PLASMA AND STAY IN THE 852 00:28:45,876 --> 00:28:46,110 PLASMA. 853 00:28:46,110 --> 00:28:48,045 AND THEN THE LAST PART OF THIS 854 00:28:48,045 --> 00:28:50,481 MODEL IS THAT FATTY ACIDS WOULD 855 00:28:50,481 --> 00:28:52,016 BE TAKEN UP INTO TISSUES, 856 00:28:52,016 --> 00:28:55,820 MUSCLE, KIDNEY, WE CAN'T TELL 857 00:28:55,820 --> 00:28:56,821 WHAT, BUT THEY'RE LEAVING THE 858 00:28:56,821 --> 00:28:58,456 PLASMA AS A RESULT OF INSULIN. 859 00:28:58,456 --> 00:28:59,457 SO JUST BEAR WITH ME. 860 00:28:59,457 --> 00:29:00,958 THIS IS THE MATH THAT'S 861 00:29:00,958 --> 00:29:02,526 UNDERNEATH ALL OF THIS. 862 00:29:02,526 --> 00:29:07,097 IT ALL GOES INTO A LARGE MODEL 863 00:29:07,097 --> 00:29:08,399 TO LOOK AT THE CHANGE OF FREE 864 00:29:08,399 --> 00:29:10,601 FATTY ACID CONCENTRATION IN FLUX 865 00:29:10,601 --> 00:29:12,570 OVER TIME FROM THE FASTING TO 866 00:29:12,570 --> 00:29:13,671 THE FED STATE. 867 00:29:13,671 --> 00:29:15,639 THAT TOP RIGHT BOX UP THERE IS 868 00:29:15,639 --> 00:29:16,707 CALLED SPILLOVER. 869 00:29:16,707 --> 00:29:19,176 THIS IS WHEN DIETARY FATTY ACIDS 870 00:29:19,176 --> 00:29:21,412 THAT ARE IN CHYLOMICRONS END UP 871 00:29:21,412 --> 00:29:23,547 IN THE FREE FATTY ACID POOL. 872 00:29:23,547 --> 00:29:25,516 THEY SHOULD BE TAKEN UP AROUND 873 00:29:25,516 --> 00:29:27,685 THE BODY, BUT LIPOLYSIS CAN 874 00:29:27,685 --> 00:29:29,553 HAPPEN SO FAST IN THE PLASMA 875 00:29:29,553 --> 00:29:31,388 THAT THEY SPILL OVER INTO THE 876 00:29:31,388 --> 00:29:32,957 FREE FATTY ACID POOL. 877 00:29:32,957 --> 00:29:36,560 AND THE ONE ON THE BOTTOM IS 878 00:29:36,560 --> 00:29:38,195 INSULIN MEDIATED UPTAKE. 879 00:29:38,195 --> 00:29:41,031 ALL RIGHT. 880 00:29:41,031 --> 00:29:42,433 SO WE DEVELOPED FROM THIS MODEL 881 00:29:42,433 --> 00:29:44,101 SOMETHING CALLED A KI. 882 00:29:44,101 --> 00:29:45,636 THIS IS THE RATE IN WHICH 883 00:29:45,636 --> 00:29:47,838 INSULIN HALF MAXIMALLY 884 00:29:47,838 --> 00:29:48,806 SUPPRESSES ADIPOSE RELEASE BY 885 00:29:48,806 --> 00:29:51,208 TURNING OFF LIPOLYSIS ENZYMES. 886 00:29:51,208 --> 00:29:54,044 A HIGH NUMBER OR HIGH KI FOR A 887 00:29:54,044 --> 00:29:56,013 PATIENT DENOTES ADIPOSE INSULIN 888 00:29:56,013 --> 00:29:57,014 RESISTANCE. 889 00:29:57,014 --> 00:29:58,048 THAT MEANS THAT YOU HAVE TO PUT 890 00:29:58,048 --> 00:29:59,517 A LOT OF INSULIN INTO THAT 891 00:29:59,517 --> 00:30:01,585 PERSON TO GET THE ADIPOSE TISSUE 892 00:30:01,585 --> 00:30:04,889 TO SHUT UP, RATE, TO TURN OFF. 893 00:30:04,889 --> 00:30:05,756 RIGHT, TO TURN OFF. 894 00:30:05,756 --> 00:30:07,057 THAT'S A HIGH KI. 895 00:30:07,057 --> 00:30:09,026 A HIGH KM IS THE RATE CONSTANT 896 00:30:09,026 --> 00:30:11,762 FOR INSULIN MEDIATED FATTY ACID 897 00:30:11,762 --> 00:30:13,297 UPTAKE, AND THIS AMOUNT IS 898 00:30:13,297 --> 00:30:16,634 NEEDED TO HALF MAXIMALLY 899 00:30:16,634 --> 00:30:17,668 STIMULATE TISSUE UPTAKE. 900 00:30:17,668 --> 00:30:19,870 A HIGH NUMBER DENOTES SKELETAL 901 00:30:19,870 --> 00:30:22,973 MUSCLE INSULIN RESISTANCE. 902 00:30:22,973 --> 00:30:24,341 WE DIDN'T MEASURE PROTEINS AT 903 00:30:24,341 --> 00:30:26,343 THE MUSCLE, BUT THROUGH 904 00:30:26,343 --> 00:30:28,846 TRANSPORTERS LIKE CD36 AND FATTY 905 00:30:28,846 --> 00:30:30,581 ACID TRANSPORT PROTEIN. 906 00:30:30,581 --> 00:30:32,783 AND IN OUR MODEL, THESE TWO 907 00:30:32,783 --> 00:30:34,818 NUMBERS TURNED OUT TO BE ABOUT 908 00:30:34,818 --> 00:30:37,254 THE SAME, WHICH MEANS THAT 909 00:30:37,254 --> 00:30:39,223 INSULIN HAS JUST ABOUT AS MUCH 910 00:30:39,223 --> 00:30:41,325 EFFECT OF CAUSING FATTY ACIDS TO 911 00:30:41,325 --> 00:30:42,960 LEAVE THE BLOOD AND GO INTO 912 00:30:42,960 --> 00:30:46,597 MUSCLE AS IT DOES TO TURN OFF 913 00:30:46,597 --> 00:30:49,867 ADIPOSE RELEASE. 914 00:30:49,867 --> 00:30:53,370 SO A HIGH RATIO DENOTES PEOPLE 915 00:30:53,370 --> 00:30:57,841 MORE INSULIN AND A LOW RATIO 916 00:30:57,841 --> 00:30:59,843 DENOTES MORE INSULIN RESISTANT 917 00:30:59,843 --> 00:31:00,711 AT SKELETAL MUSCLE. 918 00:31:00,711 --> 00:31:01,879 THESE ARE SOME OF THE PATIENTS 919 00:31:01,879 --> 00:31:03,213 THAT WE CALCULATED AND WE LOOKED 920 00:31:03,213 --> 00:31:05,282 AT THEIR WHOLE BODY FAT 921 00:31:05,282 --> 00:31:05,549 OXIDATION. 922 00:31:05,549 --> 00:31:08,485 THERE WERE A NUMBER OF 923 00:31:08,485 --> 00:31:09,353 PHENOTYPIC CHARACTERISTICS THAT 924 00:31:09,353 --> 00:31:12,957 WERE CORRELATED WITH THIS MODEL. 925 00:31:12,957 --> 00:31:14,825 AND ONE WAS THAT THE HIGHER THE 926 00:31:14,825 --> 00:31:17,227 ADIPOSE INSULIN RESISTANCE, THE 927 00:31:17,227 --> 00:31:18,696 GREATER THE FAT OXIDATION AFTER 928 00:31:18,696 --> 00:31:19,763 A MEAL. 929 00:31:19,763 --> 00:31:21,899 AND THE HIGHER THE SKELETAL 930 00:31:21,899 --> 00:31:23,801 MUSCLE INSULIN RESISTANCE, YOU 931 00:31:23,801 --> 00:31:25,636 DIDN'T HAVE GOOD OXIDATION OF 932 00:31:25,636 --> 00:31:31,875 FATTY ACID AFTER A MEAL. 933 00:31:31,875 --> 00:31:33,210 SO THESE ARE WHAT THE DATA LOOK 934 00:31:33,210 --> 00:31:33,544 LIKE. 935 00:31:33,544 --> 00:31:34,979 THIS IS FROM A SINGLE SUBJECT. 936 00:31:34,979 --> 00:31:36,847 THE MODEL WE USE, WE PUT IN ALL 937 00:31:36,847 --> 00:31:38,382 THE CONSTRAINTS WE KNOW FROM THE 938 00:31:38,382 --> 00:31:40,117 LITERATURE. 939 00:31:40,117 --> 00:31:42,319 WHAT IS THE LEVEL OF INSULIN TO 940 00:31:42,319 --> 00:31:43,854 CONTROL LIPOLYSIS ENZYMES, FOR 941 00:31:43,854 --> 00:31:44,288 INSTANCE? 942 00:31:44,288 --> 00:31:48,659 WE GET ALL THAT INFORMATION FROM 943 00:31:48,659 --> 00:31:49,760 THE LITERATURE AND WE PUT IT 944 00:31:49,760 --> 00:31:51,629 INTO A MODEL AND THEN WE SEE 945 00:31:51,629 --> 00:31:52,930 DOES THAT MODEL PREDICT OUR 946 00:31:52,930 --> 00:31:54,131 POINTS THAT WE ACTUALLY 947 00:31:54,131 --> 00:31:54,898 OBSERVED. 948 00:31:54,898 --> 00:31:56,767 IF IT DID, THEN THE ELEMENTS OF 949 00:31:56,767 --> 00:31:59,169 THE MODEL ARE LIKELY GOOD 950 00:31:59,169 --> 00:32:00,471 CONTRIBUTORS FOR FATTY ACID 951 00:32:00,471 --> 00:32:01,038 FLUX. 952 00:32:01,038 --> 00:32:03,240 SO THIS IS MIDNIGHT ON THE LEFT. 953 00:32:03,240 --> 00:32:06,176 THE BLUE MODEL IS THE ONE THAT 954 00:32:06,176 --> 00:32:09,013 INCLUDES AN INSULIN SENSITIVE 955 00:32:09,013 --> 00:32:10,347 UPTAKE OF FATTY ACIDS, A 956 00:32:10,347 --> 00:32:11,115 COMPONENT OF THE MODEL. 957 00:32:11,115 --> 00:32:13,751 WHEN THAT'S LEFT OUT, I CAN'T 958 00:32:13,751 --> 00:32:15,919 REALLY GET THE MODEL TO LINE UP 959 00:32:15,919 --> 00:32:17,554 WITH REALITY, WHICH IS WHAT WE 960 00:32:17,554 --> 00:32:18,322 OBSERVE. 961 00:32:18,322 --> 00:32:20,758 AND THAT'S A SINGLE SUBJECT. 962 00:32:20,758 --> 00:32:22,893 THESE ARE A NUMBER OF SUBJECTS, 963 00:32:22,893 --> 00:32:24,028 16 OF THEM. 964 00:32:24,028 --> 00:32:26,230 YOU CAN SEE THIS IS DURING THE 965 00:32:26,230 --> 00:32:27,631 ORAL GLUCOSE TOLERANCE TEST, WE 966 00:32:27,631 --> 00:32:29,833 WERE ABLE TO PREDICT THE PREFATY 967 00:32:29,833 --> 00:32:31,235 ACID FALL WITH INSULIN, AND THEN 968 00:32:31,235 --> 00:32:32,603 AS THE INSULIN WEARS OFF, YOU 969 00:32:32,603 --> 00:32:34,338 CAN SEE THE FATTY ACIDS COMING 970 00:32:34,338 --> 00:32:37,841 BACK OUT TO BLOOD. 971 00:32:37,841 --> 00:32:39,243 THERE ARE LOTS OF HYPOTHESES 972 00:32:39,243 --> 00:32:40,778 THAT COME FROM THIS KIND OF A 973 00:32:40,778 --> 00:32:44,515 MODEL THAT WE CAN TEST NEXT. 974 00:32:44,515 --> 00:32:45,049 ALL RIGHT. 975 00:32:45,049 --> 00:32:46,583 SO WE TALKED ABOUT LIPOGENESIS 976 00:32:46,583 --> 00:32:47,785 AND WE'VE TALKED ABOUT THE 977 00:32:47,785 --> 00:32:48,452 ADIPOSE TISSUE. 978 00:32:48,452 --> 00:32:50,521 NOW LET'S LOOK AT A CHANGE IN 979 00:32:50,521 --> 00:32:53,057 FAT IN THE LIVER. 980 00:32:53,057 --> 00:32:54,558 I'M GOING TO SHOW YOU DATA FROM 981 00:32:54,558 --> 00:32:56,460 TWO LIFESTYLE TREATMENT STUDIES. 982 00:32:56,460 --> 00:32:58,762 ONE WITH AN INTRAVENOUS GLUCOSE 983 00:32:58,762 --> 00:32:59,697 TOLERANCE TEST, THE OTHER ONE 984 00:32:59,697 --> 00:33:05,636 WITH A HYPERCLAMP AND A TEST 985 00:33:05,636 --> 00:33:07,271 MEAL AND THEN WE ALWAYS USE 986 00:33:07,271 --> 00:33:13,410 IMAGING TO MEASURE LIVER FAT. 987 00:33:13,410 --> 00:33:15,946 SO THE FIRST DIET STUDY WAS DONE 988 00:33:15,946 --> 00:33:17,581 IN NON-DIABETIC SUBJECTS SIX 989 00:33:17,581 --> 00:33:18,115 MONTHS LONG. 990 00:33:18,115 --> 00:33:19,316 THE SECOND ONE IS ONE WE 991 00:33:19,316 --> 00:33:21,518 FINISHED LAST YEAR THAT'S A DIET 992 00:33:21,518 --> 00:33:22,720 AND EXERCISE INTERVENTION IN 993 00:33:22,720 --> 00:33:25,989 DIABETICS AND NON-DIABETICS. 994 00:33:25,989 --> 00:33:30,394 AND THIS IS THE FIRST STUDY 995 00:33:30,394 --> 00:33:30,627 DESIGN. 996 00:33:30,627 --> 00:33:31,595 ON THE LEFT-HAND SIDE YOU'LL SEE 997 00:33:31,595 --> 00:33:36,333 WE CONSENTED THE SUBJECTS, AND 998 00:33:36,333 --> 00:33:38,068 THEN WE DID THE TOLERANCE TEST 999 00:33:38,068 --> 00:33:39,603 AND SOME OTHER STUDIES I WOULD 1000 00:33:39,603 --> 00:33:40,704 ANY TIME SHOW YOU "TODAY" 1001 00:33:40,704 --> 00:33:42,039 SHOWING GLUCOSE AND KETONE 1002 00:33:42,039 --> 00:33:43,674 PRODUCTION, AND THEN THEY CAME 1003 00:33:43,674 --> 00:33:45,309 BACK THE AND DID A LIPID STUDY. 1004 00:33:45,309 --> 00:33:46,777 SO THE BOTTOM IS THE FORMAT OF 1005 00:33:46,777 --> 00:33:48,278 THE INPATIENT LID IP STUDY. 1006 00:33:48,278 --> 00:33:50,748 WE'RE USING LABELED WATER TO 1007 00:33:50,748 --> 00:33:51,181 MEASURE LIPOGENESIS. 1008 00:33:51,181 --> 00:33:52,449 THE PERSON COMES IN, THEY GET AN 1009 00:33:52,449 --> 00:33:53,317 EVENING MEAL. 1010 00:33:53,317 --> 00:33:56,153 WE'RE MEASURING VLDL SYNTHETIC 1011 00:33:56,153 --> 00:33:58,188 RATE, WE GAVE THEM THE LUNCH AS 1012 00:33:58,188 --> 00:33:59,223 I SHOWED YOU BEFORE, AND A 1013 00:33:59,223 --> 00:34:00,190 COUPLE OF THESE SUBJECTS WERE 1014 00:34:00,190 --> 00:34:01,625 HEADING FOR THEIR DIAGNOSTIC 1015 00:34:01,625 --> 00:34:03,193 LIVER BIOPSY, AND SO THEY WERE 1016 00:34:03,193 --> 00:34:05,028 KEPT IN THE UNIT IF THEY WERE 1017 00:34:05,028 --> 00:34:06,029 HEADING FOR MEDICAL CARE THE 1018 00:34:06,029 --> 00:34:08,198 NEXT DAY. 1019 00:34:08,198 --> 00:34:08,966 ALL RIGHT. 1020 00:34:08,966 --> 00:34:13,504 SO WHAT DID THE WEIGHT LOSS DO? 1021 00:34:13,504 --> 00:34:15,672 10% WAS OUR GOAL AND THAT'S WHAT 1022 00:34:15,672 --> 00:34:18,142 WE ACHIEVED. 1023 00:34:18,142 --> 00:34:19,343 INSULIN SENSITIVITY INCREASED 1024 00:34:19,343 --> 00:34:19,777 WITH WEIGHT LOSS. 1025 00:34:19,777 --> 00:34:20,978 YOU DON'T ALWAYS SEE THIS, BUT 1026 00:34:20,978 --> 00:34:22,312 IN THIS CASE, WE GOT A 1027 00:34:22,312 --> 00:34:26,250 SIGNIFICANT IMPROVEMENT. 1028 00:34:26,250 --> 00:34:27,584 LIVER TRIGLYCERIDE DROPPED 1029 00:34:27,584 --> 00:34:28,418 SIGNIFICANTLY DOWN THERE. 1030 00:34:28,418 --> 00:34:30,988 LOOK HOW LOW THAT IS, 3.5%. 1031 00:34:30,988 --> 00:34:33,390 AND LASTLY, ALT BECAME 1032 00:34:33,390 --> 00:34:38,629 NORMALIZED AFTER WEIGHT LOSS. 1033 00:34:38,629 --> 00:34:40,297 SO THIS IS THE WEIGHT LOSS 1034 00:34:40,297 --> 00:34:42,366 CURVES, AND THIS DIETITIAN WAS 1035 00:34:42,366 --> 00:34:43,567 ABSOLUTELY AMAZING. 1036 00:34:43,567 --> 00:34:45,002 SOMETIMES WE SEE WEIGHT LOSS 1037 00:34:45,002 --> 00:34:46,870 COME DOWN AND THEN WE'LL SEE 1038 00:34:46,870 --> 00:34:49,373 PEOPLE REGAIN, AND YOU'LL ALSO 1039 00:34:49,373 --> 00:34:51,008 SEE THE VARIABILITY IN THESE 1040 00:34:51,008 --> 00:34:52,309 CURVES. 1041 00:34:52,309 --> 00:34:53,844 HALF OF THESE PEOPLE HAD LOW 1042 00:34:53,844 --> 00:34:55,078 LIVER FAT FOR STARTERS AND THE 1043 00:34:55,078 --> 00:34:56,713 OTHER HALF HAD HIGH, AND WE 1044 00:34:56,713 --> 00:34:59,049 WANTED TO COMPARE THE RESPONSE 1045 00:34:59,049 --> 00:35:00,784 OF ENERGY RESTRICTION IN THIS 1046 00:35:00,784 --> 00:35:02,219 SETTING. 1047 00:35:02,219 --> 00:35:04,054 THIS IS WHAT WEIGHT LOSS DID TO 1048 00:35:04,054 --> 00:35:05,689 LIVER FAT. 1049 00:35:05,689 --> 00:35:07,124 YOUR LOW LIVER FAT PEOPLE ARE 1050 00:35:07,124 --> 00:35:08,659 THERE ON THE BOTTOM. 1051 00:35:08,659 --> 00:35:09,760 INDIVIDUALS WHO STARTED WITH 1052 00:35:09,760 --> 00:35:12,162 HIGH LIVER FAT CAME DOWN AND A 1053 00:35:12,162 --> 00:35:14,364 COUPLE OF THEM ACTUALLY DID NOT 1054 00:35:14,364 --> 00:35:15,465 ACHIEVE NORMALIZATION OF THEIR 1055 00:35:15,465 --> 00:35:18,769 LIVER FAT EVEN AFTER LOSING 10% 1056 00:35:18,769 --> 00:35:24,341 BODY WEIGHT. 1057 00:35:24,341 --> 00:35:26,210 THERE WAS A MAIN EFFECT OF 1058 00:35:26,210 --> 00:35:26,877 WEIGHT LOSS IN GENERAL FOR 1059 00:35:26,877 --> 00:35:33,884 EVERYONE. 1060 00:35:33,884 --> 00:35:38,555 SO THO THESE ARE THE POSTPRANDI- 1061 00:35:38,555 --> 00:35:41,658 WHAT IS SOMEONE DOING WHEN THEY 1062 00:35:41,658 --> 00:35:43,861 LOSE WEIGHT TA LEADS TO LIVER 1063 00:35:43,861 --> 00:35:44,294 HEALTH. 1064 00:35:44,294 --> 00:35:46,029 THERE WERE NO DIABETICS HERE, 1065 00:35:46,029 --> 00:35:47,364 THIS WAS A 10% WEIGHT LOSS. 1066 00:35:47,364 --> 00:35:51,869 THE OPEN SYMBOLICS ARE BASELINE 1067 00:35:51,869 --> 00:35:53,370 AND THE FILLED ARE FOLLOW-UP AND 1068 00:35:53,370 --> 00:35:53,904 GLUCOSE DIDN'T CHANGE. 1069 00:35:53,904 --> 00:35:55,672 THIS IS THE FREE FATTY ACID CON 1070 00:35:55,672 --> 00:35:57,808 ACCCONCENTRATIONS. 1071 00:35:57,808 --> 00:35:59,209 AGAIN, WE'RE STARTING AT 1072 00:35:59,209 --> 00:36:00,844 6:00 P.M. FEEDING DINNER, THE 1073 00:36:00,844 --> 00:36:02,613 EVENING MEAL, AND ZERO IS 1074 00:36:02,613 --> 00:36:03,380 MIDNIGHT. 1075 00:36:03,380 --> 00:36:05,582 AND YOU CAN SEE INSULIN IS 1076 00:36:05,582 --> 00:36:07,217 SUPPRESSING FREE FATTY ACID 1077 00:36:07,217 --> 00:36:12,022 CONCENTRATION IN THE BLOOD. 1078 00:36:12,022 --> 00:36:14,024 YOU CAN SEE IT COME BACK AND 1079 00:36:14,024 --> 00:36:15,659 VERY REACTIVE AFTER WEIGHT LOSS. 1080 00:36:15,659 --> 00:36:17,294 YOU DON'T GET THIS SPIKE OF FREE 1081 00:36:17,294 --> 00:36:17,861 FATTY ACIDS. 1082 00:36:17,861 --> 00:36:19,396 THE OTHER THING THAT HAPPENED IS 1083 00:36:19,396 --> 00:36:23,667 WITH FASTING, THERE IS A RISE 1084 00:36:23,667 --> 00:36:25,969 TOWARD DAWN IN FREE FATTY ACIDS 1085 00:36:25,969 --> 00:36:28,138 IN MOST PATIENTS WHO STRUGGLE 1086 00:36:28,138 --> 00:36:29,373 WITH OBESITY. 1087 00:36:29,373 --> 00:36:31,742 THAT RISE RIGHT UP TO LUNCH WAS 1088 00:36:31,742 --> 00:36:32,309 MISSING AFTERWARDS. 1089 00:36:32,309 --> 00:36:35,545 AND WE HAD BASICALLY BEEN 1090 00:36:35,545 --> 00:36:36,513 STARVING THEM FOR SIX MONTHS. 1091 00:36:36,513 --> 00:36:38,148 I THINK THEY GOT MUCH BETTER AT 1092 00:36:38,148 --> 00:36:38,782 FASTING. 1093 00:36:38,782 --> 00:36:40,651 AND THEN AFTER THE SECOND MEAL, 1094 00:36:40,651 --> 00:36:42,519 THE LUNCH, YOU SEE THIS REALLY 1095 00:36:42,519 --> 00:36:44,288 GREAT SUPPRESSION OF ADIPOSE 1096 00:36:44,288 --> 00:36:52,596 TISSUE FATTY ACIDS. 1097 00:36:52,596 --> 00:36:54,665 THIS IS THE INSULIN LEVELS. 1098 00:36:54,665 --> 00:36:55,999 YOU SOMETIMES WON'T SEE A CHANGE 1099 00:36:55,999 --> 00:36:57,968 IN GLUCOSE, BUT BOY, DO YOU SEE 1100 00:36:57,968 --> 00:36:58,869 A SUPPRESSION IN THE AMOUNT OF 1101 00:36:58,869 --> 00:37:00,470 INSULIN NEEDED. 1102 00:37:00,470 --> 00:37:03,006 AND THEN LASTLY, MY OUT COME OF 1103 00:37:03,006 --> 00:37:05,208 INTEREST ARE TRIGLYCERIDES. 1104 00:37:05,208 --> 00:37:07,411 AND THE TRIGLYCERIDES OCCUR IN 1105 00:37:07,411 --> 00:37:09,246 THE OPEN SYMBOL, THE 1106 00:37:09,246 --> 00:37:11,014 TRIGLYCERIDES OCCURRING LATE AT 1107 00:37:11,014 --> 00:37:13,216 NIGHT ARE REALLY RISING 1108 00:37:13,216 --> 00:37:13,984 THROUGHOUT THE DAY. 1109 00:37:13,984 --> 00:37:15,719 FOR MOST PEOPLE, OUR 1110 00:37:15,719 --> 00:37:16,586 TRIGLYCERIDES RISE AFTER 1111 00:37:16,586 --> 00:37:18,055 BREAKFAST, THEY RISE AGAIN AFTER 1112 00:37:18,055 --> 00:37:20,023 LUNCH, AND THEY PEAK AFTER 1113 00:37:20,023 --> 00:37:20,624 DINNER. 1114 00:37:20,624 --> 00:37:21,658 AS I'VE SAID IN THE MIDDLE OF 1115 00:37:21,658 --> 00:37:23,860 THE NIGHT, WHEN WE'RE SLEEPING. 1116 00:37:23,860 --> 00:37:26,596 AND THAT PEAK WAS DAMPENED 1117 00:37:26,596 --> 00:37:28,799 EXTREMELY, AND EVEN THE LUNCH 1118 00:37:28,799 --> 00:37:35,806 RISE IS LOWER AFTER WEIGHT LOSS. 1119 00:37:35,806 --> 00:37:38,041 SO THIS IS TO REMIND ME THAT I 1120 00:37:38,041 --> 00:37:40,610 LABELED ALL THESE THREE SOURCES. 1121 00:37:40,610 --> 00:37:43,246 THE DIET, DE NOVO LIPOGENESIS, 1122 00:37:43,246 --> 00:37:44,781 AND ADIPOSE TISSUE. 1123 00:37:44,781 --> 00:37:45,882 NOW I'M GOING TO PUT THEM 1124 00:37:45,882 --> 00:37:53,223 TOGETHER FOR YOU. 1125 00:37:53,223 --> 00:37:54,324 SO THIS IS THE CONTRIBUTION OF 1126 00:37:54,324 --> 00:37:55,859 DINNER TO LIVER FAT REA PSYCHED 1127 00:37:55,859 --> 00:37:57,160 BACK THROUGH VLDL. 1128 00:37:57,160 --> 00:37:58,528 THERE'S NOT A REALLY BIG CHANGE 1129 00:37:58,528 --> 00:37:59,596 THERE. 1130 00:37:59,596 --> 00:38:01,565 THOSE INDIVIDUALS WITH HIGH 1131 00:38:01,565 --> 00:38:03,467 LIVER FAT AT BASELINE ACTUALLY 1132 00:38:03,467 --> 00:38:07,137 HAD AN INCREASE IN THIS 1133 00:38:07,137 --> 00:38:09,873 PARAMETER AFTER WEIGHT LOSS. 1134 00:38:09,873 --> 00:38:12,743 THIS IS WHAT THE FREE FATTY ACID 1135 00:38:12,743 --> 00:38:13,477 RECYCLING THROUGH THE LIVER 1136 00:38:13,477 --> 00:38:13,910 LOOKS LIKE. 1137 00:38:13,910 --> 00:38:16,246 IT'S RISING FROM MIDNIGHT, AND 1138 00:38:16,246 --> 00:38:18,515 FREE FATTY ACIDS ARE BEING USED 1139 00:38:18,515 --> 00:38:21,051 MORE FOR TRIGLYCERIDE SECRETION 1140 00:38:21,051 --> 00:38:23,687 AFTER WEIGHT LOSS. 1141 00:38:23,687 --> 00:38:24,888 THEY'RE COMING FROM THE ADIPOSE, 1142 00:38:24,888 --> 00:38:26,223 THEY GET PACKAGED, THEY'RE PUT 1143 00:38:26,223 --> 00:38:28,058 IN VLDL AND THEY'RE SENT BACK 1144 00:38:28,058 --> 00:38:30,394 OUT TO THE BODY. 1145 00:38:30,394 --> 00:38:33,230 AND LASTLY, THIS IS DE NOVO 1146 00:38:33,230 --> 00:38:33,563 LIPOGENESIS. 1147 00:38:33,563 --> 00:38:36,533 WHAT YOU SEE IS THAT IT IS DOWN 1148 00:38:36,533 --> 00:38:36,967 BY HALF. 1149 00:38:36,967 --> 00:38:39,069 IT IS THE OUTCOME THAT CHANGED 1150 00:38:39,069 --> 00:38:40,704 MOST IN THESE PATIENTS, AND WE 1151 00:38:40,704 --> 00:38:45,742 HAVE CLOSE TO 200 PHENOTYPES IN 1152 00:38:45,742 --> 00:38:47,744 ALL THE HORMONES, CONCENTRATIONS 1153 00:38:47,744 --> 00:38:50,347 OF EVERYTHING, BODY COMPOSITION, 1154 00:38:50,347 --> 00:38:50,647 EVERYTHING. 1155 00:38:50,647 --> 00:38:51,815 THIS IS THE ONE FACTOR THAT 1156 00:38:51,815 --> 00:38:53,216 PREDICTED LOSS OF LIVER FAT, WAS 1157 00:38:53,216 --> 00:38:55,552 THE SUPPRESSION OF THIS PATHWAY. 1158 00:38:55,552 --> 00:38:57,287 NOW WHAT YOU DO SEE IS THAT THE 1159 00:38:57,287 --> 00:38:59,022 INDIVIDUALS WHO STARTED WITH LOW 1160 00:38:59,022 --> 00:39:01,992 LIVER FAT, THEIR LIPOGENESIS IS 1161 00:39:01,992 --> 00:39:03,894 DOWN BELOW 5%, AND IT SUPPRESSES 1162 00:39:03,894 --> 00:39:05,529 VERY QUICKLY. 1163 00:39:05,529 --> 00:39:06,596 THE INDIVIDUALS THAT STARTED 1164 00:39:06,596 --> 00:39:09,599 WITH HIGH LIVER FAT STILL HAVE 1165 00:39:09,599 --> 00:39:13,837 THIS KIND OF SU CIRCADIAN 1166 00:39:13,837 --> 00:39:15,806 DISRUPTION IN THE PATHWAY AND IT 1167 00:39:15,806 --> 00:39:17,074 STAYS HIGH ALMOST ALL NIGHT. 1168 00:39:17,074 --> 00:39:18,842 AND THAT PERSISTED AFTER WEIGHT 1169 00:39:18,842 --> 00:39:24,948 LOSS. 1170 00:39:24,948 --> 00:39:27,184 SO IF YOU LOOK IN VLDL IN THE 1171 00:39:27,184 --> 00:39:28,285 FASTING STATE, THIS IS WHAT YOU 1172 00:39:28,285 --> 00:39:28,485 SEE. 1173 00:39:28,485 --> 00:39:30,887 PEOPLE WITH LOW LIVER FAT ARE ON 1174 00:39:30,887 --> 00:39:31,721 THE LEFT-HAND SIDE AND HIGH ON 1175 00:39:31,721 --> 00:39:32,222 THE RIGHT. 1176 00:39:32,222 --> 00:39:34,191 THESE ARE THE PROPORTIONS OF THE 1177 00:39:34,191 --> 00:39:36,393 VARIOUS SOURCES THAT THE LIVER 1178 00:39:36,393 --> 00:39:38,895 MACHINERY IS DEALING WITH, AND 1179 00:39:38,895 --> 00:39:45,902 CHOOSING HOW TO STERIFY THEM. 1180 00:39:45,902 --> 00:39:48,872 YOU SEE THE MAJORITY IS COMING 1181 00:39:48,872 --> 00:39:50,874 FROM THE FATTY ACID POOL. 1182 00:39:50,874 --> 00:39:52,209 LIPOGENESIS IS SIGNIFICANTLY 1183 00:39:52,209 --> 00:39:53,743 HIGHER IN THE INDIVIDUALS WITH 1184 00:39:53,743 --> 00:39:56,046 FATTY LIVER. 1185 00:39:56,046 --> 00:39:57,547 AFTER WEIGHT LOSS, LAY POE 1186 00:39:57,547 --> 00:39:58,548 GENESIS COMES DOWN IN PEOPLE 1187 00:39:58,548 --> 00:40:00,417 WITH LOW LIVER FAT, BUT THERE 1188 00:40:00,417 --> 00:40:03,253 REALLY AREN'T ANY OTHER CHANGES. 1189 00:40:03,253 --> 00:40:04,154 WHERE AFTER WEIGHT LOSS IN 1190 00:40:04,154 --> 00:40:05,122 INDIVIDUALS WITH FATTY LIVER 1191 00:40:05,122 --> 00:40:06,656 DISEASE, WE ESSENTIALLY 1192 00:40:06,656 --> 00:40:08,191 NORMALIZE THE PROCESSING OF 1193 00:40:08,191 --> 00:40:10,627 FATTY ACIDS, AND THE ONLY 1194 00:40:10,627 --> 00:40:12,796 VARIABLE THAT PREDICTED THIS WAS 1195 00:40:12,796 --> 00:40:14,764 A REDUCTION IN DE NOVO 1196 00:40:14,764 --> 00:40:19,569 LIPOGENESIS. 1197 00:40:19,569 --> 00:40:21,404 TO LOOK AT IT ANOTHER WAY, IF 1198 00:40:21,404 --> 00:40:23,340 YOU LIKE CYCLES, DIET IS UP 1199 00:40:23,340 --> 00:40:24,407 THERE ON THE LEFT-HAND SIDE. 1200 00:40:24,407 --> 00:40:26,209 IT'S SPILLING OVER ITS FATTY 1201 00:40:26,209 --> 00:40:27,511 ACIDS INTO THE FREE FATTY ACID 1202 00:40:27,511 --> 00:40:28,545 POOL AND THOSE ARE COMING INTO 1203 00:40:28,545 --> 00:40:30,046 THE LIVER, AND THERE WAS NO 1204 00:40:30,046 --> 00:40:32,549 CHANGE IN THAT CIRCLE ON THE 1205 00:40:32,549 --> 00:40:33,850 RIGHT IN THE GREEN, IN THE 1206 00:40:33,850 --> 00:40:36,620 DIETARY CONTRIBUTION TO LIVER 1207 00:40:36,620 --> 00:40:37,454 FAT. 1208 00:40:37,454 --> 00:40:39,256 ADIPOSE FREE FATTY ACIDS, THEY 1209 00:40:39,256 --> 00:40:42,959 WERE 6 IT%, THEY WERE REDUCED 1210 00:40:42,959 --> 00:40:46,396 62%, AND DE NOVO LIPOGENESIS WAS 1211 00:40:46,396 --> 00:40:46,963 REDUCED 42%. 1212 00:40:46,963 --> 00:40:48,665 AND WHEN YOU ADD THOSE TOGETHER, 1213 00:40:48,665 --> 00:40:51,668 YOU GET A 66% REDUCTION IN LIVER 1214 00:40:51,668 --> 00:40:54,070 FAT BY THE MODEL, WHICH ALSO 1215 00:40:54,070 --> 00:40:56,673 CORRELATED WITH IMAGING. 1216 00:40:56,673 --> 00:41:00,310 FROM MRS. 1217 00:41:00,310 --> 00:41:01,011 ALL RIGHT. 1218 00:41:01,011 --> 00:41:03,213 I'LL QUICKLY END HERE WITH DIET 1219 00:41:03,213 --> 00:41:06,583 PLUS EXERCISE. 1220 00:41:06,583 --> 00:41:08,451 SO NOW WE'RE REALLY GOING TO 1221 00:41:08,451 --> 00:41:10,120 FOCUS ON WE'VE REDUCED FOOD 1222 00:41:10,120 --> 00:41:11,221 INTAKE, WHICH SHOULD MAKE 1223 00:41:11,221 --> 00:41:11,988 MATTERS BETTER IN THE LIVER. 1224 00:41:11,988 --> 00:41:13,757 I ALSO THEN WANT TO SEND 1225 00:41:13,757 --> 00:41:16,293 CALORIES OVER TO THE MUSCLE. 1226 00:41:16,293 --> 00:41:19,329 THAT WAS OUR HYPOTHESIS HERE, 1227 00:41:19,329 --> 00:41:21,331 COULD WE PROTECT THE LIVER BY 1228 00:41:21,331 --> 00:41:24,301 REROUTING ENERGY AWAY FROM IT. 1229 00:41:24,301 --> 00:41:27,804 I WAS COLLABORATOR ON THIS STUDY 1230 00:41:27,804 --> 00:41:31,107 WITH SCOTT RICHTER AND ABDUL AT 1231 00:41:31,107 --> 00:41:31,608 UNIVERSITY OF MISSOURI. 1232 00:41:31,608 --> 00:41:33,343 MOST OF NEW THIS ROOM KNOW HOW 1233 00:41:33,343 --> 00:41:34,611 MUCH WORK IT TAKES TO GELTS 1234 00:41:34,611 --> 00:41:37,581 THGET THESESTUDIES DONE. 1235 00:41:37,581 --> 00:41:38,481 WE RECRUIT THROUGH THE LIVER 1236 00:41:38,481 --> 00:41:39,816 CLINIC, WE HAVE AN INPATIENT 1237 00:41:39,816 --> 00:41:42,219 UNIT AND OUR IMAGING SUITE IS 1238 00:41:42,219 --> 00:41:42,852 REALLY GREAT. 1239 00:41:42,852 --> 00:41:45,088 THIS TIME WE RECRUITED PATIENTS 1240 00:41:45,088 --> 00:41:46,189 ONLY FROM THE LIVER CLINIC, SO 1241 00:41:46,189 --> 00:41:47,490 THESE WERE INDIVIDUALS WITH 1242 00:41:47,490 --> 00:41:48,258 DOCUMENTED LIVER DISEASE BY 1243 00:41:48,258 --> 00:41:48,792 HISTOLOGY. 1244 00:41:48,792 --> 00:41:53,330 WE DID BASELINE TESTS AND 1245 00:41:53,330 --> 00:41:55,832 EXERCISE TREADMILL DEX, WE DID 1246 00:41:55,832 --> 00:41:58,268 DEXA AND IMAGING AND THEY WERE 1247 00:41:58,268 --> 00:41:59,269 RANDOMIZED EITHER TO CONTROL 1248 00:41:59,269 --> 00:42:03,173 WHICH WAS FOLLOWING THE CARE OF 1249 00:42:03,173 --> 00:42:04,274 THEIR PHYSICIAN OR ENERGY 1250 00:42:04,274 --> 00:42:06,376 RESTRICTION AND HIGH INTENSITY 1251 00:42:06,376 --> 00:42:07,177 INTERVAL TRAINING. 1252 00:42:07,177 --> 00:42:09,246 AND THEN AFTER NINE MONTHS OF 1253 00:42:09,246 --> 00:42:13,817 HARD LABOR, WE FOLLOWED UP ALL 1254 00:42:13,817 --> 00:42:16,186 THOSE TESTS AND THESE 1255 00:42:16,186 --> 00:42:17,387 INDIVIDUALS ELECTED FOR A 1256 00:42:17,387 --> 00:42:18,021 FOLLOW-UP LIVER BIOPSY. 1257 00:42:18,021 --> 00:42:20,023 IF YOU ASK THEM AT THE BEGINNING 1258 00:42:20,023 --> 00:42:21,224 WHY THEY WOULD DO THE STUDY OR 1259 00:42:21,224 --> 00:42:24,928 WOULDN'T DO THE STUDY, IT WAS 1260 00:42:24,928 --> 00:42:26,596 NOT THE FOLLOW-UP LIVER BIOPSY 1261 00:42:26,596 --> 00:42:27,931 THAT KEPT THEM FROM DOING THE 1262 00:42:27,931 --> 00:42:28,698 STUDY. 1263 00:42:28,698 --> 00:42:29,899 THEY ALL HAD HAD ONE, THEY KNEW 1264 00:42:29,899 --> 00:42:31,101 WHAT THEY WERE SIGNING UP FOR. 1265 00:42:31,101 --> 00:42:32,936 THEY COULD DECIDE LATER TO NOT 1266 00:42:32,936 --> 00:42:36,273 DO IT, THAT WAS FINE, BUT WE 1267 00:42:36,273 --> 00:42:37,474 DIDN'T HAVE A SINGLE SUBJECT WHO 1268 00:42:37,474 --> 00:42:38,608 DIDN'T WANT TO KNOW WHERE THEY 1269 00:42:38,608 --> 00:42:40,443 WERE WITH THEIR DISEASE AFTER 1270 00:42:40,443 --> 00:42:43,213 NINE MONTHS. 1271 00:42:43,213 --> 00:42:45,382 IF I HAD TO ASK YOU WAS IT THE 1272 00:42:45,382 --> 00:42:46,650 EXERCISE OR THE DIET THAT MADE 1273 00:42:46,650 --> 00:42:47,851 PEOPLE THE MOST SCARED, WHAT 1274 00:42:47,851 --> 00:42:49,586 WOULD YOU SAY, THAT THEY DIDN'T 1275 00:42:49,586 --> 00:42:50,787 WANT TO DO THE STUDY BECAUSE OF 1276 00:42:50,787 --> 00:42:54,591 ONE OF THOSE, WHAT WOULD IT BE? 1277 00:42:54,591 --> 00:42:55,525 >> EXERCISE. 1278 00:42:55,525 --> 00:42:57,193 >> IT WASN'T, IT WAS THE DIET. 1279 00:42:57,193 --> 00:42:58,295 AND THAT'S BECAUSE WHEN YOU 1280 00:42:58,295 --> 00:42:59,829 EXERCISE WITH A COACH, AND WE 1281 00:42:59,829 --> 00:43:01,698 HAD GRAD STUDENTS AS COACHES, 1282 00:43:01,698 --> 00:43:02,632 THERE'S SOMEONE THERE THREE 1283 00:43:02,632 --> 00:43:05,235 TIMES A WEEK, YOU'RE ON THE 1284 00:43:05,235 --> 00:43:07,170 TREADMILL, IT'S 20 MINUTES OF 1285 00:43:07,170 --> 00:43:08,405 HIT TRAINING, YOU CHECK IT OFF, 1286 00:43:08,405 --> 00:43:10,407 YOU GO HOME AND YOU FEEL VERY 1287 00:43:10,407 --> 00:43:11,474 VIRTUE U YOU DID YOUR STUDY 1288 00:43:11,474 --> 00:43:12,042 WORK. 1289 00:43:12,042 --> 00:43:14,878 WHEREAS YOU AND I KNOW THAT A 1290 00:43:14,878 --> 00:43:15,912 DIET IS CHALLENGING. 1291 00:43:15,912 --> 00:43:17,013 EVERY MINUTE OF THE DAY, YOU'RE 1292 00:43:17,013 --> 00:43:18,315 BY YOURSELF, YOU'RE IN THE 1293 00:43:18,315 --> 00:43:20,450 GROCERY STORE, AND OUR DIETITIAN 1294 00:43:20,450 --> 00:43:22,719 FIELDED CALLS FROM ALL OVER TO 1295 00:43:22,719 --> 00:43:24,487 TRY AND SUPPORT THESE SUBJECTS. 1296 00:43:24,487 --> 00:43:25,789 THEY KNEW THAT CHANGING THEIR 1297 00:43:25,789 --> 00:43:30,193 DIET WOULD BE MORE DIFFICULT. 1298 00:43:30,193 --> 00:43:30,860 SO WHO ARE THEY? 1299 00:43:30,860 --> 00:43:31,628 HERE THEY WERE. 1300 00:43:31,628 --> 00:43:33,797 IT'S A SMALL GROUP. 1301 00:43:33,797 --> 00:43:37,300 THEY WERE 75% WERE DIABETIC IN 1302 00:43:37,300 --> 00:43:39,302 THE CONTROL AND 63% IN THE 1303 00:43:39,302 --> 00:43:40,937 INTERVENTION. 1304 00:43:40,937 --> 00:43:42,472 THIS IS -- THEY WERE HIGHLY 1305 00:43:42,472 --> 00:43:42,806 SEDENTARY. 1306 00:43:42,806 --> 00:43:44,474 IF YOU LOOK AT THE VO2 MAX ON 1307 00:43:44,474 --> 00:43:46,343 THE BOTTOM, SOME OF THESE 1308 00:43:46,343 --> 00:43:48,445 INDIVIDUALS HAD NEVER EXERCISED 1309 00:43:48,445 --> 00:43:51,314 OUTSIDE OF THEIR GRADE SCHOOL 1310 00:43:51,314 --> 00:43:55,251 GYM CLASS. 1311 00:43:55,251 --> 00:43:56,219 WEIGHT LOSS LOOKED LIKE THIS, 1312 00:43:56,219 --> 00:43:57,487 AND THIS IS WHAT WE EXPECTED 1313 00:43:57,487 --> 00:43:58,088 WOULD HAPPEN. 1314 00:43:58,088 --> 00:43:59,856 SOME INDIVIDUALS IN THE CONTROL 1315 00:43:59,856 --> 00:44:01,091 GROUP WOULD LOSE WEIGHT, AND 1316 00:44:01,091 --> 00:44:02,392 THAT'S BECAUSE THEY HAD JUST 1317 00:44:02,392 --> 00:44:03,793 BEEN DIAGNOSED WITH SIGNIFICANT 1318 00:44:03,793 --> 00:44:04,894 LIVER DISEASE. 1319 00:44:04,894 --> 00:44:06,896 THEY HAD BEEN TOLD, YOU HAVE 1320 00:44:06,896 --> 00:44:09,332 FATTY LIVER WITH A GRADE OF 4 OR 1321 00:44:09,332 --> 00:44:10,133 GREATER. 1322 00:44:10,133 --> 00:44:10,934 AND THEN ON THE RIGHT-HAND SIDE, 1323 00:44:10,934 --> 00:44:15,872 YOU SEE SOME OF THE INDIVIDUALS 1324 00:44:15,872 --> 00:44:17,340 IN THE DIET AND EXERCISE GROUP 1325 00:44:17,340 --> 00:44:19,843 DID NOT LOSE WEIGHT AT ALL, SOME 1326 00:44:19,843 --> 00:44:20,977 LOST WEIGHT AND GAINED IT BACK. 1327 00:44:20,977 --> 00:44:23,046 I WANT TO SHOW YOU OR HAVE YOU 1328 00:44:23,046 --> 00:44:25,882 LISTEN TO SOME WORDS FROM ONE OF 1329 00:44:25,882 --> 00:44:26,616 THE PATIENTS. 1330 00:44:26,616 --> 00:44:28,251 >> WHEN I WOULD COME HOME FROM 1331 00:44:28,251 --> 00:44:31,421 WORK, I WOULD HAVE TO TAKE A 1332 00:44:31,421 --> 00:44:33,323 NAP, I WOULD NOT DO MUCH BECAUSE 1333 00:44:33,323 --> 00:44:37,360 I'D BE TIRED JUST WALKING, 1334 00:44:37,360 --> 00:44:38,561 GETTING IN AND OUT OF THE CAR 1335 00:44:38,561 --> 00:44:40,029 WOULD WEAR ME OUT. 1336 00:44:40,029 --> 00:44:42,232 MY PRIMARY CARE DOCTOR RAN TESTS 1337 00:44:42,232 --> 00:44:43,733 AND I GOT DIAGNOSED FOR HAVING 1338 00:44:43,733 --> 00:44:44,934 FATTY LIVER DISEASE, AND I 1339 00:44:44,934 --> 00:44:45,969 DIDN'T REALIZE FATTY LIVER 1340 00:44:45,969 --> 00:44:47,270 DISEASE COULD BE FATAL IF I 1341 00:44:47,270 --> 00:44:48,471 DIDN'T TAKE CARE OF IT. 1342 00:44:48,471 --> 00:44:50,073 I WANT TO BE AROUND FOR MY KIDS, 1343 00:44:50,073 --> 00:44:51,474 EVEN THOUGH THEY'RE GROWN NOW, 1344 00:44:51,474 --> 00:44:52,575 THEY STILL NEED ME. 1345 00:44:52,575 --> 00:44:54,644 I NEED THEM. 1346 00:44:54,644 --> 00:44:56,746 THIS PAST NINE MONTHS, I'VE LOST 1347 00:44:56,746 --> 00:44:57,113 40 POUNDS. 1348 00:44:57,113 --> 00:44:58,648 I FEEL MUCH BETTER. 1349 00:44:58,648 --> 00:45:00,517 I USED TO BE ON SOME MEDICATION, 1350 00:45:00,517 --> 00:45:01,751 AND NOW I DON'T HAVE TO TAKE 1351 00:45:01,751 --> 00:45:03,286 THOSE MEDICATIONS ANYMORE. 1352 00:45:03,286 --> 00:45:05,355 I THINK IT'S GREAT THAT MIZZOU 1353 00:45:05,355 --> 00:45:07,023 IS DOING THIS RESEARCH AND 1354 00:45:07,023 --> 00:45:07,590 HELPING PEOPLE. 1355 00:45:07,590 --> 00:45:14,397 I'M PROUD TO BE A PART OF THAT. 1356 00:45:14,397 --> 00:45:17,634 >> SO SHE WAS QUITE SUCCESSFUL. 1357 00:45:17,634 --> 00:45:20,303 THIS IS THE CHANGE IN LIVER 1358 00:45:20,303 --> 00:45:22,505 HISTOLOGY, AND I'LL SHOW YOU HER 1359 00:45:22,505 --> 00:45:23,573 DATA IN A LITTLE BIT. 1360 00:45:23,573 --> 00:45:25,442 YOU CAN SEE STANDARD OF CARE OF 1361 00:45:25,442 --> 00:45:26,776 A COUPLE OF THE SUBJECTS GOT 1362 00:45:26,776 --> 00:45:27,877 WORSE OVER NINE MONTHS. 1363 00:45:27,877 --> 00:45:29,312 ONE GOT BETTER. 1364 00:45:29,312 --> 00:45:33,416 THIS IS THE TREATMENT GROUP, AND 1365 00:45:33,416 --> 00:45:35,585 FERN STARTED AT A 5 AND ENDED AT 1366 00:45:35,585 --> 00:45:36,052 A ZERO. 1367 00:45:36,052 --> 00:45:37,887 SO THIS IS COMPLETE REGRESSION. 1368 00:45:37,887 --> 00:45:40,089 WE HAD A WOMAN WHO WENT FROM A 1369 00:45:40,089 --> 00:45:43,293 SCORE OF 6 TO 0. 1370 00:45:43,293 --> 00:45:44,494 8 IS CIRRHOSIS. 1371 00:45:44,494 --> 00:45:46,830 SO YOU WANT TO BE DOWN A LOWER 1372 00:45:46,830 --> 00:45:47,263 NUMBER. 1373 00:45:47,263 --> 00:45:50,333 THESE ARE THE STEATOSIS SCORES 1374 00:45:50,333 --> 00:45:52,635 WITH THE TREATMENT GROUP 1375 00:45:52,635 --> 00:45:54,170 SIGNIFICANTLY LOWERING LIVER 1376 00:45:54,170 --> 00:45:55,038 FAT. 1377 00:45:55,038 --> 00:45:56,840 HERE'S LOBULAR INFLAMMATION, 1378 00:45:56,840 --> 00:45:57,373 DOWN. 1379 00:45:57,373 --> 00:45:58,908 AND THERE'S HEPATOCELLULAR 1380 00:45:58,908 --> 00:45:59,709 BALLOONING AND WE'LL LOOK AT 1381 00:45:59,709 --> 00:46:00,577 THAT IN A SECOND. 1382 00:46:00,577 --> 00:46:02,545 THAT'S WHEN THE CELLS ACTUALLY 1383 00:46:02,545 --> 00:46:04,581 DIE AND THEY LOOK HOLLOW WITH A 1384 00:46:04,581 --> 00:46:07,650 LITTLE BIT OF CELLULAR DEBRIS IN 1385 00:46:07,650 --> 00:46:08,084 THE MIDDLE. 1386 00:46:08,084 --> 00:46:09,152 THAT WAS SIGNIFICANTLY DOWN. 1387 00:46:09,152 --> 00:46:12,722 AND THEN HERE IS FIBROSIS. 1388 00:46:12,722 --> 00:46:14,290 IT WAS A SIGNIFICANT INTERACTION 1389 00:46:14,290 --> 00:46:15,225 BETWEEN THE CHANGES IN THE TWO 1390 00:46:15,225 --> 00:46:18,828 GROUPS. 1391 00:46:18,828 --> 00:46:20,230 SO WHAT DID THE HISTOLOGY LOOK 1392 00:46:20,230 --> 00:46:20,630 LIKE? 1393 00:46:20,630 --> 00:46:21,898 SO IN THE UPPER LEFT-HAND SIDE, 1394 00:46:21,898 --> 00:46:23,132 THIS IS -- I KNOW YOU CAN'T SEE 1395 00:46:23,132 --> 00:46:24,133 THIS VERY WELL. 1396 00:46:24,133 --> 00:46:26,569 THIS IS A GRADE OF 7 OUT OF 8. 1397 00:46:26,569 --> 00:46:28,438 THE DROPLETS, THE LITTLE WHITE 1398 00:46:28,438 --> 00:46:29,973 DOTS YOU'RE SEEING ARE ALL FAT 1399 00:46:29,973 --> 00:46:30,940 IN THE LIVER. 1400 00:46:30,940 --> 00:46:32,976 THE VERY DARK BLUE DOTS ARE 1401 00:46:32,976 --> 00:46:36,579 IMMUNE CELLS AS WELL. 1402 00:46:36,579 --> 00:46:39,215 AND THEN AT FOLLOW-UP, THIS 1403 00:46:39,215 --> 00:46:41,117 PERSON HAD A SCORE OF 7, THE 1404 00:46:41,117 --> 00:46:42,585 PERSON ON THE BOTTOM WENT FROM A 1405 00:46:42,585 --> 00:46:43,620 6 TO A 5. 1406 00:46:43,620 --> 00:46:45,288 HERE'S THE TREATMENT GROUPS. 1407 00:46:45,288 --> 00:46:47,056 THESE ARE TWO -- THERE'S OUR 1408 00:46:47,056 --> 00:46:49,259 STELLAR EXAMPLE OF A WOMAN WHO 1409 00:46:49,259 --> 00:46:51,027 WENT FROM 7, AND YOU'RE SEEING 1410 00:46:51,027 --> 00:46:53,329 DEAD CELLS, LOTS OF HOLES 1411 00:46:53,329 --> 00:46:55,198 BASICALLY IN THE TISSUE. 1412 00:46:55,198 --> 00:46:57,700 AND THEN ON THE RIGHT, ONE 1413 00:46:57,700 --> 00:46:59,269 PATHOLOGIST TOLD ME THAT'S THE 1414 00:46:59,269 --> 00:47:00,603 HISTOLOGY OF WHAT LOOKS LIKE A 1415 00:47:00,603 --> 00:47:01,337 COLLEGE ATHLETE. 1416 00:47:01,337 --> 00:47:03,206 THAT'S A NORMAL, HEALTHY LIVER 1417 00:47:03,206 --> 00:47:04,340 THERE ON THE RIGHT. 1418 00:47:04,340 --> 00:47:05,575 THE PERSON ON THE BOTTOM WENT 1419 00:47:05,575 --> 00:47:08,711 FROM A 6 TO A 2. 1420 00:47:08,711 --> 00:47:11,247 HERE ARE FERN'S RESULTS WHICH I 1421 00:47:11,247 --> 00:47:12,148 SHARE WITH YOU WITH HER 1422 00:47:12,148 --> 00:47:13,349 PERMISSION. 1423 00:47:13,349 --> 00:47:16,085 SHE STARTED WITH MACRO AND MICRO 1424 00:47:16,085 --> 00:47:19,455 VEST PARTICULAR STEATOSIS WITH 1425 00:47:19,455 --> 00:47:20,623 HEPATOCELLULAR BALLOONING AND 1426 00:47:20,623 --> 00:47:23,026 DEGENERATION OF THE CELLS. 1427 00:47:23,026 --> 00:47:25,061 HER STEATOHEPATITIS WAS THERE 1428 00:47:25,061 --> 00:47:27,363 AND SHE HAD EARLY BRIDGING 1429 00:47:27,363 --> 00:47:30,967 FIBROSIS FROM ACROSS THE LOBULE. 1430 00:47:30,967 --> 00:47:32,535 SHE LOST WEIGHT. 1431 00:47:32,535 --> 00:47:35,371 HER LIVER FAT WENT TO 2.5%. 1432 00:47:35,371 --> 00:47:37,774 HER PLASMA ALT CAME DOWN. 1433 00:47:37,774 --> 00:47:39,909 HER NASH SCORE DROPPED. 1434 00:47:39,909 --> 00:47:42,178 HER GLUCOSE DISPOSAL WENT UP AS 1435 00:47:42,178 --> 00:47:43,112 A RESULT OF ALL THAT EX-ARE 1436 00:47:43,112 --> 00:47:45,715 SEISE AND HER TRIGLYCERIDES 1437 00:47:45,715 --> 00:47:46,950 DROPPED. 1438 00:47:46,950 --> 00:47:47,817 AFTERWARDS, THIS HIS TOLL GIST 1439 00:47:47,817 --> 00:47:49,552 WHO WAS BLINDED DESCRIBED A 1440 00:47:49,552 --> 00:47:52,021 SIGNIFICANT REDUCTION IN 1441 00:47:52,021 --> 00:47:53,556 STEATOSIS, INFLAMMATION, HE PO 1442 00:47:53,556 --> 00:47:55,959 TOE CELLULAR DEGENERATION WAS 1443 00:47:55,959 --> 00:47:56,426 SIGNIFICANTLY LOWER. 1444 00:47:56,426 --> 00:47:57,427 YOU'RE GOING TO SEE A CRACK IN 1445 00:47:57,427 --> 00:47:59,062 THE TISSUE THERE. 1446 00:47:59,062 --> 00:48:01,464 THAT HAPPENS DURING THE 1447 00:48:01,464 --> 00:48:02,565 HISTOLOGICAL PREP BUT YOU SEE 1448 00:48:02,565 --> 00:48:03,833 MUCH LESS DROPLETS THERE, AND 1449 00:48:03,833 --> 00:48:05,535 WHEN YOU BLOW THIS UP UNDER THE 1450 00:48:05,535 --> 00:48:06,769 MICROSCOPE, YOU CAN SEE THAT THE 1451 00:48:06,769 --> 00:48:12,175 TISSUE IS MUCH MORE INTACT. 1452 00:48:12,175 --> 00:48:14,177 SO I'M GOING TO SHOW YOU A FEW 1453 00:48:14,177 --> 00:48:15,278 PHYSICAL RELATIONSHIPS BETWEEN 1454 00:48:15,278 --> 00:48:16,179 THE OUTCOME VARIABLES. 1455 00:48:16,179 --> 00:48:17,947 THIS IS THE WEIGHT CHANGE WITH 1456 00:48:17,947 --> 00:48:22,518 THE BLUE BEING THE TREATMENT AND 1457 00:48:22,518 --> 00:48:24,320 DE NOVO LIPOGENESIS DROPPING ON 1458 00:48:24,320 --> 00:48:26,990 THE Y AXIS. 1459 00:48:26,990 --> 00:48:30,159 THIS IS DE NOVO LIPOGENESIS AND 1460 00:48:30,159 --> 00:48:34,530 LIVER FAT BY MRI. 1461 00:48:34,530 --> 00:48:35,865 HERE IS THE ACTIVITY SCORE, 1462 00:48:35,865 --> 00:48:38,301 AGAIN THE LOWER THE BETTER, AND 1463 00:48:38,301 --> 00:48:39,268 CARDIORESPIRATORY FITNESS. 1464 00:48:39,268 --> 00:48:41,404 SO AS INDIVIDUALS INCREASE THEIR 1465 00:48:41,404 --> 00:48:43,706 FITNESS ON THE RIGHT, THAT WAS 1466 00:48:43,706 --> 00:48:45,541 ASSOCIATED WITH IMPROVEMENT IN 1467 00:48:45,541 --> 00:48:47,310 LIVER DISEASE, EVEN IF YOU TAKE 1468 00:48:47,310 --> 00:48:49,445 THAT UNBELIEVABLE PERSON THERE 1469 00:48:49,445 --> 00:48:50,947 OUT ON THE RIGHT, THERE'S STILL 1470 00:48:50,947 --> 00:48:51,881 A SIGNIFICANT RELATIONSHIP 1471 00:48:51,881 --> 00:48:53,016 THERE. 1472 00:48:53,016 --> 00:48:55,184 AND THEN LASTLY, A CHANGE IN 1473 00:48:55,184 --> 00:48:57,020 LIVER FAT WITH A CHANGE IN 1474 00:48:57,020 --> 00:49:03,826 HEPATIC GLUCOSE PRODUCTION. 1475 00:49:03,826 --> 00:49:04,594 SO WHAT IS THIS? 1476 00:49:04,594 --> 00:49:05,928 I CALL THIS THE REROUTE 1477 00:49:05,928 --> 00:49:07,163 HYPOTHESIS. 1478 00:49:07,163 --> 00:49:08,731 THIS IS ELIMINATING NUTRIENT 1479 00:49:08,731 --> 00:49:08,998 OVERLOAD. 1480 00:49:08,998 --> 00:49:10,366 IT STARTS WITH ENERGY 1481 00:49:10,366 --> 00:49:11,134 RESTRICTION, REDUCTION IN BODY 1482 00:49:11,134 --> 00:49:14,837 WEIGHT AND INCREASE IN PHYSICAL 1483 00:49:14,837 --> 00:49:15,304 ACTIVITY. 1484 00:49:15,304 --> 00:49:17,106 THAT IN MY VIEW, AND WE HAVE THE 1485 00:49:17,106 --> 00:49:20,610 TISSUE TO TEST THESE GENE 1486 00:49:20,610 --> 00:49:21,778 EXPRESSION, YOU REDUCE 1487 00:49:21,778 --> 00:49:23,880 TRANSCRIPTION FACTORS THAT 1488 00:49:23,880 --> 00:49:25,348 CONTROL LIPOGENESIS. 1489 00:49:25,348 --> 00:49:26,749 YOU REDUCE THE SUBSTRATES TO 1490 00:49:26,749 --> 00:49:29,118 MAKE FATTY ACIDS BECAUSE PEOPLE 1491 00:49:29,118 --> 00:49:32,689 ARE EATING LESS FOOD AND LESS 1492 00:49:32,689 --> 00:49:33,356 CARBOHYDRATE. 1493 00:49:33,356 --> 00:49:35,525 FITNESS CAUSED A REDUCTION IN 1494 00:49:35,525 --> 00:49:37,527 OUR THEORY OF NUTRIENT OVERLOAD 1495 00:49:37,527 --> 00:49:38,961 ON THE LIVER. 1496 00:49:38,961 --> 00:49:41,898 THIS REDUCES LIVER FAT AND CELL 1497 00:49:41,898 --> 00:49:43,332 DEATH. 1498 00:49:43,332 --> 00:49:46,102 IT LOWERS HEPATIC GLUCOSE 1499 00:49:46,102 --> 00:49:47,336 PRODUCTION, AND THEN WE SAW 1500 00:49:47,336 --> 00:49:49,605 REMISSION OF NASH AND 1501 00:49:49,605 --> 00:49:50,606 PREDIABETES AND DIABETES IN THIS 1502 00:49:50,606 --> 00:49:58,281 POPULATION. 1503 00:49:58,281 --> 00:49:59,649 SO I JUST GOT A BUNCH OF PAPERS 1504 00:49:59,649 --> 00:50:00,917 TO SHOW YOU THIS HISTORICAL 1505 00:50:00,917 --> 00:50:01,184 ROUTE. 1506 00:50:01,184 --> 00:50:05,421 WE STARTED BY DEFINING SUGAR 1507 00:50:05,421 --> 00:50:06,989 STIMULATION OF LIPOGENESIS IN 1508 00:50:06,989 --> 00:50:07,990 HEALTHY INDIVIDUALS. 1509 00:50:07,990 --> 00:50:09,358 PEOPLE THOUGHT LIPOGENESIS WAS 1510 00:50:09,358 --> 00:50:11,494 ZERO IN HUMANS. 1511 00:50:11,494 --> 00:50:13,930 AND MY ENTIRE POSTDOC, I DID IN 1512 00:50:13,930 --> 00:50:14,363 FASTED INDIVIDUALS. 1513 00:50:14,363 --> 00:50:15,698 THEY WERE FASTED FOR 20 HOURS 1514 00:50:15,698 --> 00:50:17,467 AND THEN I MEASURED LIPOGENESIS. 1515 00:50:17,467 --> 00:50:19,569 AND IT WAS VERY LOW. 1516 00:50:19,569 --> 00:50:21,204 IT TURNS OUT WHEN YOU BEGIN TO 1517 00:50:21,204 --> 00:50:22,405 EAT, IT TURNS ON. 1518 00:50:22,405 --> 00:50:23,973 THEN WE DISCOVER THAT 1519 00:50:23,973 --> 00:50:25,641 LIPOGENESIS WAS ELEVATED IN 1520 00:50:25,641 --> 00:50:29,445 PATIENTS WITH LIVER DISEASE. 1521 00:50:29,445 --> 00:50:31,414 AND THEN WE ALSO SHOW THAT IT 1522 00:50:31,414 --> 00:50:34,217 HAD LOST ITS CIRCADIAN RHYTHM. 1523 00:50:34,217 --> 00:50:36,352 WE'VE TESTED M MITOCHONDRIA FROM 1524 00:50:36,352 --> 00:50:38,054 THE LIVERS OF INDIVIDUALS WHO 1525 00:50:38,054 --> 00:50:40,790 BEFORE AND AFTER WEIGHT LOSS AND 1526 00:50:40,790 --> 00:50:43,426 WE'VE QUANTIFIED THE 1527 00:50:43,426 --> 00:50:45,061 MITOCHONDRIAL ACTIVITY AND SHOWN 1528 00:50:45,061 --> 00:50:47,330 THAT IT IS IMPROVED WITH WEIGHT 1529 00:50:47,330 --> 00:50:49,265 LOSS AND EXERCISE. 1530 00:50:49,265 --> 00:50:53,102 I SHOWED YOU THE INIFA MODEL, 1531 00:50:53,102 --> 00:50:57,073 AND WE HAVE SPENT A LOT OF TIME 1532 00:50:57,073 --> 00:51:02,345 MO MODELING DIETARY FATTEN TRI D 1533 00:51:02,345 --> 00:51:03,312 REMOVAL FROM BLOOD. 1534 00:51:03,312 --> 00:51:06,015 WE PERFORMED PHARMACEUTICAL 1535 00:51:06,015 --> 00:51:07,784 STUDIES SO SHOW THAT REDUCTIONS 1536 00:51:07,784 --> 00:51:09,252 IN LIPOGENESIS WITH MEDICATION 1537 00:51:09,252 --> 00:51:10,653 LOWERS LIVER FAT, AND THEN WE'VE 1538 00:51:10,653 --> 00:51:11,888 ALSO COLLABORATED WITH PEOPLE 1539 00:51:11,888 --> 00:51:18,261 HERE AT THE NIH STUDYING SPECIAL 1540 00:51:18,261 --> 00:51:20,129 POPULATIONS, WE'VE DONE STUDIES 1541 00:51:20,129 --> 00:51:22,632 IN ISOTOPES IN WOMEN WHO ARE 1542 00:51:22,632 --> 00:51:23,733 LACTATING AND THEN GENETIC 1543 00:51:23,733 --> 00:51:26,836 CAUSES OF FATTY LIVER. 1544 00:51:26,836 --> 00:51:29,472 SO IN SUMMARY, LIPOGENESIS 1545 00:51:29,472 --> 00:51:31,607 STIMULATED BY DIETARY SUGAR, AND 1546 00:51:31,607 --> 00:51:32,909 IN PARTICULAR LIQUID SUGAR 1547 00:51:32,909 --> 00:51:35,545 INTAKE AS OPPOSED TO RICE OR 1548 00:51:35,545 --> 00:51:35,978 BEANS. 1549 00:51:35,978 --> 00:51:41,751 COOL LKOOL-AID IS A LOT WORSE TN 1550 00:51:41,751 --> 00:51:45,555 SOLID CARBS. 1551 00:51:45,555 --> 00:51:50,993 SUGARS IN ALCOHOL STILL WERE THE 1552 00:51:50,993 --> 00:51:52,195 DRIVING FORCE IN THAT STUDY. 1553 00:51:52,195 --> 00:51:53,863 THE INDIVIDUALS WHO HAD THE 1554 00:51:53,863 --> 00:51:54,697 GREATEST LIPOGENESIS, IT WASN'T 1555 00:51:54,697 --> 00:51:56,098 THAT THEY CONSUMED THE MOST 1556 00:51:56,098 --> 00:51:56,532 ALCOHOL. 1557 00:51:56,532 --> 00:51:59,035 IT WAS SUGAR INTAKE. 1558 00:51:59,035 --> 00:52:02,538 ABOVE ALL ELSE, METABOLICALLY 1559 00:52:02,538 --> 00:52:04,340 ASSOCIATED STEE A TOE HEPATITIS 1560 00:52:04,340 --> 00:52:06,409 IS DISTINCTLY CHARACTERIZED BY 1561 00:52:06,409 --> 00:52:08,144 AN UPREGULATION IN THIS 1562 00:52:08,144 --> 00:52:09,412 BIOCHEMICAL PATHWAY. 1563 00:52:09,412 --> 00:52:11,147 AND IT'S LOST ITS CIRCADIAN 1564 00:52:11,147 --> 00:52:11,614 RHYTHM. 1565 00:52:11,614 --> 00:52:12,882 IT SHOULD BE SUPPRESSED AT NIGHT 1566 00:52:12,882 --> 00:52:14,550 AND DURING FASTING, AND THE 1567 00:52:14,550 --> 00:52:18,120 SUPPRESSION IS MISSING IN 1568 00:52:18,120 --> 00:52:19,655 PATIENTS. 1569 00:52:19,655 --> 00:52:21,157 IT'S AS IF THEIR LEVELS IN THE 1570 00:52:21,157 --> 00:52:22,158 FASTING STATE ARE VERY HIGH AND 1571 00:52:22,158 --> 00:52:23,526 THEY DON'T GET BETTER. 1572 00:52:23,526 --> 00:52:24,493 THERE'S A CEILING. 1573 00:52:24,493 --> 00:52:28,097 THEY DON'T GET HIGHER THAN ABOUT 1574 00:52:28,097 --> 00:52:28,631 40 TO 50%. 1575 00:52:28,631 --> 00:52:30,433 THEY NEVER GO UP BUT THEY ALSO 1576 00:52:30,433 --> 00:52:36,239 DON'T GO DOWN. 1577 00:52:36,239 --> 00:52:37,874 HIGH LEVELS OF DE NOVO 1578 00:52:37,874 --> 00:52:38,741 LIPOGENESIS ARE ASSOCIATED WITH 1579 00:52:38,741 --> 00:52:40,443 HIGHER LEVELS OF LIVER DISEASE. 1580 00:52:40,443 --> 00:52:42,178 REMOVING TO TOXICITY IN THE LIVR 1581 00:52:42,178 --> 00:52:42,845 CAN RESOLVE THIS. 1582 00:52:42,845 --> 00:52:45,815 AND I WANT TO END BY EMPHASIZING 1583 00:52:45,815 --> 00:52:48,017 THE IDEA OF MEASURING FLUX. 1584 00:52:48,017 --> 00:52:51,754 THAT'S OUR LAB MOTTO AND MY 1585 00:52:51,754 --> 00:52:52,588 UNDERGRADS MAKE SURE I SAY THAT 1586 00:52:52,588 --> 00:52:53,055 EVERY TIME. 1587 00:52:53,055 --> 00:52:55,424 WE WOULD HAVE NO DATA IF A 1588 00:52:55,424 --> 00:52:56,192 PERSON DIDN'T RAISE THEIR HAND 1589 00:52:56,192 --> 00:52:58,761 TO BE IN OUR STUDIES, AND MOST 1590 00:52:58,761 --> 00:53:01,397 APPRECIATION GOES TO THEM. 1591 00:53:01,397 --> 00:53:03,132 OUR FUNDING, THESE ARE THE 1592 00:53:03,132 --> 00:53:05,501 INDIVIDUALS IN MY LABORATORY WHO 1593 00:53:05,501 --> 00:53:07,236 HAVE GENERATED THE DATA. 1594 00:53:07,236 --> 00:53:08,571 THE 51 STUDENTS WHO COME IN -- 1595 00:53:08,571 --> 00:53:10,806 HAVE COME IN OVER THE YEARS, AND 1596 00:53:10,806 --> 00:53:11,908 ONE ASKED ME ONCE IF I WAS GOING 1597 00:53:11,908 --> 00:53:13,109 TO WIN THE NOBEL PRIZE. 1598 00:53:13,109 --> 00:53:15,745 YOU KNOW, THEY GET TURNED ONTO 1599 00:53:15,745 --> 00:53:16,779 SCIENCE AND THEY REALIZE WHAT 1600 00:53:16,779 --> 00:53:18,514 YOU'RE DOING. 1601 00:53:18,514 --> 00:53:19,615 AND THEN THINGS GET REALLY, 1602 00:53:19,615 --> 00:53:23,019 REALLY FUN. 1603 00:53:23,019 --> 00:53:24,487 STAFF, AND THEN THESE ARE THE 1604 00:53:24,487 --> 00:53:26,555 UNIVERSITY OF MISSOURI 1605 00:53:26,555 --> 00:53:27,890 COLLABORATORS. 1606 00:53:27,890 --> 00:53:29,859 STATISTICIANS, HEPATOLOGISTS, WE 1607 00:53:29,859 --> 00:53:30,893 REALLY DO THIS ALL TOGETHER. 1608 00:53:30,893 --> 00:53:32,528 AND THEN THE COLLABORATORS FROM 1609 00:53:32,528 --> 00:53:35,831 OTHER PLACES, U.T. SOUTHWESTERN 1610 00:53:35,831 --> 00:53:37,433 MEDICAL CENTER AND THE NIH 1611 00:53:37,433 --> 00:53:38,801 OKLAHOMA HEALTH SCIENCES, AND 1612 00:53:38,801 --> 00:53:40,136 THE UNIVERSITY OF COLORADO. 1613 00:53:40,136 --> 00:53:41,003 I'LL STOP THERE. 1614 00:53:41,003 --> 00:53:41,704 THANK YOU VERY MUCH. 1615 00:53:41,704 --> 00:53:50,012 [APPLAUSE] 1616 00:53:50,012 --> 00:53:51,580 >> THANK YOU VERY MUCH FOR A 1617 00:53:51,580 --> 00:53:52,248 FANTASTIC TALK. 1618 00:53:52,248 --> 00:53:53,749 FOR THOSE WHO ARE IN THE ROOM, 1619 00:53:53,749 --> 00:53:55,318 IF YOU HAVE QUESTIONS, PLEASE 1620 00:53:55,318 --> 00:54:00,623 COME UP TO THE MICROPHONE, AND 1621 00:54:00,623 --> 00:54:03,059 THEN IS DR. PARIK HERE 1622 00:54:03,059 --> 00:54:03,793 MONITORING -- OKAY, THANK YOU. 1623 00:54:03,793 --> 00:54:04,694 SO LET US KNOW. 1624 00:54:04,694 --> 00:54:05,695 IS SOMEBODY COMING UP WITH A 1625 00:54:05,695 --> 00:54:08,664 QUESTION? 1626 00:54:08,664 --> 00:54:13,202 >> I HAVE A QUESTION. 1627 00:54:13,202 --> 00:54:15,404 YOU SAID IN YOUR PEN ULTIMATE 1628 00:54:15,404 --> 00:54:18,341 SLIDE THAT SENSITIVE INDIVIDUALS 1629 00:54:18,341 --> 00:54:21,711 HAVE MORE SUGAR SENSITIVITY TO 1630 00:54:21,711 --> 00:54:22,578 FAT DEPOSITION. 1631 00:54:22,578 --> 00:54:26,582 I KIND OF MISSED, SENSITIVE IS 1632 00:54:26,582 --> 00:54:28,551 CHARACTERIZED BY YOUR RATIO, KI 1633 00:54:28,551 --> 00:54:29,652 OVER KM? 1634 00:54:29,652 --> 00:54:31,220 OR HOW ARE YOU CHARACTERIZING 1635 00:54:31,220 --> 00:54:35,424 THAT SENSITIVITY? 1636 00:54:35,424 --> 00:54:36,759 >> I'VE SHOWN ABOUT FOUR 1637 00:54:36,759 --> 00:54:38,661 DIFFERENT WAYS -- SO I WASN'T 1638 00:54:38,661 --> 00:54:41,297 SPECIFIC WHEN I USED THAT TERM. 1639 00:54:41,297 --> 00:54:44,233 SENSITIVE CAN BE THAT THEY TURN 1640 00:54:44,233 --> 00:54:46,102 ON LIPOGENESIS VERY QUICKLY, OR 1641 00:54:46,102 --> 00:54:47,570 THAT THEY NEVER TURN IT OFF. 1642 00:54:47,570 --> 00:54:48,871 IT COULD BE BOTH OF THOSE 1643 00:54:48,871 --> 00:54:49,405 THINGS. 1644 00:54:49,405 --> 00:54:53,776 WE KNOW THAT IN THE LIVER, 1645 00:54:53,776 --> 00:54:55,945 INSULIN SHOULD TURN OFF GLUCOSE 1646 00:54:55,945 --> 00:54:58,114 PRODUCTION AND TURN ON 1647 00:54:58,114 --> 00:54:58,781 LIPOGENESIS, AND INDIVIDUALS 1648 00:54:58,781 --> 00:55:02,585 APPEAR TO BE INSULIN RESISTANT 1649 00:55:02,585 --> 00:55:03,953 IN THE GLUCOSE SIDE OF THAT, 1650 00:55:03,953 --> 00:55:05,588 THEY KEEP PUTTING GLUCOSE OUT, 1651 00:55:05,588 --> 00:55:07,256 BUT THEY'RE SENSITIVE WITH 1652 00:55:07,256 --> 00:55:09,125 RESPECT TO FATTY ACID SYNTHESIS, 1653 00:55:09,125 --> 00:55:12,461 SO THERE'S THIS DICHOTOMY IN 1654 00:55:12,461 --> 00:55:13,763 SENSITIVITY IN THE LIVER. 1655 00:55:13,763 --> 00:55:17,166 >> GREAT, THANKS. 1656 00:55:17,166 --> 00:55:18,501 >> THAT WAS REALLY WONDERFUL. 1657 00:55:18,501 --> 00:55:19,201 THANK YOU SO MUCH. 1658 00:55:19,201 --> 00:55:19,635 SO CLEAR. 1659 00:55:19,635 --> 00:55:20,369 >> THANK YOU. 1660 00:55:20,369 --> 00:55:23,339 >> AND SO MY QUESTION, YOU KNOW 1661 00:55:23,339 --> 00:55:25,174 I'M INTERESTED IN THE POST 1662 00:55:25,174 --> 00:55:28,344 WEIGHT REDUCED STATE. 1663 00:55:28,344 --> 00:55:29,745 YOU'VE RECOVERED SOME OF THAT 1664 00:55:29,745 --> 00:55:32,581 METABOLIC FLEXIBILITY, YOU'VE 1665 00:55:32,581 --> 00:55:34,517 GOTTEN RID OF SOME OF THE FAT, 1666 00:55:34,517 --> 00:55:36,252 YOU SUPPRESSED THE DE NOVO 1667 00:55:36,252 --> 00:55:37,253 LIPOGENESIS WHEN THE CALORIE 1668 00:55:37,253 --> 00:55:38,087 INTAKE IS LOW. 1669 00:55:38,087 --> 00:55:40,923 SO ON THE BACKGROUND OF THAT, 1670 00:55:40,923 --> 00:55:46,829 THESE PATIENTS ARE SO IMPROVED 1671 00:55:46,829 --> 00:55:49,165 THEN WHAT HAPPENS IF THEY DO 1672 00:55:49,165 --> 00:55:50,699 REBOUND WITH THEIR EATING? 1673 00:55:50,699 --> 00:55:54,203 ESPECIALLY IN THIS ERA NOW WHERE 1674 00:55:54,203 --> 00:55:55,805 PEOPLE ARE TAKING ALL THESE 1675 00:55:55,805 --> 00:55:57,339 DRUGS TO SUPPRESS THEIR FOOD 1676 00:55:57,339 --> 00:55:59,408 INTAKE, WHAT HAPPENS THEN IF 1677 00:55:59,408 --> 00:56:00,376 THEY GO OFF THE DRUG? 1678 00:56:00,376 --> 00:56:02,078 >> NO ONE HAS -- THE QUESTION IS 1679 00:56:02,078 --> 00:56:03,612 ABOUT THE REBOUND IN BODY WEIGHT 1680 00:56:03,612 --> 00:56:04,713 THAT CAN OCCUR. 1681 00:56:04,713 --> 00:56:06,849 NO ONE TO MY KNOWLEDGE HAS 1682 00:56:06,849 --> 00:56:07,850 MEASURED LIPOGENESIS AFTER 1683 00:56:07,850 --> 00:56:12,788 WEIGHT REGAIN. 1684 00:56:12,788 --> 00:56:15,057 I THINK OF LIPOGENESIS AS ECK 1685 00:56:15,057 --> 00:56:16,692 QIS ITALY SENSITIVE TO RECENT 1686 00:56:16,692 --> 00:56:17,626 FOOD INTAKE. 1687 00:56:17,626 --> 00:56:19,595 SO MY SENSE WOULD BE, THE MINUTE 1688 00:56:19,595 --> 00:56:21,330 THAT BODY WEIGHT START TO COME 1689 00:56:21,330 --> 00:56:23,833 BACK UP, THAT MEANS CALORIC 1690 00:56:23,833 --> 00:56:27,636 INTAKE IS UP, FATTY LIVER COMES 1691 00:56:27,636 --> 00:56:28,537 BACK, LIPOGENESIS WILL COME 1692 00:56:28,537 --> 00:56:28,971 BACK. 1693 00:56:28,971 --> 00:56:30,906 BUT WE'VE FOUND THAT THIS 1694 00:56:30,906 --> 00:56:34,510 PATHWAY DRIVES LIVER FAT ACCRUAL 1695 00:56:34,510 --> 00:56:36,011 REGARDLESS OF AGE, IT'S BEEN 1696 00:56:36,011 --> 00:56:40,483 SHOWN IN CHILDREN, SEX, RACE AND 1697 00:56:40,483 --> 00:56:41,450 ETHNICITY, IN INDIVIDUALS WHO 1698 00:56:41,450 --> 00:56:43,085 HAVE EXCESS LIVER FAT, THE 1699 00:56:43,085 --> 00:56:43,986 PATHWAY IS ON. 1700 00:56:43,986 --> 00:56:47,690 SO IT SEEMS TO BE VERY, VERY 1701 00:56:47,690 --> 00:56:49,825 SENSITIVE TO EXCESS ENERGY. 1702 00:56:49,825 --> 00:56:52,228 RIGHT THERE. 1703 00:56:52,228 --> 00:56:53,963 SO MY PREDICTION WOULD BE THAT 1704 00:56:53,963 --> 00:56:55,698 IT WOULD COME BACK EASILY. 1705 00:56:55,698 --> 00:56:57,566 WHEN YOU THINK ABOUT IT, THE 1706 00:56:57,566 --> 00:56:58,868 INDIVIDUALS WHO LOST 10% OF 1707 00:56:58,868 --> 00:57:00,970 THEIR BODY WEIGHT, THEY ARE 1708 00:57:00,970 --> 00:57:03,105 STILL IN THE OVERWEIGHT OBESE 1709 00:57:03,105 --> 00:57:03,506 CATEGORY. 1710 00:57:03,506 --> 00:57:08,878 SO IT'S THAT SET OF FOOD INTAKE 1711 00:57:08,878 --> 00:57:10,646 THAT'S REDUCING LIPOGENESIS. 1712 00:57:10,646 --> 00:57:14,950 THEY ALSO PROBABLY TOOK 10 TO 15 1713 00:57:14,950 --> 00:57:17,820 YEARS TO GET LIVER DISEASE, AN 1714 00:57:17,820 --> 00:57:20,523 TO SEE A BIOPSY SHOW LACK OF ANY 1715 00:57:20,523 --> 00:57:22,358 DISEASE NINE MONTHS LATER IS 1716 00:57:22,358 --> 00:57:23,993 ASTOUNDING TO ME. 1717 00:57:23,993 --> 00:57:25,961 AND WE'VE EVEN TALKED IN THE LAB 1718 00:57:25,961 --> 00:57:26,629 ABOUT WHETHER OR NOT THERE WOULD 1719 00:57:26,629 --> 00:57:30,633 BE A MEMORY, JUST AS INSULIN 1720 00:57:30,633 --> 00:57:34,003 TREATMENT EARLY IN DIABETES HAS 1721 00:57:34,003 --> 00:57:36,539 A MEMORY THAT IF WE CAN IMPROVE 1722 00:57:36,539 --> 00:57:40,109 THE LIVER, WILL IT TAKE AS MUCH 1723 00:57:40,109 --> 00:57:42,945 TIME TO GET BACK TO THE SAME 1724 00:57:42,945 --> 00:57:43,579 DISEASE STATE? 1725 00:57:43,579 --> 00:57:45,247 WILL IT TAKE LONGER? 1726 00:57:45,247 --> 00:57:46,882 HOW LONG WILL THESE BENEFITS 1727 00:57:46,882 --> 00:57:48,250 LAST? 1728 00:57:48,250 --> 00:57:49,985 AND SO I THINK ALTHOUGH 1729 00:57:49,985 --> 00:57:53,923 LIPOGENESIS ITSELF IS REALLY 1730 00:57:53,923 --> 00:57:58,260 SENSITIVE TO IMMEDIATE INTAKE, 1731 00:57:58,260 --> 00:57:59,895 ALL THE OTHER BENEFITS THEY DID 1732 00:57:59,895 --> 00:58:00,763 FOR NINE MONTHS ARE GOING TO 1733 00:58:00,763 --> 00:58:01,330 LAST LONGER. 1734 00:58:01,330 --> 00:58:02,731 >> WELL, AND THERE'S ALL THIS 1735 00:58:02,731 --> 00:58:07,836 INTEREST NOW IN INTERMITTENT 1736 00:58:07,836 --> 00:58:08,070 FASTING. 1737 00:58:08,070 --> 00:58:09,538 >> LIPOGENESIS HAS NOT BEEN 1738 00:58:09,538 --> 00:58:11,073 MEASURED IN INTERMITTENT 1739 00:58:11,073 --> 00:58:12,374 FASTING, AND OF COURSE MY 1740 00:58:12,374 --> 00:58:14,810 PREDICTION WOULD BE THAT 1741 00:58:14,810 --> 00:58:16,812 PERIODS, LONGER PERIODS OF 1742 00:58:16,812 --> 00:58:17,479 FASTING WOULD REDUCE THE 1743 00:58:17,479 --> 00:58:23,819 PATHWAY. 1744 00:58:23,819 --> 00:58:25,354 >> DO WE HAVE ANY QUESTIONS THAT 1745 00:58:25,354 --> 00:58:26,689 HAVE BEEN POSTED THROUGH THE 1746 00:58:26,689 --> 00:58:27,256 WEBSITE? 1747 00:58:27,256 --> 00:58:27,623 NOTHING YET? 1748 00:58:27,623 --> 00:58:28,023 OKAY. 1749 00:58:28,023 --> 00:58:29,792 I'M GOING TO TAKE ADVANTAGE OF 1750 00:58:29,792 --> 00:58:30,559 BEING HERE TO ASK YOU A 1751 00:58:30,559 --> 00:58:31,060 QUESTION. 1752 00:58:31,060 --> 00:58:32,661 SO I HAVE A STRONG INTEREST IN 1753 00:58:32,661 --> 00:58:35,097 THE EFFECTS OF INSULIN ON LIPID 1754 00:58:35,097 --> 00:58:36,332 METABOLISM, AND I WAS VERY 1755 00:58:36,332 --> 00:58:39,668 EXCITED TO SEE YOUR INEFA DATA. 1756 00:58:39,668 --> 00:58:40,769 I'M WONDERING IF YOU CAN 1757 00:58:40,769 --> 00:58:42,204 SPECULATE ON THE MECHANISMS BY 1758 00:58:42,204 --> 00:58:44,673 WHICH INSULIN IS INCREASING 1759 00:58:44,673 --> 00:58:47,977 FATTY ACID UPTAKE BY THE MUSCLE. 1760 00:58:47,977 --> 00:58:50,412 >> THERE HAVE BEEN A NUMBER OF 1761 00:58:50,412 --> 00:58:52,815 STUDIES, CLAMP STUDY WITH MUSCLE 1762 00:58:52,815 --> 00:58:54,583 BIOPSY THAT SAYS CD36 IS 1763 00:58:54,583 --> 00:58:56,652 CONTROLLED BY INSULIN SO THE 1764 00:58:56,652 --> 00:58:58,153 FATTY ACID TRANSPORTER ARE 1765 00:58:58,153 --> 00:58:59,555 INCREASED WITH INSULIN ACUTELY 1766 00:58:59,555 --> 00:59:00,789 WITH MEALS. 1767 00:59:00,789 --> 00:59:03,158 ALL THE TRIGLYCERIDE 1768 00:59:03,158 --> 00:59:05,628 SYNTHESIZING ENZYMES, ALL OF 1769 00:59:05,628 --> 00:59:07,162 THOSE ARE STIMULATED BY INSULIN 1770 00:59:07,162 --> 00:59:11,467 AS WELL, SO I THINK FOR ME, WE 1771 00:59:11,467 --> 00:59:12,701 KNOW A LOT ABOUT INSULIN 1772 00:59:12,701 --> 00:59:14,470 RESISTANCE TO GLUCOSE AT THE 1773 00:59:14,470 --> 00:59:14,770 MUSCLE. 1774 00:59:14,770 --> 00:59:16,438 I'M INTERESTED IN INSULIN 1775 00:59:16,438 --> 00:59:18,474 RESISTANCE TO FATTY ACID UPTAKE 1776 00:59:18,474 --> 00:59:19,508 AT THE MUSCLE. 1777 00:59:19,508 --> 00:59:21,076 AS WELL. 1778 00:59:21,076 --> 00:59:23,912 AND AGAIN, THAT REBOUND AFTER AN 1779 00:59:23,912 --> 00:59:26,282 ORAL GLUCOSE TOLERANCE TEST OR 1780 00:59:26,282 --> 00:59:28,450 AN INTRAVENOUS GLUCOSE TOLERANCE 1781 00:59:28,450 --> 00:59:30,753 TEST, WHEN ADIPOSE HAS BEEN 1782 00:59:30,753 --> 00:59:32,488 TURNED OFF FOR THREE, FOUR HOURS 1783 00:59:32,488 --> 00:59:33,789 AND THEN IT START TO RELEASE 1784 00:59:33,789 --> 00:59:35,591 FATTY ACIDS, YOU END UP WITH A 1785 00:59:35,591 --> 00:59:36,925 FREE FATTY ACID CONCENTRATION 1786 00:59:36,925 --> 00:59:37,459 HIGHER THAN FASTING. 1787 00:59:37,459 --> 00:59:39,762 SO THERE IS A CONTROL THERE THAT 1788 00:59:39,762 --> 00:59:42,398 IS NOT STRAIGHTFORWARD, TURN 1789 00:59:42,398 --> 00:59:43,565 ADIPOSE OFF, TURN IT ON AGAIN. 1790 00:59:43,565 --> 00:59:46,201 THERE'S SOMETHING ELSE GOING ON. 1791 00:59:46,201 --> 00:59:48,237 >> DR. PARKS, I JUST WANT TO 1792 00:59:48,237 --> 00:59:50,506 CONGRATULATE YOU FIRST OF ALL ON 1793 00:59:50,506 --> 00:59:53,342 THIS WONDERFUL BODY OF WORK AND 1794 00:59:53,342 --> 00:59:54,810 SORT OF TAKING US THROUGH THIS 1795 00:59:54,810 --> 00:59:55,944 JOURNEY OF LEARNING OVER THE 1796 00:59:55,944 --> 00:59:56,812 LAST COUPLE OF DECADES. 1797 00:59:56,812 --> 00:59:58,480 I KNOW IT'S BEEN A LOT AND WE 1798 00:59:58,480 --> 00:59:59,281 ALL APPRECIATE IT. 1799 00:59:59,281 --> 01:00:03,285 I THINK MY QUESTION GOES TO THE 1800 01:00:03,285 --> 01:00:05,521 REGULATORS OF DNL, AND YOU SHOW 1801 01:00:05,521 --> 01:00:07,222 PRETTY CONVINCINGLY THAT SUGARS 1802 01:00:07,222 --> 01:00:08,991 ARE AN IMPORTANT PART OF THAT. 1803 01:00:08,991 --> 01:00:10,426 I KEEP GOING BACK TO THE SECOND 1804 01:00:10,426 --> 01:00:11,794 OR THIRD SLIDE YOU SHOWED WITH 1805 01:00:11,794 --> 01:00:14,630 THE ATHLETE YOU MENTIONED. 1806 01:00:14,630 --> 01:00:16,165 IS THERE ANYTHING ELSE? 1807 01:00:16,165 --> 01:00:19,768 COULD THERE ALSO BE A GENOTYPE 1808 01:00:19,768 --> 01:00:22,004 DIFFERENCE OR EPIGENETIC 1809 01:00:22,004 --> 01:00:24,206 INFLUENCES THAT WOULD ALTER DNL 1810 01:00:24,206 --> 01:00:25,741 RATE OR PROPENSITY FOR -- 1811 01:00:25,741 --> 01:00:27,443 >> THANK YOU FOR ASKING THE 1812 01:00:27,443 --> 01:00:29,411 QUESTION ABOUT GENOTYPE. 1813 01:00:29,411 --> 01:00:30,746 AND I'VE SAID THIS THE LAST 1814 01:00:30,746 --> 01:00:32,881 YEAR, I THINK, TWICE IN TALKS. 1815 01:00:32,881 --> 01:00:34,516 NO ONE HAS MEASURED LIPOGENESIS 1816 01:00:34,516 --> 01:00:35,617 IN FAMILIES. 1817 01:00:35,617 --> 01:00:37,486 WE DON'T KNOW HOW HERITABLE IT 1818 01:00:37,486 --> 01:00:38,120 IS. 1819 01:00:38,120 --> 01:00:41,390 IT'S A HUGE GAP. 1820 01:00:41,390 --> 01:00:42,825 AND ALSO TO SEE THE SUBJECTS, 1821 01:00:42,825 --> 01:00:44,560 THE FEW SUBJECTS WITH FATTY 1822 01:00:44,560 --> 01:00:48,163 LIVER WHO LOST WEIGHT, 1823 01:00:48,163 --> 01:00:49,565 EQUIVALENT AMOUNTS OF WEIGHT BUT 1824 01:00:49,565 --> 01:00:50,966 THEIR LIVER FAT DIDN'T COME WAY, 1825 01:00:50,966 --> 01:00:53,168 WAY DOWN, THEY JUST SAT THERE AT 1826 01:00:53,168 --> 01:00:54,336 7%, WHAT'S GOING ON WITH THEM? 1827 01:00:54,336 --> 01:00:55,871 BECAUSE THEY HAD IMPROVEMENTS IN 1828 01:00:55,871 --> 01:00:57,606 INSULIN SENSITIVITY. 1829 01:00:57,606 --> 01:01:00,743 AND SO I THINK FOR ME, THAT'S 1830 01:01:00,743 --> 01:01:02,077 THE FUTURE BECAUSE IT WILL HELP 1831 01:01:02,077 --> 01:01:06,548 US UNDERSTAND HOW TO TREAT FATTY 1832 01:01:06,548 --> 01:01:08,317 LIVER DISEASE SPECIFICALLY 1833 01:01:08,317 --> 01:01:10,018 TARGETING THE FLUX -- PATHWAY. 1834 01:01:10,018 --> 01:01:11,520 THERE ARE ARGUMENTS IN MY FIELD 1835 01:01:11,520 --> 01:01:12,721 OF WHETHER IT'S INSULIN THAT 1836 01:01:12,721 --> 01:01:15,958 TURNS ON LIPID SYNTHESIS OR 1837 01:01:15,958 --> 01:01:18,026 HORMONE CHRBP OR IS IT JUST 1838 01:01:18,026 --> 01:01:21,196 CARBONS FLOWING DOWN GLYCOLYSIS. 1839 01:01:21,196 --> 01:01:22,498 AND FRUCTOSE, YOU MIGHT 1840 01:01:22,498 --> 01:01:25,000 REMEMBER, ENTERS GLYCOLYSIS 1841 01:01:25,000 --> 01:01:26,068 AFTER THE CONTROL STEP, WHICH IS 1842 01:01:26,068 --> 01:01:27,302 AT THE TOP. 1843 01:01:27,302 --> 01:01:29,905 YOU'VE GOT A POLICEMAN AT THE 1844 01:01:29,905 --> 01:01:31,640 TOP AND SOMEONE COMING IN ON THE 1845 01:01:31,640 --> 01:01:33,275 STREET IN THE MIDDLE. 1846 01:01:33,275 --> 01:01:34,476 SO IT DOESN'T MATTER HOW MUCH 1847 01:01:34,476 --> 01:01:36,612 CONTROL YOU GIVE, FRUCTOSE 1848 01:01:36,612 --> 01:01:38,280 FLOODS THE GLYCOLYTIC PATHWAY 1849 01:01:38,280 --> 01:01:40,015 AND IT IS THE MOST LIPOGENIC AND 1850 01:01:40,015 --> 01:01:41,850 AS YOU KNOW, IT DOESN'T RAISE 1851 01:01:41,850 --> 01:01:43,085 INSULIN VERY MUCH, SO THERE ARE 1852 01:01:43,085 --> 01:01:44,920 A LOT OF DATA TO SUGGEST IT'S 1853 01:01:44,920 --> 01:01:47,289 SIMPLY TOO MANY CARBONS, TOO 1854 01:01:47,289 --> 01:01:48,590 MUCH GOING DOWN THROUGH 1855 01:01:48,590 --> 01:01:49,491 GLYCOLYSIS. 1856 01:01:49,491 --> 01:01:50,359 >> THANK YOU. 1857 01:01:50,359 --> 01:01:53,529 >> THANKS. 1858 01:01:53,529 --> 01:01:55,631 >> HI, DR. PARKS. 1859 01:01:55,631 --> 01:01:57,099 I'VE BEEN A FAN OF YOURS 1860 01:01:57,099 --> 01:01:57,666 FOREVER. 1861 01:01:57,666 --> 01:01:58,200 BRILLIANT WORK. 1862 01:01:58,200 --> 01:02:01,336 I DID MY PH.D. IN FATTY LIVER, 1863 01:02:01,336 --> 01:02:03,639 SO I SO APPRECIATE YOUR 1864 01:02:03,639 --> 01:02:04,206 CONTRIBUTIONS. 1865 01:02:04,206 --> 01:02:05,274 THIS HAS BEEN A BURNING 1866 01:02:05,274 --> 01:02:07,409 QUESTION, AND I WAS ASKED IN MY 1867 01:02:07,409 --> 01:02:09,178 COMPREHENSIVE EXAMS, AND I SAID 1868 01:02:09,178 --> 01:02:10,179 ONE DAY I'M GOING TO SEE HER AND 1869 01:02:10,179 --> 01:02:11,814 I'M GOING TO ASK HER THIS. 1870 01:02:11,814 --> 01:02:13,749 YOU PROBABLY KNOW IT. 1871 01:02:13,749 --> 01:02:16,151 BUT I THINK MY QUESTION HAS 1872 01:02:16,151 --> 01:02:18,320 ALWAYS BEEN, YOU KNOW, WE THINK 1873 01:02:18,320 --> 01:02:19,855 THAT FATTY LIVER AND ALL OF THE 1874 01:02:19,855 --> 01:02:22,891 WAYS THAT IT IS IS THIS 1875 01:02:22,891 --> 01:02:23,592 INCREASED DEPOSITION OF FAT IN 1876 01:02:23,592 --> 01:02:25,761 THE LIVER, AND WE THINK OF 1877 01:02:25,761 --> 01:02:26,929 PATIENTS WITH FATTY LIVER AS A 1878 01:02:26,929 --> 01:02:30,199 FAILURE OF TH GETTING THAT FAT . 1879 01:02:30,199 --> 01:02:31,567 AND SOMETHING THAT'S ALWAYS 1880 01:02:31,567 --> 01:02:32,334 PERPLEXED ME AND I THINK IT BEEN 1881 01:02:32,334 --> 01:02:33,435 IN THE LITERATURE AS WELL IS 1882 01:02:33,435 --> 01:02:35,304 THAT WE SEE INCREASES IN DNL 1883 01:02:35,304 --> 01:02:37,673 THAT YOU'VE NOTED ACROSS THE 1884 01:02:37,673 --> 01:02:39,775 BOARD, BUT WHAT HAPPENS TO VLDL 1885 01:02:39,775 --> 01:02:41,410 EXPORT IN THE LIVER? 1886 01:02:41,410 --> 01:02:42,711 SO IN OTHER WORDS, WE SEE THESE 1887 01:02:42,711 --> 01:02:45,414 INCREASES IN DNL, BUT WHAT HAS 1888 01:02:45,414 --> 01:02:49,551 REMAINED UNCLEAR TO ME IS, DOES 1889 01:02:49,551 --> 01:02:50,519 VLDL PRODUCTION INCREASE TO 1890 01:02:50,519 --> 01:02:53,155 MATCH THAT INCREASED LOAD? 1891 01:02:53,155 --> 01:02:55,457 AND IF IT DOESN'T, ARE THOSE THE 1892 01:02:55,457 --> 01:02:57,826 PATIENTS THAT PROGRESS ON TO 1893 01:02:57,826 --> 01:02:59,895 ADVANCED STAGES OF NASH? 1894 01:02:59,895 --> 01:03:03,198 >> THIS IS AN IMPORTANT QUESTION 1895 01:03:03,198 --> 01:03:04,366 THAT'S BEEN RAISED BY A NUMBER 1896 01:03:04,366 --> 01:03:05,234 OF EXPERTS. 1897 01:03:05,234 --> 01:03:07,870 I'VE EVEN HEARD PEOPLE SAY THAT 1898 01:03:07,870 --> 01:03:09,671 PESKY VLDL, THE LIVER IS NOT 1899 01:03:09,671 --> 01:03:11,106 PUTTING OUT ENOUGH TO RELIEVE 1900 01:03:11,106 --> 01:03:12,007 THE LIPID THAT'S STUCK. 1901 01:03:12,007 --> 01:03:13,509 THAT'S THE ONE WAY TO GET LIPID 1902 01:03:13,509 --> 01:03:15,277 OUT OF THE LIVER. 1903 01:03:15,277 --> 01:03:18,080 THIS WOULD BE -- TO GET THAT 1904 01:03:18,080 --> 01:03:19,615 MUCH EXPORT OF TRIGLYCERIDE OUT 1905 01:03:19,615 --> 01:03:21,250 OF THE LIVER, IT WOULD BE LIKE 1906 01:03:21,250 --> 01:03:22,851 TAKING YOUR VOLKSWAGEN ON THE 1907 01:03:22,851 --> 01:03:24,052 HIGHWAY AND GOING 400 MILES AN 1908 01:03:24,052 --> 01:03:24,386 HOUR. 1909 01:03:24,386 --> 01:03:27,022 IT'S NOT GOING TO HAPPEN. 1910 01:03:27,022 --> 01:03:29,491 SO IT IS NOT A FAILURE OF VLDL 1911 01:03:29,491 --> 01:03:29,858 EXPORT. 1912 01:03:29,858 --> 01:03:31,126 YOU CAN'T MAKE THAT MUCH TO BE 1913 01:03:31,126 --> 01:03:32,561 ABLE TO -- 1914 01:03:32,561 --> 01:03:33,762 >> JUST OVERWHELMING. 1915 01:03:33,762 --> 01:03:36,498 >> YOU NEED TO MAKE KETONES, 1916 01:03:36,498 --> 01:03:38,367 BURN FATTY ACIDS. 1917 01:03:38,367 --> 01:03:40,402 THERE'S LOTS OF WAYS TO GET RID 1918 01:03:40,402 --> 01:03:41,970 OF FAT IN THE LIVER AND WE DON'T 1919 01:03:41,970 --> 01:03:44,106 ALWAYS BLAME ONE PATHWAY. 1920 01:03:44,106 --> 01:03:45,807 LIPID SYNTHESIS IS ELEVATED, 1921 01:03:45,807 --> 01:03:48,243 EXPORT IS ELEVATED, APOE B 1922 01:03:48,243 --> 01:03:49,678 SECRETION RATE IS ELEVATED. 1923 01:03:49,678 --> 01:03:51,513 SO IN MY VIEW, THE LIVER IS 1924 01:03:51,513 --> 01:03:53,882 DOING AS BEST IT CAN TO GET RID 1925 01:03:53,882 --> 01:03:57,753 OF THE EXCESS LIPID. 1926 01:03:57,753 --> 01:03:59,588 AND SO I DON'T THINK WE CAN TURN 1927 01:03:59,588 --> 01:04:00,656 THAT UP. 1928 01:04:00,656 --> 01:04:02,324 THAT'S NOT GOING TO BE 1929 01:04:02,324 --> 01:04:02,991 PHYSIOLOGICALLY POSSIBLE. 1930 01:04:02,991 --> 01:04:05,260 >> OKAY. 1931 01:04:05,260 --> 01:04:08,964 >> WE DO KNOW THAT PARTICLES ARE 1932 01:04:08,964 --> 01:04:10,165 BIGGER, AND THERE ARE MORE OF 1933 01:04:10,165 --> 01:04:10,499 THEM. 1934 01:04:10,499 --> 01:04:13,635 BUT YOU REALLY DON'T SEE FATTY 1935 01:04:13,635 --> 01:04:14,636 LIVER -- PATIENTS WITH FATTY 1936 01:04:14,636 --> 01:04:17,139 LIVER HAVING LOW VLDL SECRETION, 1937 01:04:17,139 --> 01:04:20,943 UNLESS IT'S AN APOE B GENETIC 1938 01:04:20,943 --> 01:04:21,176 DEFECT. 1939 01:04:21,176 --> 01:04:27,416 >> THANK YOU. 1940 01:04:27,416 --> 01:04:28,598 >> PLEASE JOIN ME IN THANKING 1941 01:04:28,598 --> 01:04:29,866 DR. PARKS FOR A FANTASTIC 1942 01:04:29,866 --> 01:04:30,500 PRESENTATION AND AN AMAZING BODY 1943 01:04:30,500 --> 01:04:31,167 OF WORK. 1944 01:04:31,167 --> 01:04:32,035 >> THANKS. 1945 01:04:32,035 --> 01:04:45,233 [APPLAUSE]