1 00:00:11,440 --> 00:00:13,640 Welcome to the Clinical Center Grand Rounds, 2 00:00:13,640 --> 00:00:17,440 a weekly series of educational lectures for physicians and 3 00:00:17,440 --> 00:00:20,080 health care professionals broadcast from the Clinical 4 00:00:20,080 --> 00:00:23,040 Center at the National Institutes of Health in 5 00:00:23,040 --> 00:00:24,840 Bethesda, MD. 6 00:00:24,840 --> 00:00:28,400 The NIH Clinical Center is the world's largest hospital totally 7 00:00:28,400 --> 00:00:32,080 dedicated to investigational research and leads the global 8 00:00:32,080 --> 00:00:35,040 effort in training today's investigators and discovering 9 00:00:35,040 --> 00:00:37,200 tomorrow's cures. 10 00:00:37,200 --> 00:00:46,240 Learn more by visiting us online at http://clinicalcenter.nih.gov 11 00:00:46,240 --> 00:00:47,440 >> IT IS MY GREAT PLEASURE 12 00:00:47,440 --> 00:00:49,600 TO WELCOME OUR SPEAKER, 13 00:00:49,600 --> 00:00:53,600 DR. REBECCA J. BROWN. 14 00:00:53,600 --> 00:01:00,320 AN LASKAR TENURE TRACK 15 00:01:00,320 --> 00:01:01,920 INVESTIGATOR IN OBESITY BRANCH 16 00:01:01,920 --> 00:01:03,320 AT THE NATIONAL INSTITUTE OF 17 00:01:03,320 --> 00:01:05,200 DIABETES AND DIGESTIVE AND 18 00:01:05,200 --> 00:01:06,240 KIDNEY DISEASES. 19 00:01:06,240 --> 00:01:08,200 DR. BROWN EARNED HER MEDICAL 20 00:01:08,200 --> 00:01:11,840 DEGREE FROM THE MAYO MEDICAL 21 00:01:11,840 --> 00:01:13,200 SCHOOL IN 2002. 22 00:01:13,200 --> 00:01:14,840 WHILE AS A STUDENT WAS A 23 00:01:14,840 --> 00:01:19,200 RESEARCH FELLOW AT THE NIH 24 00:01:19,200 --> 00:01:21,920 HOWARD HUGHES TRAINING PROGRAM A 25 00:01:21,920 --> 00:01:23,040 PREDECESSOR OF THE RESEARCH 26 00:01:23,040 --> 00:01:23,440 SCHOLARS PROGRAM. 27 00:01:23,440 --> 00:01:27,240 SHE COMPLETED HER RESIDENCY AT 28 00:01:27,240 --> 00:01:29,640 RAINBOW BABIES AND CHILDREN'S 29 00:01:29,640 --> 00:01:31,480 HOPPED AND IN 2005 JOINED THE 30 00:01:31,480 --> 00:01:32,880 NATIONAL INSTITUTE OF CHILD AND 31 00:01:32,880 --> 00:01:35,120 HUMAN DEVELOPMENT AS A CLINICAL 32 00:01:35,120 --> 00:01:37,880 FELLOW IN PEDIATRIC 33 00:01:37,880 --> 00:01:38,240 ENDOCRINOLOGY. 34 00:01:38,240 --> 00:01:40,280 AFTER COMPLETE RESEARCH FELLOW 35 00:01:40,280 --> 00:01:43,120 AT NIDDK AND EARNING A MASTER'S 36 00:01:43,120 --> 00:01:44,840 OF SCIENCE IN CLINICAL RESEARCH 37 00:01:44,840 --> 00:01:47,160 FROM DUKE UNIVERSITY, SHE WAS 38 00:01:47,160 --> 00:01:49,200 INVITED TO JOIN THE INSTITUTE AS 39 00:01:49,200 --> 00:01:51,760 AN ASSISTANT CLINICAL 40 00:01:51,760 --> 00:01:53,720 INVESTIGATOR BEFORE BECOMING THE 41 00:01:53,720 --> 00:01:58,640 FIRST TENURED TRACK AT NIDDK IN 42 00:01:58,640 --> 00:01:58,840 2015. 43 00:01:58,840 --> 00:02:01,680 HER CURRENT RESEARCH FOCUSES ON 44 00:02:01,680 --> 00:02:08,800 THE PATH OWE -- PATHOPHYSIOLOGY 45 00:02:08,800 --> 00:02:10,240 OF THE DYSFUNCTION OF THE 46 00:02:10,240 --> 00:02:12,840 INSULIN RECEPTOR. 47 00:02:12,840 --> 00:02:14,200 SEEKING TO DEVELOP THERAPEUTICS 48 00:02:14,200 --> 00:02:15,480 FOR THE RARE DISEASES AND 49 00:02:15,480 --> 00:02:18,160 PATHWAY MAY SERVE AS DRUG 50 00:02:18,160 --> 00:02:20,080 TARGETS FOR MORE COMMON DISORDER 51 00:02:20,080 --> 00:02:21,400 OF INSULIN RESISTANCE. 52 00:02:21,400 --> 00:02:22,640 A CURRENT FOCUS OF HER 53 00:02:22,640 --> 00:02:26,760 LABORATORY IS UNDERSTANDING THE 54 00:02:26,760 --> 00:02:27,560 PHYSIOLOGIC WAYS WHERE THE 55 00:02:27,560 --> 00:02:30,920 LECTIN ALTERS INSULIN RESIST AND 56 00:02:30,920 --> 00:02:34,280 AND ENERGY METABOLISM BOTH 57 00:02:34,280 --> 00:02:36,560 DEPENDENT ON AND INDEPENDENT ON 58 00:02:36,560 --> 00:02:37,040 FOOD INTAKE. 59 00:02:37,040 --> 00:02:40,280 DR. BROWN IS A NATIONALLY AND 60 00:02:40,280 --> 00:02:40,840 INTERNATIONALLY RECOGNIZED 61 00:02:40,840 --> 00:02:44,240 INVESTIGATOR ESPECIALLY ON 62 00:02:44,240 --> 00:02:47,040 LECTIN WITH 80 PEER-REVIEWED 63 00:02:47,040 --> 00:02:50,240 ARTICLES AND THREE BOOK 64 00:02:50,240 --> 00:02:50,520 CHAPTERS. 65 00:02:50,520 --> 00:02:52,960 BOARD CERTIFIED BY THE AMERICAN 66 00:02:52,960 --> 00:02:57,000 BOARD OF PEDIATRICS SERVES AS A 67 00:02:57,000 --> 00:03:03,840 MEMBER OF THE BOARD OF ADVISORS 68 00:03:03,840 --> 00:03:07,080 TO THE COMMITTEE AND NIDDK'S 69 00:03:07,080 --> 00:03:10,240 STABLE WORKING GROUP. 70 00:03:10,240 --> 00:03:15,240 DR. BROWN ALSO IS PART OF THE 71 00:03:15,240 --> 00:03:16,640 DIABETES CENSUS COMMITTEE GROUP, 72 00:03:16,640 --> 00:03:20,320 THE ENDOCRINE SOCIETY, OBESITY 73 00:03:20,320 --> 00:03:25,280 SOCIETY AND THE EUROPE 74 00:03:25,280 --> 00:03:30,440 CONSORTIUM OF DYSTROPHIES AND 75 00:03:30,440 --> 00:03:31,440 PLEASE WELCOME DR. BROWN. 76 00:03:31,440 --> 00:03:32,400 >> THANK YOU FOR THE KIND 77 00:03:32,400 --> 00:03:34,360 INTRODUCTION. 78 00:03:34,360 --> 00:03:38,080 BEFORE WE START I WANT TO 79 00:03:38,080 --> 00:03:42,640 DISCLOSE THAT METRO LEPTIN THE 80 00:03:42,640 --> 00:03:44,560 PHARMACEUTICAL FORM OF LEPTIN 81 00:03:44,560 --> 00:03:45,560 FOR MOST THE STUDIES WAS DONATE 82 00:03:45,560 --> 00:03:46,400 THE PHARMACEUTICAL COMPANIES 83 00:03:46,400 --> 00:03:50,080 LISTED HERE AND UNRELATED TO THE 84 00:03:50,080 --> 00:03:58,080 TALK I RECEIVED RESEARCH SUPPORT 85 00:03:58,080 --> 00:04:00,600 FROM REGENERON. 86 00:04:00,600 --> 00:04:05,600 AND ALL OTHER USES IN THE 87 00:04:05,600 --> 00:04:07,440 PRESENTATION ARE 88 00:04:07,440 --> 00:04:07,800 INVESTIGATIONAL. 89 00:04:07,800 --> 00:04:09,600 OUR LEARNING OBJECTIVE HAVE TO 90 00:04:09,600 --> 00:04:13,520 IDENTIFY THE BIOLOGICAL 91 00:04:13,520 --> 00:04:18,000 FUNCTIONS OF LEPTIN LOOK AT 92 00:04:18,000 --> 00:04:21,000 SUFFICIENCY AND EXCESS AND LOOK 93 00:04:21,000 --> 00:04:25,520 AT NON-RESPONSIVE FROM 94 00:04:25,520 --> 00:04:26,600 NON-RESPONSIVE LEPTIN STATES. 95 00:04:26,600 --> 00:04:29,520 IN MEDICAL SCHOOL I WAS TAUGHT 96 00:04:29,520 --> 00:04:31,680 LITTLE ABOUT THE FUNCTION OF 97 00:04:31,680 --> 00:04:34,080 ADIPOSE TISSUE EXCEPT FOR THE 98 00:04:34,080 --> 00:04:40,640 STORAGE OF AN ENERGY DEPO. 99 00:04:40,640 --> 00:04:43,200 RESEARCH HAS REVEALED WHITE 100 00:04:43,200 --> 00:04:48,360 ADIPOSE TISSUE ALSO FUNCTIONS AS 101 00:04:48,360 --> 00:04:53,480 AN ENDOCRINE ORGAN RELEASING 102 00:04:53,480 --> 00:04:56,240 HORMONES AND ONE IS LEPTIN THE 103 00:04:56,240 --> 00:04:58,160 TOPIC OF TODAY'S PRESENTATION. 104 00:04:58,160 --> 00:05:00,360 LEPTIN WAS DISCOVERED BY JEFF 105 00:05:00,360 --> 00:05:01,680 FREEDMAN'S LAB AT THE 106 00:05:01,680 --> 00:05:03,520 ROCKEFELLER IN THE 1990s AND 107 00:05:03,520 --> 00:05:08,360 BASED ON THIS SPONTANEOUSLY 108 00:05:08,360 --> 00:05:11,160 OCCURRING MOUSE MODEL OF OBESITY 109 00:05:11,160 --> 00:05:14,520 THE OBOB MASS. 110 00:05:14,520 --> 00:05:17,480 OBESITY WAS KNOWN TO FOLLOW A 111 00:05:17,480 --> 00:05:18,280 RECESSIVE PATTERN LONG BEFORE 112 00:05:18,280 --> 00:05:20,760 YOU CAN SEQUENCE A GENOME FOR 113 00:05:20,760 --> 00:05:23,840 UNDER $1,000 AND TOOK YEARS OF 114 00:05:23,840 --> 00:05:25,440 EFFORTS TO IDENTIFY THE EFFECTED 115 00:05:25,440 --> 00:05:27,000 GENE AND LEARN ITS FUNCTION. 116 00:05:27,000 --> 00:05:31,200 IN 1994, THE FREEDMAN LAB 117 00:05:31,200 --> 00:05:32,160 REPORTED MUTATIONS IN THE GENE 118 00:05:32,160 --> 00:05:34,160 ENCODING LEPTIN IN THESE 119 00:05:34,160 --> 00:05:34,480 ANIMALS. 120 00:05:34,480 --> 00:05:40,120 THE WORD LEPTIN WAS DERIVED FROM 121 00:05:40,120 --> 00:05:45,720 THE GREEK WORD LEPTOS AND IF YOU 122 00:05:45,720 --> 00:05:47,280 REPLACED THE MISSING HORMONE 123 00:05:47,280 --> 00:05:50,400 LEPTIN IN THE ANIMALS IT 124 00:05:50,400 --> 00:05:51,560 COMPLETELY CORRECTED THEIR 125 00:05:51,560 --> 00:05:54,400 HYPERPHAGIA AND RESULTED IN A 126 00:05:54,400 --> 00:05:56,360 HEALTHY LEAN MOUSE AS SHOWN 127 00:05:56,360 --> 00:05:56,800 HERE. 128 00:05:56,800 --> 00:06:04,360 IN 1997, A GROUP IN THE U.K. 129 00:06:04,360 --> 00:06:07,560 IDENTIFIED CHILDREN FROM 130 00:06:07,560 --> 00:06:08,240 CONSANGUINIOUS FAMILIES AND 131 00:06:08,240 --> 00:06:12,160 FOUND SOME CHILDREN LIKE THE 132 00:06:12,160 --> 00:06:19,560 OBOB MOUSE HAD A RECESSSIVE IN 133 00:06:19,560 --> 00:06:22,000 LOW LEPTIN CONCENTRATIONS. 134 00:06:22,000 --> 00:06:24,760 WE SEE A 4-YEAR-OLD CHILD WITH 135 00:06:24,760 --> 00:06:26,520 THE CONDITION WEIGHING THREE 136 00:06:26,520 --> 00:06:27,560 TIMES AS MUCH AS A TYPICAL CHILD 137 00:06:27,560 --> 00:06:31,320 HIS AGE. 138 00:06:31,320 --> 00:06:33,760 IN 1999, THEY SHOWED LEPTIN 139 00:06:33,760 --> 00:06:35,080 ADMINISTRATION WORKED JUST AS 140 00:06:35,080 --> 00:06:38,400 WELL IN THE HUMAN PATIENTS AS IT 141 00:06:38,400 --> 00:06:40,200 DID IN MICE. 142 00:06:40,200 --> 00:06:41,680 THIS PICTURE SHOWS THE SAME 143 00:06:41,680 --> 00:06:43,560 CHILD AS ABOVE AS AGE 7 AFTER 144 00:06:43,560 --> 00:06:46,680 BEING TREATED WITH LEPTIN AND 145 00:06:46,680 --> 00:06:51,560 WEIGHS LESS AT AGE 7 THAN AGE 4. 146 00:06:51,560 --> 00:06:53,840 NATURALLY, IT WAS THOUGHT LEPTIN 147 00:06:53,840 --> 00:06:56,240 MIGHT BE THE MIRACLE CURE FOR 148 00:06:56,240 --> 00:06:56,480 OBESITY. 149 00:06:56,480 --> 00:06:59,320 ALSO IN 1999 THERE WAS A LARGE 150 00:06:59,320 --> 00:06:59,880 CLINICAL TRIAL OF LEPTIN 151 00:06:59,880 --> 00:07:02,880 ADMINISTRATION IN ADULTS WITH 152 00:07:02,880 --> 00:07:03,720 COMMON FORMS OF OBESITY. 153 00:07:03,720 --> 00:07:05,400 WHILE THERE WAS SOME MODEST 154 00:07:05,400 --> 00:07:06,760 WEIGHT LOSS IN PATIENTS WHO WERE 155 00:07:06,760 --> 00:07:10,440 TREATED WITH THE HIGHEST DOSES 156 00:07:10,440 --> 00:07:12,960 OF LEPTIN THERE WERE REALLY NO 157 00:07:12,960 --> 00:07:16,000 DRAMATIC EFFECTS ON BODY WEIGHT. 158 00:07:16,000 --> 00:07:17,560 SO DID LEPTIN ADMINISTRATION 159 00:07:17,560 --> 00:07:19,000 HAVE LITTLE EFFECT IN COMMON 160 00:07:19,000 --> 00:07:20,360 FORMS OF OBESITY? 161 00:07:20,360 --> 00:07:24,280 WELL, LEPTIN IS MADE BY 162 00:07:24,280 --> 00:07:25,040 ADIPOSITES IN PER ASSOCIATION TO 163 00:07:25,040 --> 00:07:25,800 FAT MASS. 164 00:07:25,800 --> 00:07:29,720 HERE IN THE GRAPH WE SEE DATA 165 00:07:29,720 --> 00:07:35,080 SHOWING PERCENT BODY FAT ON THE 166 00:07:35,080 --> 00:07:39,560 Y AXIS AND LEPTIN -- PERCENT 167 00:07:39,560 --> 00:07:42,320 BODY FAT ON THE Y AND LEPTIN ON 168 00:07:42,320 --> 00:07:43,960 THE X FOR HUMANS ACROSS A WIDE 169 00:07:43,960 --> 00:07:45,400 RANGE OF BODY FAT. 170 00:07:45,400 --> 00:07:48,560 THE LOG OF SERUM LEPTIN 171 00:07:48,560 --> 00:07:57,840 CORRELATES WELL WITH ADIPOSITY 172 00:07:57,840 --> 00:08:00,360 AND IS REPRESENTED HERE BY FAT 173 00:08:00,360 --> 00:08:09,120 STORAGE. 174 00:08:09,120 --> 00:08:13,400 LEPTIN OCCURS AS A STARVATION 175 00:08:13,400 --> 00:08:15,960 SIGNAL AND LOW EFFICIENCY STATES 176 00:08:15,960 --> 00:08:17,560 STARVATION TO NON-STARVATION 177 00:08:17,560 --> 00:08:19,280 STATES SIGNALLING AN END TO 178 00:08:19,280 --> 00:08:19,560 STARVATION. 179 00:08:19,560 --> 00:08:22,800 IN PATIENTS WITH NON-DEFICIENT 180 00:08:22,800 --> 00:08:24,680 FORMS OF OBESITY WHICH IS ALMOST 181 00:08:24,680 --> 00:08:25,960 EVERYONE SERUM LEPTIN IS ALREADY 182 00:08:25,960 --> 00:08:29,920 HIGH AND WELL ABOVE THE 183 00:08:29,920 --> 00:08:31,680 RESPONSIVE RANGE THUS ADDING 184 00:08:31,680 --> 00:08:32,640 ADDITIONAL LEPTIN TO THESE 185 00:08:32,640 --> 00:08:36,360 ALREADY HIGH LEPTIN LEVELS HAS 186 00:08:36,360 --> 00:08:38,200 LITTLE CLINICAL AFFECT. 187 00:08:38,200 --> 00:08:40,760 SO HOW DOES LEPTIN FUNCTION TO 188 00:08:40,760 --> 00:08:43,760 MAINTAIN HOMEOSTASIS OF FAT 189 00:08:43,760 --> 00:08:44,360 STORAGE? 190 00:08:44,360 --> 00:08:47,680 LET'S IMAGINE YOU'RE A HEALTHY 191 00:08:47,680 --> 00:08:55,840 LEAN INDIVIDUAL AND YOU'RER ADIPOSE 192 00:08:55,840 --> 00:08:57,880 SITES MAYBE A NORMAL AMOUNT AND 193 00:08:57,880 --> 00:09:00,800 THE LOW LEPTIN GETS SENSED BY 194 00:09:00,800 --> 00:09:03,560 THE HYPOTHALAMUS AS A STARVATION 195 00:09:03,560 --> 00:09:05,680 SIGNAL AND LEADS TO NUMEROUS 196 00:09:05,680 --> 00:09:08,360 ADAPTATIONS TO STARVATION AND 197 00:09:08,360 --> 00:09:10,240 MOST IMPORTANTLY MAKES YOU FEEL 198 00:09:10,240 --> 00:09:11,320 CONSTANTLY HUNGRY. 199 00:09:11,320 --> 00:09:13,200 AFTER YOU EAT A LARGE MEAL YOU 200 00:09:13,200 --> 00:09:15,040 STILL WON'T FEEL SATIATED. 201 00:09:15,040 --> 00:09:17,520 IF WE NOW IMAGINE THE FAMINE IS 202 00:09:17,520 --> 00:09:22,360 OVER YOU'LL EAT A LOT OF FIND 203 00:09:22,360 --> 00:09:25,440 YOUR LEPTIN LEVEL WILL TURN TO 204 00:09:25,440 --> 00:09:27,560 NORMAL AND HOMEOSTASIS IS 205 00:09:27,560 --> 00:09:28,360 RESTORED. 206 00:09:28,360 --> 00:09:29,840 IT DOESN'T MEAN YOU WON'T STILL 207 00:09:29,840 --> 00:09:31,960 BE HUNGRY SEVERAL TIMES A DAY 208 00:09:31,960 --> 00:09:34,520 BUT AFTER YOU EAT A MEAL YOU'LL 209 00:09:34,520 --> 00:09:38,200 NOW FEEL SATIATED AND MANY 210 00:09:38,200 --> 00:09:39,560 THINGS REGULATE IT DURING THE 211 00:09:39,560 --> 00:09:42,640 COURSE OF THE DAY AND LEPTIN IS 212 00:09:42,640 --> 00:09:43,320 A LONG-TERM PLAYER. 213 00:09:43,320 --> 00:09:45,040 NOW LET'S IMAGINE THE OPPOSITE. 214 00:09:45,040 --> 00:09:49,320 YOU LIVE IN AN URBAN OR SUBURBAN 215 00:09:49,320 --> 00:09:51,680 ENVIRONMENT AND SURROUNDED BY 216 00:09:51,680 --> 00:09:54,520 CALORIE DENSE FOODS AND HAVE 217 00:09:54,520 --> 00:09:55,520 LITTLE OPPORTUNITY TO EXERCISE 218 00:09:55,520 --> 00:09:58,840 AND AS YOU GAIN FAT THE SERUM 219 00:09:58,840 --> 00:10:02,520 LEPTIN LEVEL RISE AND IT SHOULD 220 00:10:02,520 --> 00:10:04,480 SUPPRESS YOUR APPETITE AND 221 00:10:04,480 --> 00:10:05,600 RESTORE HOMEOSTASIS. 222 00:10:05,600 --> 00:10:08,240 WE KNOW THIS IS NOT THE CASE OR 223 00:10:08,240 --> 00:10:10,240 WE WOULD NOT BE LIVING IN AN 224 00:10:10,240 --> 00:10:12,320 OBESITY EPIDEMIC. 225 00:10:12,320 --> 00:10:15,800 SO WHY DOESN'T HIGH LEPTIN 226 00:10:15,800 --> 00:10:17,280 SUPPRESS APPETITE? 227 00:10:17,280 --> 00:10:18,920 THE PRIMARY FUNCTIONAL ROLE OF 228 00:10:18,920 --> 00:10:23,320 LEPTIN IS APPARENTLY TO DEFEND 229 00:10:23,320 --> 00:10:25,560 NOT REDUCE BODY FAT BY 230 00:10:25,560 --> 00:10:28,880 INCREASING FOOD SEEKING AND 231 00:10:28,880 --> 00:10:30,600 DECREASING ENERGY EXPENDITURE 232 00:10:30,600 --> 00:10:32,280 WHEN FA FAT STORES ARE 233 00:10:32,280 --> 00:10:32,600 INSUFFICIENT. 234 00:10:32,600 --> 00:10:35,360 SO LOW LEPTIN ACTS AS A 235 00:10:35,360 --> 00:10:37,000 STARVATION SIGNAL INCREASING 236 00:10:37,000 --> 00:10:39,280 APPETITE BUT HIGH LEPTIN DOES 237 00:10:39,280 --> 00:10:40,960 NOT ACT AS AN OVER NUTRITION 238 00:10:40,960 --> 00:10:46,200 SIGNAL AND DECREASE APPETITE. 239 00:10:46,200 --> 00:10:50,360 THIS GRAPH SHOWS SERUM LEPTIN 240 00:10:50,360 --> 00:10:54,960 CONCENTRATIONS ON THE X AXIS AND 241 00:10:54,960 --> 00:10:56,160 DEFICIENCY ON THE Y AXIS. 242 00:10:56,160 --> 00:11:02,240 LEMENTIN IS INEFFECTIVE IN HIGH 243 00:11:02,240 --> 00:11:04,800 LEPTIN STATES WHERE LEPTIN 244 00:11:04,800 --> 00:11:09,000 LEVELS ARE HIGH 20 TO 100 245 00:11:09,000 --> 00:11:12,960 NANOGRAMS AND LEPTIN IS 246 00:11:12,960 --> 00:11:16,200 INEFFECTIVE IN THESE PATIENTS. 247 00:11:16,200 --> 00:11:20,880 LEPTIN THERAPY HAS DRAMATIC 248 00:11:20,880 --> 00:11:27,360 AFFECTS IN SEVERELY LEPTIN 249 00:11:27,360 --> 00:11:29,640 DEFICIENT PATIENTS. 250 00:11:29,640 --> 00:11:32,200 THEY HAVE LEVELS LESS THAN 1 251 00:11:32,200 --> 00:11:32,960 NANOGRAM. 252 00:11:32,960 --> 00:11:34,600 SO IN ORDER TO UNDERSTAND THE 253 00:11:34,600 --> 00:11:35,960 DIE LOGICAL ROLE OF LEPTIN WE 254 00:11:35,960 --> 00:11:39,560 HAVE TO STUDY HUMANS WIN LEPTIN 255 00:11:39,560 --> 00:11:41,560 DEFICIENT STATES WHO ARE LEPTIN 256 00:11:41,560 --> 00:11:41,880 RESPONSIVE. 257 00:11:41,880 --> 00:11:45,160 IN FACT STUDIES OF PATIENTS WITH 258 00:11:45,160 --> 00:11:48,160 LEPTIN DEFICIENCY TAUGHT US A 259 00:11:48,160 --> 00:11:48,920 LOT ABOUT THE BIOLOGY. 260 00:11:48,920 --> 00:11:55,080 WE KNOW IT PRODUCES THE 261 00:11:55,080 --> 00:11:57,440 HYPERPHAGIA OF STARVATION AND 262 00:11:57,440 --> 00:12:01,520 LEPTIN RECAPITULATES THE ENERGY 263 00:12:01,520 --> 00:12:04,000 CONSERVATION STATE INCLUDING 264 00:12:04,000 --> 00:12:08,560 INCREASED THYROID HORMONE WHICH 265 00:12:08,560 --> 00:12:14,200 IS REVERSED AND REPRODUCTION IS 266 00:12:14,200 --> 00:12:15,240 ENERGY INSENSITIVE AND PATIENTS 267 00:12:15,240 --> 00:12:19,320 WITH CONGENITAL LEPTIN 268 00:12:19,320 --> 00:12:21,680 DEFICIENCY HAVE TAUGHT US IT'S 269 00:12:21,680 --> 00:12:23,560 PERMISSIVE FOR REPRODUCTION AND 270 00:12:23,560 --> 00:12:25,760 THE CHALLENGE IS THE EXTREME 271 00:12:25,760 --> 00:12:28,320 RARITY OF THIS CONDITION WITH 272 00:12:28,320 --> 00:12:30,960 LESS THAN 30 PATIENTS REPORTED 273 00:12:30,960 --> 00:12:31,280 WORLDWIDE. 274 00:12:31,280 --> 00:12:33,600 SO WHAT OTHER LOW-LEPTIN 275 00:12:33,600 --> 00:12:36,320 CONDITIONS CAN WE STUDY IN 276 00:12:36,320 --> 00:12:36,600 HUMANS? 277 00:12:36,600 --> 00:12:39,000 STARVATION IS THE OBVIOUS CHOICE 278 00:12:39,000 --> 00:12:40,520 AS THIS IS THE PHYSIOLOGIC 279 00:12:40,520 --> 00:12:41,840 CONDITION OF LOW LEPTIN. 280 00:12:41,840 --> 00:12:47,400 NOW, DOING STUDIES OF AN 281 00:12:47,400 --> 00:12:49,640 APPETITE SUPPRESSING MEDICATION 282 00:12:49,640 --> 00:12:51,360 IS CLINICALLY ETHICALLY FRAUGHT. 283 00:12:51,360 --> 00:12:52,720 INTERESTING ACCUSE STARVATION 284 00:12:52,720 --> 00:12:55,520 EXPERIMENTS BY WHICH I MEAN A 285 00:12:55,520 --> 00:12:57,720 72-HOUR FAST HAVE BEEN DONE IN 286 00:12:57,720 --> 00:13:00,360 HEALTHY VOLUNTEERS AND THEY 287 00:13:00,360 --> 00:13:02,560 SHOWED LEPTIN REPLACEMENT IN 288 00:13:02,560 --> 00:13:03,960 THIS CONTEXT DID SUPPRESS 289 00:13:03,960 --> 00:13:05,160 APPETITE. 290 00:13:05,160 --> 00:13:08,280 THERE WAS EVEN A BOLD TEAM THAT 291 00:13:08,280 --> 00:13:16,120 GAVE IT TO A PATIENT WITH 292 00:13:16,120 --> 00:13:18,280 ANOREXIA AND THEY FOUND 293 00:13:18,280 --> 00:13:19,960 INCREASES IN THYROID AND SEX 294 00:13:19,960 --> 00:13:23,360 HORMONES IN PATIENTS WITH 295 00:13:23,360 --> 00:13:23,760 ANOREXIA NERVOSA. 296 00:13:23,760 --> 00:13:25,840 WE CAN ADD STARVATION TO OUR 297 00:13:25,840 --> 00:13:28,160 MODEL OF LEPTIN BIOLOGY AS A LOW 298 00:13:28,160 --> 00:13:28,760 LEPTIN STATE RESPONSIVE TO 299 00:13:28,760 --> 00:13:39,240 LEPTIN ADMINISTRATION. 300 00:13:39,240 --> 00:13:45,360 HOWEVER LONG-TERM EXPERIMENTS 301 00:13:45,360 --> 00:13:51,720 ARE NOT COMMONLY DONE AND WE 302 00:13:51,720 --> 00:13:55,040 HAVE THIS CONDITION ASSOCIATED 303 00:13:55,040 --> 00:13:57,520 WITH THE REPRODUCTIVE 304 00:13:57,520 --> 00:13:59,880 DYSFUNCTION. 305 00:13:59,880 --> 00:14:06,360 A GROUP AT MASS GENERAL SHOWED 306 00:14:06,360 --> 00:14:08,360 LEPTIN THERAPY WITH SOME WOMEN 307 00:14:08,360 --> 00:14:12,160 WITH THIS CONDITION IMPROVED 308 00:14:12,160 --> 00:14:20,120 FUNCTION OF THE HYPERTHALAMIC 309 00:14:20,120 --> 00:14:21,640 GONAD AXIS AND HAD SOME WEIGHT 310 00:14:21,640 --> 00:14:21,840 LOSS. 311 00:14:21,840 --> 00:14:22,760 WHAT OTHER LOW LEPTIN CONDITIONS 312 00:14:22,760 --> 00:14:24,920 CAN WE STUDY IN HUMANS? 313 00:14:24,920 --> 00:14:27,040 THE CONDITION WE STUDIED 314 00:14:27,040 --> 00:14:29,440 EXTENSIVELY AT NIH IS A RARE 315 00:14:29,440 --> 00:14:31,680 DISEASE CALLED LIPO DYSTROPHY. 316 00:14:31,680 --> 00:14:36,120 HERE I'LL WALK YOU THROUGH THE 317 00:14:36,120 --> 00:14:37,520 PATHOPHYSIOLOGY OF THIS. 318 00:14:37,520 --> 00:14:39,000 THE FUNDAMENTAL PROBLEMS IS LOW 319 00:14:39,000 --> 00:14:44,320 FAT MASS WHICH CAN BE GENETIC OR 320 00:14:44,320 --> 00:14:44,880 ACQUIRED. 321 00:14:44,880 --> 00:14:46,760 VARIETY PEOPLE WITH 322 00:14:46,760 --> 00:14:52,280 LIPODYSTROPHY HAVE LOW LEVELS OF 323 00:14:52,280 --> 00:14:52,600 ADIPOSEKINES. 324 00:14:52,600 --> 00:14:56,240 THAT GETS SENSEDS A STARVATION 325 00:14:56,240 --> 00:15:03,080 SIGNAL AND RESULTS IN 326 00:15:03,080 --> 00:15:12,680 HYPERPHAGIA. 327 00:15:12,680 --> 00:15:17,640 AN PATIENT WITH LIPODYSTROPHY 328 00:15:17,640 --> 00:15:24,360 THEY CAN'T STORE CALORIES IN 329 00:15:24,360 --> 00:15:27,080 ADIPO 330 00:15:27,080 --> 00:15:27,960 ADIPOSECITES THEY GET STORED IN 331 00:15:27,960 --> 00:15:32,120 THE MUSCLE AND LIVER AND FOR 332 00:15:32,120 --> 00:15:38,560 COMPLICATE REASONS WE CAN CALL 333 00:15:38,560 --> 00:15:44,080 LIPOTOXICITY AND IT LOODZ LEADS 334 00:15:44,080 --> 00:15:49,040 TO INSULIN RESISTANCE AND CAN 335 00:15:49,040 --> 00:15:51,840 LEAD TO NON-FATTY LIVER DISEASE 336 00:15:51,840 --> 00:15:53,560 AND OTHERS. 337 00:15:53,560 --> 00:15:59,240 THE PATHOPHYSIOLOGY IS SIMILAR 338 00:15:59,240 --> 00:16:02,160 TO PATIENTS WITH LIPO DYSTROPHY. 339 00:16:02,160 --> 00:16:07,200 OBVIOUSLY THERE'S MAJOR 340 00:16:07,200 --> 00:16:08,480 DIFFERENCES. 341 00:16:08,480 --> 00:16:10,960 AND AS A RESULT THEY HAVE HIGH 342 00:16:10,960 --> 00:16:22,680 CIRCULATING LEPTIN. 343 00:16:22,680 --> 00:16:25,920 THEY CAN STORE IN THEIR 344 00:16:25,920 --> 00:16:28,000 ADIPOCYTES BUT THEY MAY EXCEED 345 00:16:28,000 --> 00:16:30,680 THE STORAGE CAPACITY OF THEIR 346 00:16:30,680 --> 00:16:32,440 ADIPOCYTES AND AT THAT POINT YOU 347 00:16:32,440 --> 00:16:36,000 GET SPILLOVER EFFECTS INTO THE 348 00:16:36,000 --> 00:16:37,640 ECTOPIC LIPID STORAGE DEPOTS 349 00:16:37,640 --> 00:16:40,480 LIKE THE MUSCLE AND LIVER 350 00:16:40,480 --> 00:16:43,200 LEADING TO INSULIN RESISTANCE 351 00:16:43,200 --> 00:16:47,520 AND THE DOWN STREAM CONSEQUENCES 352 00:16:47,520 --> 00:16:47,760 WE SEE. 353 00:16:47,760 --> 00:16:49,960 THERE ARE TWO MAJOR CATEGORIES 354 00:16:49,960 --> 00:16:53,000 OF LIPODYSTROPHY. 355 00:16:53,000 --> 00:16:55,000 THOSE HERE SHOWN IN THE 356 00:16:55,000 --> 00:16:57,760 ADOLESCENT ON THE LEFT ARE 357 00:16:57,760 --> 00:16:59,920 MISSING NATIONALLY ALL ADIPOSE 358 00:16:59,920 --> 00:17:01,600 TISSUES IN THEIR BODIES. 359 00:17:01,600 --> 00:17:03,880 PATIENTS WITH LIPODYSTROPHY AS 360 00:17:03,880 --> 00:17:06,480 ILLUSTRATED BY THE TEENAGE GIRL 361 00:17:06,480 --> 00:17:08,520 ON THE RIGHT AND BOTH PICTURES 362 00:17:08,520 --> 00:17:10,760 ARE OF THE SAME PATIENT. 363 00:17:10,760 --> 00:17:15,120 THEY HAVE LOSS IN FAT IN CERTAIN 364 00:17:15,120 --> 00:17:21,040 DEPOTS TYPICALLY THE EXTREMITIES 365 00:17:21,040 --> 00:17:23,080 WITH INCREASED FAT IN THE HEAD, 366 00:17:23,080 --> 00:17:24,360 NECK AND TRUNK. 367 00:17:24,360 --> 00:17:27,680 BECAUSE LEPTIN IS SECRETED IN 368 00:17:27,680 --> 00:17:29,400 PROPORTION TO FAT MASS JUST AS 369 00:17:29,400 --> 00:17:31,080 IN THE GENERAL POPULATION, 370 00:17:31,080 --> 00:17:32,360 LEPTIN LEVELS SHOWN IN THE GRAPH 371 00:17:32,360 --> 00:17:34,960 ARE UNIFORMLY LOW IN PATIENTS 372 00:17:34,960 --> 00:17:37,680 WITH GENERALIZED LIPODYSTROPHY 373 00:17:37,680 --> 00:17:39,840 INDICATED BY THE BLUE DOTS BUT 374 00:17:39,840 --> 00:17:41,800 LEPTIN TENDS TO BE HIGHER IN 375 00:17:41,800 --> 00:17:45,440 PATIENTS WITH PARTIAL 376 00:17:45,440 --> 00:17:48,120 LIPODYSTROPHY SHOWN IN THE RED 377 00:17:48,120 --> 00:17:48,360 SQUARES. 378 00:17:48,360 --> 00:18:01,160 IN 2000 WAS A STUDY OF HORMONE 379 00:18:01,160 --> 00:18:04,560 REPLACEMENT WITH PATIENTS WITH A 380 00:18:04,560 --> 00:18:10,440 MEAN SERUM LEPTIN LEVEL AND 381 00:18:10,440 --> 00:18:12,360 TREATED THEM AT ESCALATING DOSES 382 00:18:12,360 --> 00:18:16,400 UP TO A MAXIMUM OF TWOFOLD THE 383 00:18:16,400 --> 00:18:17,960 ESTIMATED PHYSIOLOGIC 384 00:18:17,960 --> 00:18:20,080 REPLACEMENT DOSE AND THE RESULTS 385 00:18:20,080 --> 00:18:21,360 WERE DRAMATIC. 386 00:18:21,360 --> 00:18:24,960 DIABETES IMPROVED WITH A 387 00:18:24,960 --> 00:18:30,800 REDUCTION OF HEMOGLOBIN A1C FROM 388 00:18:30,800 --> 00:18:33,080 9% TO NEAR BASELINE AFTER FOUR 389 00:18:33,080 --> 00:18:34,160 MINUTES OF TREATMENT. 390 00:18:34,160 --> 00:18:36,760 THERE WAS A 60% REDUCTION IN 391 00:18:36,760 --> 00:18:42,160 SERUM TRIGLYCERIDES TO 1,000 AT 392 00:18:42,160 --> 00:18:44,360 BASELINE TO UNDER 400 AND LIVER 393 00:18:44,360 --> 00:18:47,640 VOLUME REDUCED BY 20% PRESUMABLY 394 00:18:47,640 --> 00:18:52,400 DUE TO A REDUCTION OF FAT AND 395 00:18:52,400 --> 00:18:56,560 FOOD INTAKE REDUCED BY 50% FROM 396 00:18:56,560 --> 00:19:00,360 ABOUT 2700 CALORIES A DAY AT 397 00:19:00,360 --> 00:19:02,960 BASELINE TO 1600 A DAY AT 398 00:19:02,960 --> 00:19:03,360 FOLLOW-UP. 399 00:19:03,360 --> 00:19:05,440 22 YEARS LATER, HUNDREDS OF 400 00:19:05,440 --> 00:19:10,840 PATIENTS WITH THIS RARE DISEASE 401 00:19:10,840 --> 00:19:13,120 HAVE BEEN TREATED WITH LEPTIN 402 00:19:13,120 --> 00:19:16,160 AND WITH STUDIES LEPTIN WAS FDA 403 00:19:16,160 --> 00:19:20,360 APPROVED WITH PATIENTS WITH 404 00:19:20,360 --> 00:19:22,360 GENERALIZED LIPODYSTROPHY IN 405 00:19:22,360 --> 00:19:22,560 2004. 406 00:19:22,560 --> 00:19:26,520 THIS ILLUSTRATE THE DRAMATIC 407 00:19:26,520 --> 00:19:28,360 CHANGE IN A SUBJECT WITH 408 00:19:28,360 --> 00:19:29,600 GENERALIZED LIPODYSTROPHY. 409 00:19:29,600 --> 00:19:32,360 THIS PATIENT CAME TO US AT AGE 410 00:19:32,360 --> 00:19:35,440 21 WITH POORLY CONTROLLED 411 00:19:35,440 --> 00:19:40,360 DIABETES AND HAD DIABETIC KETO A 412 00:19:40,360 --> 00:19:43,960 AACIDOSIS AND THESE GRAPHS SHOW 413 00:19:43,960 --> 00:19:46,160 HER LABORATORY PARAMETERS PRIOR 414 00:19:46,160 --> 00:19:47,920 TO LEPTIN TREATMENT IN BLUE AND 415 00:19:47,920 --> 00:19:50,280 AFTER ONE YEAR OF LEPTIN 416 00:19:50,280 --> 00:19:51,160 TREATMENT IN PURPLE. 417 00:19:51,160 --> 00:19:53,960 HER HEMOGLOBIN A1C DECREASED 418 00:19:53,960 --> 00:19:56,760 FROM 13.1 TO THE NON-DIABETIC 419 00:19:56,760 --> 00:19:59,280 RANGE OF 5.1. 420 00:19:59,280 --> 00:20:00,760 THIS WAS DESPITE DISCONTINUING 421 00:20:00,760 --> 00:20:02,840 INSULIN ENTIRELY FROM AN INITIAL 422 00:20:02,840 --> 00:20:06,280 DOSE OF 280 UNITS PER DAY. 423 00:20:06,280 --> 00:20:08,160 HER TRIGLYCERIDES DECREASED FROM 424 00:20:08,160 --> 00:20:12,320 OVER 6,000 TO LESS THAN 200 AND 425 00:20:12,320 --> 00:20:14,760 HER URINE PROTEIN SECRETION 426 00:20:14,760 --> 00:20:16,360 DECREASED FROM OVER 6 GRAMS PER 427 00:20:16,360 --> 00:20:18,640 DAY TO LESS THAN 1 GRAM PER DAY. 428 00:20:18,640 --> 00:20:20,960 THIS IS A PHOTO OF THE PATIENT 429 00:20:20,960 --> 00:20:22,360 PRIOR TO LEPTIN TREATMENT. 430 00:20:22,360 --> 00:20:24,320 YOU CAN APPRECIATE HER 431 00:20:24,320 --> 00:20:26,720 GENERALIZED LACK OF ADIPOSE 432 00:20:26,720 --> 00:20:27,000 TISSUE. 433 00:20:27,000 --> 00:20:31,760 SHE HAS STIGMATA OF INSULIN 434 00:20:31,760 --> 00:20:35,200 RESISTANCE IN THIS AREA AND HAS 435 00:20:35,200 --> 00:20:39,720 INCREASED ABDOMINAL GIRTH DUE TO 436 00:20:39,720 --> 00:20:40,040 HEPATOMEGLY. 437 00:20:40,040 --> 00:20:41,840 AFTER THE MOST DRAMATIC CHANGE 438 00:20:41,840 --> 00:20:47,240 YOU CAN OBSERVE IS REDUCTION IN 439 00:20:47,240 --> 00:20:49,360 ABDOMINAL GIRTH FROM EFFLUX OF 440 00:20:49,360 --> 00:20:51,400 ECTOPIC LIPID. 441 00:20:51,400 --> 00:20:54,240 THUS, WHILE WE HAVE NOT YET 442 00:20:54,240 --> 00:20:57,480 CURED THE UNDERLYING PROBLEM IN 443 00:20:57,480 --> 00:21:00,400 PATIENTS WITH LIPODYSTROPHY WE 444 00:21:00,400 --> 00:21:11,960 CAN REPLACE A KEY MISSING 445 00:21:11,960 --> 00:21:15,600 ADIPOKINE AND IT REDUCES ECTOPIC 446 00:21:15,600 --> 00:21:25,200 LIPID STORAGE IN THE MUFFSCLES AND 447 00:21:25,200 --> 00:21:28,320 IMPROVES INSULIN RESISTANCE AND 448 00:21:28,320 --> 00:21:38,280 NON-ALCOHOL FATTY LIVER DEED. 449 00:21:38,280 --> 00:21:40,320 AND AS YOU KNOW DECREASING FOOD 450 00:21:40,320 --> 00:21:43,920 INTAKE WHICH WE CAN ALSO CALL 451 00:21:43,920 --> 00:21:48,320 GOING ON A DIET HAS METABOLIC 452 00:21:48,320 --> 00:21:49,800 BENEFITS IN PEOPLE WITH OBESITY. 453 00:21:49,800 --> 00:21:52,520 THE BENEFITS OF REDUCED FOOD 454 00:21:52,520 --> 00:21:54,560 INTAKE ACHIEVED THROUGH DIETING 455 00:21:54,560 --> 00:21:55,400 IN PATIENTS WITH OBESITY ARE 456 00:21:55,400 --> 00:21:59,600 SIMILAR TO THOSE ACHIEVED BY 457 00:21:59,600 --> 00:22:01,520 LEPTIN ADMINISTRATION IN 458 00:22:01,520 --> 00:22:03,400 PATIENTS WITH LIPODYSTROPHY WITH 459 00:22:03,400 --> 00:22:08,240 IN INSULIN SENSITIVE AND HEPATIC 460 00:22:08,240 --> 00:22:08,960 TRIGLYCERIDES. 461 00:22:08,960 --> 00:22:11,520 THIS BEGS THE QUESTION ARE ALL 462 00:22:11,520 --> 00:22:13,440 LEPTIN'S METABOLIC BENEFITS DUE 463 00:22:13,440 --> 00:22:16,160 TO REDUCTIONS IN FOOD INTAKE OR 464 00:22:16,160 --> 00:22:18,400 DOES LEPTIN HAVE METABOLIC 465 00:22:18,400 --> 00:22:19,560 BENEFITS ABOVE AND BEYOND THE 466 00:22:19,560 --> 00:22:22,560 EFFECTS TO REDUCE HUNGER? 467 00:22:22,560 --> 00:22:25,760 HOW DO WE DETERMINE IF LEPTIN 468 00:22:25,760 --> 00:22:27,640 HAS METABOLIC BENEFITS 469 00:22:27,640 --> 00:22:29,920 INDEPENDENT OF ITS ACTION TO 470 00:22:29,920 --> 00:22:31,640 SUPPRESS FOOD INTAKE? 471 00:22:31,640 --> 00:22:33,480 STUDIES IN MICE IS EASY. 472 00:22:33,480 --> 00:22:35,360 IT'S CALLED A PAIRED FEEDING 473 00:22:35,360 --> 00:22:35,640 EXPERIMENT. 474 00:22:35,640 --> 00:22:39,000 YOU TAKE A GROUP OF LEPTIN 475 00:22:39,000 --> 00:22:42,920 DEFICIENT MICE WHO ARE HYPER 476 00:22:42,920 --> 00:22:46,360 HYPERPHAGIC AND MEASURE HOW MUCH 477 00:22:46,360 --> 00:22:48,120 THEY EAT AND TAKE A SECOND GROUP 478 00:22:48,120 --> 00:22:51,760 OF LEPTIN DEFICIENT MICE AND 479 00:22:51,760 --> 00:22:53,200 ONLY LET THEM EAT THE SAME 480 00:22:53,200 --> 00:22:55,040 AMOUNT AS THE LEPTIN TREATED 481 00:22:55,040 --> 00:22:55,320 MICE. 482 00:22:55,320 --> 00:22:57,480 THEN YOU MEASURE DIFFERENCES IN 483 00:22:57,480 --> 00:22:58,960 YOUR OUTCOMES OF INTEREST SO WE 484 00:22:58,960 --> 00:23:02,200 HAVE TWO GROUPS OF MICE, ONE 485 00:23:02,200 --> 00:23:03,320 WITH LEPTIN AND ONE WITHOUT 486 00:23:03,320 --> 00:23:06,720 EATING THE SAME AMOUNT OF FOOD. 487 00:23:06,720 --> 00:23:11,160 STUDIES HAVE SHOWN IN MICE LEAPT 488 00:23:11,160 --> 00:23:17,120 INIMPROVES INSULIN RESISTANCE 489 00:23:17,120 --> 00:23:40,040 BUT NOT LIPE -- DISLIPDISLIPODEMIA. 490 00:23:40,040 --> 00:23:42,480 WE HAD ONE COHORT NOT PREVIOUSLY 491 00:23:42,480 --> 00:23:47,960 TREATED WITH LEPTIN AND TREATED 492 00:23:47,960 --> 00:23:49,560 WITH LEPTIN FOR TWO WEEKS DURING 493 00:23:49,560 --> 00:23:52,560 PERIOD TWO THE LEFTIN WITHDRAWAL 494 00:23:52,560 --> 00:23:54,960 COHORT HAD PATIENTS WITH 495 00:23:54,960 --> 00:23:56,160 LIPODYSTROPHY ALREADY TAKING 496 00:23:56,160 --> 00:23:56,360 LEPTIN. 497 00:23:56,360 --> 00:23:58,960 THEY WERE STUDIED ON THEIR USUAL 498 00:23:58,960 --> 00:24:02,360 DOSE OF LEPTIN IN PERIOD ONE AND 499 00:24:02,360 --> 00:24:04,360 TAKEN OFF LEPTIN FOR TWO WEEKS 500 00:24:04,360 --> 00:24:05,400 IN PERIOD TWO. 501 00:24:05,400 --> 00:24:07,880 THE KEY TO THE STUDY DESIGN WAS 502 00:24:07,880 --> 00:24:10,840 FOOD INTAKE WAS HELD CONSTANT 503 00:24:10,840 --> 00:24:12,560 DURING BOTH PERIOD ONE AND TWO 504 00:24:12,560 --> 00:24:16,120 AS PATIENTS WERE HOUSED 505 00:24:16,120 --> 00:24:19,720 IN-PATIENT AT THE CLINICAL 506 00:24:19,720 --> 00:24:22,160 CENTER ALLOWING US TO ASSESS 507 00:24:22,160 --> 00:24:25,400 METABOLIC HEALTH IN ON LEPTIN 508 00:24:25,400 --> 00:24:26,760 AND OFF LEPTIN CONDITIONS WITH 509 00:24:26,760 --> 00:24:28,120 NO DIFFERENCE IN FOOD INTAKE. 510 00:24:28,120 --> 00:24:29,920 FOR OUR RESULTS TO BE 511 00:24:29,920 --> 00:24:30,960 INTERPRETABLE WE FIRST HAD TO 512 00:24:30,960 --> 00:24:33,520 SHOW OUR EXPERIMENTAL DESIGN WAS 513 00:24:33,520 --> 00:24:33,800 SUCCESSFUL. 514 00:24:33,800 --> 00:24:37,640 THOUGH WE ASKED PATIENTS TO EAT 515 00:24:37,640 --> 00:24:39,360 100% OF THE FOOD WE PROVIDED, NO 516 00:24:39,360 --> 00:24:41,640 MORE, NO LESS. 517 00:24:41,640 --> 00:24:43,320 WE DIDN'T FORCE FEED THEM. 518 00:24:43,320 --> 00:24:46,600 INSTEAD WE MEASURED UNEATEN FOOD 519 00:24:46,600 --> 00:24:47,800 AND CALCULATED ACTUAL FOOD 520 00:24:47,800 --> 00:24:48,040 INTAKE. 521 00:24:48,040 --> 00:24:49,760 THIS SHOWS THE MEAN DIFFERENCE 522 00:24:49,760 --> 00:24:52,160 IN FOOD INTAKE BETWEEN THE ON 523 00:24:52,160 --> 00:24:55,320 AND OFF LEPTIN CONDITIONS IN THE 524 00:24:55,320 --> 00:24:57,480 LEPTIN INITIATION COHORT SHOWN 525 00:24:57,480 --> 00:25:01,760 ON THE LEFT AND THE LEPTIN 526 00:25:01,760 --> 00:25:03,080 WITHDRAWAL ON THE RIGHT. 527 00:25:03,080 --> 00:25:06,160 NUMBERS GREATER THAN ZERO MEAN 528 00:25:06,160 --> 00:25:08,360 SUBJECTS ATE MORE IN THE ON 529 00:25:08,360 --> 00:25:10,440 LEPTIN CONDITION AND LESS THAN 530 00:25:10,440 --> 00:25:13,560 ZERO MEANS THEY EIGHT MORE. 531 00:25:13,560 --> 00:25:14,160 FORTUNATELY OUR PATIENTS 532 00:25:14,160 --> 00:25:15,800 COMPLIED PRETTY WELL WITH THE 533 00:25:15,800 --> 00:25:17,240 STUDY AND FOUND NO STATISTICAL 534 00:25:17,240 --> 00:25:18,440 DIFFERENCES IN FOOD INTAKE IN 535 00:25:18,440 --> 00:25:20,800 THE ON VERSUS OFF LEPTIN PERIODS 536 00:25:20,800 --> 00:25:23,680 IN EITHER THE INITIATION COHORT 537 00:25:23,680 --> 00:25:24,760 IN KWHOEM THE DIFFERENCE WAS 538 00:25:24,760 --> 00:25:27,560 VERY CLOSE TO ZERO OR THE 539 00:25:27,560 --> 00:25:29,440 WITHDRAWAL COHORT IN WHO HAD 540 00:25:29,440 --> 00:25:31,920 ABOUT 60 CALORIES PER DAY LESS 541 00:25:31,920 --> 00:25:36,000 FOOD INTAKE IN THE OFF LEPTIN 542 00:25:36,000 --> 00:25:37,560 AVERAGE BUT WITH NO STATISTICAL 543 00:25:37,560 --> 00:25:39,040 DIFFERENCE BETWEEN THE ON AND 544 00:25:39,040 --> 00:25:51,400 OFF PERIODS. 545 00:25:51,400 --> 00:25:54,720 THIS GRAPH SHOWS INSULIN 546 00:25:54,720 --> 00:25:55,920 SENSITIVITY WITH A GLYCEMIC 547 00:25:55,920 --> 00:25:56,320 CLAMP. 548 00:25:56,320 --> 00:25:58,760 FOR THIS STUDY HIGHER VALUES 549 00:25:58,760 --> 00:26:00,360 INDICATE GREATER INSULIN 550 00:26:00,360 --> 00:26:02,160 SENSITIVITY AND LOWER VALUES 551 00:26:02,160 --> 00:26:03,920 INDICATE GREATER INSULIN 552 00:26:03,920 --> 00:26:04,360 RESISTANCE. 553 00:26:04,360 --> 00:26:07,040 THE LEPTIN INITIATION COHORT 554 00:26:07,040 --> 00:26:09,160 SHOWN ON THE LEFT AND WITHDRAWAL 555 00:26:09,160 --> 00:26:11,040 COHORT ON THE RIGHT. 556 00:26:11,040 --> 00:26:13,320 THE WHITE BARS SHOW THE OFF 557 00:26:13,320 --> 00:26:15,400 LEPTIN CONDITIONS AND THE BLACK 558 00:26:15,400 --> 00:26:16,360 BARS SHOW THE ON LEPTIN 559 00:26:16,360 --> 00:26:17,800 CONDITION FOR BOTH GROUPS. 560 00:26:17,800 --> 00:26:20,000 INSULIN SENSITIVITY WAS GREATER 561 00:26:20,000 --> 00:26:22,920 IN THE ON LEPTIN CONDITION IN 562 00:26:22,920 --> 00:26:24,280 BOTH COHORTS SHOWING THAT AS IT 563 00:26:24,280 --> 00:26:28,680 DOES IN RODENTS, IT IMPROVE 564 00:26:28,680 --> 00:26:30,320 SENSITIVITY INDEPENDENT OF FOOD 565 00:26:30,320 --> 00:26:31,120 INTAKE IN HUMANS. 566 00:26:31,120 --> 00:26:33,160 WHETHER THIS IS MEDIATED THROUGH 567 00:26:33,160 --> 00:26:35,360 EFFECTS OF LEPTIN IN THE CENTRAL 568 00:26:35,360 --> 00:26:37,360 NERVOUS SYSTEM OR ACTIONS IN THE 569 00:26:37,360 --> 00:26:37,880 PERIPHERY REMAINS TO BE 570 00:26:37,880 --> 00:26:41,760 DETERMINED. 571 00:26:41,760 --> 00:26:43,520 INTERESTINGLY WE ALSO FOUND THAT 572 00:26:43,520 --> 00:26:46,360 IN CONTRAST TO RODENT STUDIES, 573 00:26:46,360 --> 00:26:48,960 LEPTIN ALSO IMPROVED 574 00:26:48,960 --> 00:26:49,560 TRIGLYCERIDES INDEPENDENT OF 575 00:26:49,560 --> 00:26:51,760 FOOD INTAKE IN HUMANS AT LEAST 576 00:26:51,760 --> 00:26:53,720 WITHIN THE LEPTIN INITIATION 577 00:26:53,720 --> 00:26:54,160 COHORT. 578 00:26:54,160 --> 00:26:56,160 THIS IS ONLY ONE OF MANY ASPECTS 579 00:26:56,160 --> 00:26:58,360 OF LEPTIN BIOLOGY THAT APPEARED 580 00:26:58,360 --> 00:27:01,240 TO DIFFER IN RODENTS AND HUMANS 581 00:27:01,240 --> 00:27:03,320 AND EMPHASIZES THE IMPORTANCE OF 582 00:27:03,320 --> 00:27:04,520 CONDUCTING RESEARCH IN HUMAN 583 00:27:04,520 --> 00:27:07,280 SUBJECTS. 584 00:27:07,280 --> 00:27:10,960 SO TO RETURN TO OUR MODEL OF 585 00:27:10,960 --> 00:27:15,120 LEPTIN BIOLOGY WE CAN ADD 586 00:27:15,120 --> 00:27:17,720 GENERALIZED LIPODYSTROPHY WHERE 587 00:27:17,720 --> 00:27:21,760 LEPTIN THERAPY DECREASES 588 00:27:21,760 --> 00:27:22,040 APPETITE. 589 00:27:22,040 --> 00:27:24,640 I DIDN'T SHOW THIS DATA BUT WE 590 00:27:24,640 --> 00:27:26,240 FOUND IT REVERSES OTHER 591 00:27:26,240 --> 00:27:30,520 ADAPTATION IN PATIENTS WITH 592 00:27:30,520 --> 00:27:31,640 LIPODYSTROPHY INCLUDING 593 00:27:31,640 --> 00:27:34,160 INCREASING THYROID HORMONE AND 594 00:27:34,160 --> 00:27:35,880 PERMITTING NORMAL PUBERTY AND 595 00:27:35,880 --> 00:27:36,200 REPRODUCTION. 596 00:27:36,200 --> 00:27:40,360 IN ADDITION, PATIENTS WITH 597 00:27:40,360 --> 00:27:43,000 GENERALIZED LIPODYSTROPHY ADDED 598 00:27:43,000 --> 00:27:45,520 TO OUR KNOWLEDGE OF THIS BY 599 00:27:45,520 --> 00:27:47,680 SHOWING IT INCREASES LEPTIN 600 00:27:47,680 --> 00:27:49,760 SENSITIVITY EVEN BEYOND THE 601 00:27:49,760 --> 00:27:55,040 EFFECTS TO REDUCE APPETITE AS 602 00:27:55,040 --> 00:28:00,840 WELL AS DIABETES CONTROL AND 603 00:28:00,840 --> 00:28:01,160 HYPERGLYCEMIA. 604 00:28:01,160 --> 00:28:04,120 WE LEARN GENERALIZED 605 00:28:04,120 --> 00:28:06,680 LIPODYSTROPHY IS A SEVERE LEPTIN 606 00:28:06,680 --> 00:28:12,760 STATE RECEPTIVE TO LEPTIN 607 00:28:12,760 --> 00:28:13,160 THERAPY. 608 00:28:13,160 --> 00:28:16,400 HOW LOW DOES IT NEED TO BE AND 609 00:28:16,400 --> 00:28:17,920 WHERE CAN WE DRAW THE LINE 610 00:28:17,920 --> 00:28:19,920 BETWEEN LEPTIN RESPONSIVE AND 611 00:28:19,920 --> 00:28:21,360 NON-RESPONSIVE STATES? 612 00:28:21,360 --> 00:28:25,120 WE STUDIED PATIENTS WITH PARTIAL 613 00:28:25,120 --> 00:28:26,600 LIPODYSTROPHY IN WHOM THERE'S A 614 00:28:26,600 --> 00:28:29,120 LARGE RANGE OF SERUM LEPTIN 615 00:28:29,120 --> 00:28:29,480 CONCENTRATIONS. 616 00:28:29,480 --> 00:28:31,000 TO EVALUATE THE EFFICACY OF 617 00:28:31,000 --> 00:28:34,120 LEPTIN TREATMENT IN PATIENTS 618 00:28:34,120 --> 00:28:38,360 WITH GENERALIZED VERSUS PARTIAL 619 00:28:38,360 --> 00:28:41,120 FORMS OF LIPODYSTROPHY WE 620 00:28:41,120 --> 00:28:44,360 STUDIED 86 PATIENTS WITH 621 00:28:44,360 --> 00:28:48,440 LIPODYSTROPHY AND LOOKED AT THE 622 00:28:48,440 --> 00:28:50,720 EFFECT ON DIABETES CONTROL 623 00:28:50,720 --> 00:28:54,600 MEASURED BY HEMOGLOBIN A1C AND 624 00:28:54,600 --> 00:28:57,600 TRIGLYCERIDES IN 55 PATIENTS 625 00:28:57,600 --> 00:29:00,160 WITH A MEAN SERUM LEPTIN OF 1 626 00:29:00,160 --> 00:29:02,400 AND 32 WITH PARTIAL 627 00:29:02,400 --> 00:29:05,160 LIPODYSTROPHY WITH A MEAN SERUM 628 00:29:05,160 --> 00:29:06,000 LEPTIN OF AROUND 6. 629 00:29:06,000 --> 00:29:09,760 IN THE LEFT YOU SEE REDUCTION IN 630 00:29:09,760 --> 00:29:11,600 HEMOGLOBIN A1C AFTER SIX AND 12 631 00:29:11,600 --> 00:29:13,560 MONTHS OF TREATMENT. 632 00:29:13,560 --> 00:29:16,200 PATIENTS WITH GENERALIZED 633 00:29:16,200 --> 00:29:17,760 LIPODYSTROPHY ARE IN BLUE AND 634 00:29:17,760 --> 00:29:19,960 WITH PARTIAL IN RED. 635 00:29:19,960 --> 00:29:27,720 THOUGH A1C DIG SIGNIFICANTLY 636 00:29:27,720 --> 00:29:30,240 DECREASED IN BOTH GROUPS SOME 637 00:29:30,240 --> 00:29:32,560 REACHED LEVELS LESS THAN 7%. 638 00:29:32,560 --> 00:29:36,360 ON THE RIGHT YOU SEE REDUCTIONS 639 00:29:36,360 --> 00:29:38,640 IN TRIGLYCERIDES SHOWING 640 00:29:38,640 --> 00:29:40,360 IMPROVEMENT IN GENERALIZED AND 641 00:29:40,360 --> 00:29:42,640 PARTIAL LIPODYSTROPHY GROUPS BUT 642 00:29:42,640 --> 00:29:45,120 GREATER EFFICACY AMONG THOSE 643 00:29:45,120 --> 00:29:47,080 WITH GENERALIZED LIPODYSTROPHY. 644 00:29:47,080 --> 00:29:49,960 ARMED WITH THE KNOWLEDGE THAT 645 00:29:49,960 --> 00:29:53,880 PATIENTS WITH PARTIAL 646 00:29:53,880 --> 00:29:58,040 LIPODYSTROPHY HAVE SMALLER 647 00:29:58,040 --> 00:30:00,280 IMPROVEMENTS, THEY SET OUT TO 648 00:30:00,280 --> 00:30:02,480 ANSWER THE QUESTION HOW HIGH A 649 00:30:02,480 --> 00:30:04,360 SERUM LEPTIN LEVEL IS TO HIGH TO 650 00:30:04,360 --> 00:30:06,960 RESPOND TO LEPTIN TREATMENT IN 651 00:30:06,960 --> 00:30:10,080 PATIENTS WITH LEPTIN DYSTROPHY. 652 00:30:10,080 --> 00:30:11,360 IN COLLABORATION WITH THE 653 00:30:11,360 --> 00:30:13,200 UNIVERSITY OF MICHIGAN THEY 654 00:30:13,200 --> 00:30:16,320 ANALYZED DATA IN 143 PATIENTS 655 00:30:16,320 --> 00:30:16,760 WITH LIPODYSTROPHY. 656 00:30:16,760 --> 00:30:22,840 6 6 HAD ED AND 81 WITH PARTIAL 657 00:30:22,840 --> 00:30:27,360 AND WERE TREATED WITH OPEN LABEL 658 00:30:27,360 --> 00:30:29,400 LEPTIN AT NIH AND THE UNIVERSITY 659 00:30:29,400 --> 00:30:31,000 OF MICHIGAN. 660 00:30:31,000 --> 00:30:32,680 WE DEFINED PATIENTS AS 661 00:30:32,680 --> 00:30:36,280 RESPONDERS TO LEPTIN IF THEY 662 00:30:36,280 --> 00:30:38,640 ACHIEVED EITHER AN A1C REDUCTION 663 00:30:38,640 --> 00:30:40,960 OF AT LEAST 1% OR TRIGLYCERIDE 664 00:30:40,960 --> 00:30:46,560 REDUCTION OF AT LEAST 30%S. 665 00:30:46,560 --> 00:30:48,600 PATIENTS WERE NON DEFINERS IF 666 00:30:48,600 --> 00:30:50,320 THEY DIDN'T REACH EITHER OF 667 00:30:50,320 --> 00:30:50,960 THOSE BENCH MARKS. 668 00:30:50,960 --> 00:30:53,640 WE COMPARED SERUM LEPTIN IN 669 00:30:53,640 --> 00:30:55,480 PATIENTS WITH GENERALIZED 670 00:30:55,480 --> 00:30:57,840 LIPODYSTROPHY IN RED CIRCLES AND 671 00:30:57,840 --> 00:31:00,360 WITH PARTIAL IN THE BLUE AMONG 672 00:31:00,360 --> 00:31:02,760 NON-RESPONDERS NR ON THE LEFT 673 00:31:02,760 --> 00:31:06,040 COMPARED TO RESPONDERS R ON THE 674 00:31:06,040 --> 00:31:06,240 RIGHT. 675 00:31:06,240 --> 00:31:08,280 NOW WHEN WE COMBINED BOTH 676 00:31:08,280 --> 00:31:10,560 PATIENTS WITH GENERALIZED AND 677 00:31:10,560 --> 00:31:13,720 PARTIAL LIPO DE JOE DIODYSTROPHY YOU CAN 678 00:31:13,720 --> 00:31:15,760 SEE SERUM LEPTIN WAS LOWER AMONG 679 00:31:15,760 --> 00:31:18,360 THE RESPONDERS COMPARED TO THE 680 00:31:18,360 --> 00:31:18,760 NON-RESPONDERS. 681 00:31:18,760 --> 00:31:24,320 HOWEVER, THIS IS DRIVEN BY THE 682 00:31:24,320 --> 00:31:25,600 HUGE PREPONDERANCE WITH THOSE 683 00:31:25,600 --> 00:31:27,200 WITH LOWER LEPTIN CONCENTRATIONS 684 00:31:27,200 --> 00:31:30,160 WITHIN THE RESPONDER CATEGORY. 685 00:31:30,160 --> 00:31:32,320 NOW IN THE RIGHT HAND GRAPH 686 00:31:32,320 --> 00:31:35,160 WE'RE ISOLATING PATIENTS WITH 687 00:31:35,160 --> 00:31:35,960 PARTIAL LIPODYSTROPHY IN BLUE 688 00:31:35,960 --> 00:31:39,440 AND AMONG PATIENTS WITH PARTIAL 689 00:31:39,440 --> 00:31:41,480 LIPODYSTROPHY THERE'S NO 690 00:31:41,480 --> 00:31:43,200 STATISTICAL DIFFERENCE IN SERUM 691 00:31:43,200 --> 00:31:46,640 LEPTIN IN RESPONDERS VERSUS 692 00:31:46,640 --> 00:31:47,160 NON-RESPONDERS. 693 00:31:47,160 --> 00:31:49,360 WE THEN ENDEAVORED TO FIND A CUT 694 00:31:49,360 --> 00:31:54,160 POINT TO PREDICT LEPTIN 695 00:31:54,160 --> 00:31:55,360 RESPONSIVENESS USING RECEIVER 696 00:31:55,360 --> 00:31:57,920 OPERATOR CURVE ANALYSTS AND WE 697 00:31:57,920 --> 00:31:58,560 ANALYZED EVERY POSSIBLE CUT 698 00:31:58,560 --> 00:32:00,120 POINT FOR SERUM LEPTIN WITHIN 699 00:32:00,120 --> 00:32:04,160 OUR DATA SET AND CALCULATE THE 700 00:32:04,160 --> 00:32:05,520 SENSITIVITY AND SPECIFICITY TO 701 00:32:05,520 --> 00:32:07,600 PREDICT RESPONDER VERSUS 702 00:32:07,600 --> 00:32:10,240 NON-RESPONDER STATUS. 703 00:32:10,240 --> 00:32:12,640 WE THEN PLOT 1 MINUS SPECIFICITY 704 00:32:12,640 --> 00:32:14,960 ON THE X AND SENSITIVITY ON THE 705 00:32:14,960 --> 00:32:16,160 Y AXIS. 706 00:32:16,160 --> 00:32:19,280 IF LEPTIN HAS ZERO 707 00:32:19,280 --> 00:32:19,800 DISCRIMINATORY POWER TO 708 00:32:19,800 --> 00:32:20,560 DETERMINE RESPONDER STATUS WE'LL 709 00:32:20,560 --> 00:32:26,680 SEE THE DOTTED RED LINE SHOWN ON 710 00:32:26,680 --> 00:32:27,360 THE DIAGONAL. 711 00:32:27,360 --> 00:32:30,120 ON THE OTHER HAND IF SERUM 712 00:32:30,120 --> 00:32:30,960 LEPTIN HAD PERFECT 713 00:32:30,960 --> 00:32:31,960 DISCRIMINATORY POWER WE WOULD 714 00:32:31,960 --> 00:32:34,080 SEE A LINE GOING UP THE LEFT AND 715 00:32:34,080 --> 00:32:36,120 ACROSS THE TOP WITH AN AREA 716 00:32:36,120 --> 00:32:38,760 UNDER THE CURVE OF 1 OR 100%. 717 00:32:38,760 --> 00:32:41,360 THE ACTUAL DATA IS SHOWN IN THIS 718 00:32:41,360 --> 00:32:44,240 SOLID BLACK LINE HERE WHICH 719 00:32:44,240 --> 00:32:46,840 REPRESENTS THE COMBINED COHORT 720 00:32:46,840 --> 00:32:49,160 OF GENERALIZED PLUS 721 00:32:49,160 --> 00:32:50,400 LIPODYSTROPHY. 722 00:32:50,400 --> 00:32:54,120 IN THIS GROUP SERUM LEPTIN HAD 723 00:32:54,120 --> 00:32:55,960 FAIR PREDICTIVE POWER WITH AN 724 00:32:55,960 --> 00:32:59,680 AREA UNDER THE CURVE OF 0.74. 725 00:32:59,680 --> 00:33:03,120 HOWEVER, FOR THE SUB GROUP WITH 726 00:33:03,120 --> 00:33:06,560 PARTIAL LIPODYSTROPHY SHOWN IN 727 00:33:06,560 --> 00:33:07,160 THE DASHED BLUE LINE THE AREA 728 00:33:07,160 --> 00:33:09,080 UNDER THE CURVE WAS ONLY 6.3 AND 729 00:33:09,080 --> 00:33:09,720 NOT STATISTICALLY DIFFERENT FROM 730 00:33:09,720 --> 00:33:12,240 CHANCE. 731 00:33:12,240 --> 00:33:14,560 THE OPTIMAL CUT POINT BASED ON 732 00:33:14,560 --> 00:33:16,760 THE SUM OF SENSITIVITY AND 733 00:33:16,760 --> 00:33:20,160 FESTIVITY WE CAN IDENTIFY WAS 734 00:33:20,160 --> 00:33:25,640 THE SERUM LEPTIN BUT IT HAS LOW 735 00:33:25,640 --> 00:33:27,360 ACCURACY WITH THE SENSITIVITY OF 736 00:33:27,360 --> 00:33:32,120 ONLY 56% AND SPECIFICITY OF 78% 737 00:33:32,120 --> 00:33:34,120 TO PREDICT RESPONDER STATUS. 738 00:33:34,120 --> 00:33:36,440 SO WHY WAS SERUM LECTIN SUCH A 739 00:33:36,440 --> 00:33:38,680 POOR PREDICTOR OF RESPONSE TO 740 00:33:38,680 --> 00:33:40,160 LEPTIN TREATMENT? 741 00:33:40,160 --> 00:33:42,480 WELL, ONE POTENTIAL EXPLANATION 742 00:33:42,480 --> 00:33:44,320 SAID THIS DATA CAME FROM OPEN 743 00:33:44,320 --> 00:33:45,480 LABEL STUDIES. 744 00:33:45,480 --> 00:33:48,080 I'M SURE YOU'RE ALL FAMILIAR 745 00:33:48,080 --> 00:33:49,520 WITH THE HAWTHORNE EFFECT AND 746 00:33:49,520 --> 00:33:51,960 YOU BRING THEM IN WHETHER 747 00:33:51,960 --> 00:33:54,240 THEY'RE GETTING DRUG NORT AND 748 00:33:54,240 --> 00:33:55,840 THE LACK OF A PLACEBO GROUP 749 00:33:55,840 --> 00:33:57,040 MAKES IT IMPOSSIBLE TO 750 00:33:57,040 --> 00:33:57,960 DISTINGUISH HOW MUCH IMPROVEMENT 751 00:33:57,960 --> 00:33:59,880 IS RELATED TO THE ACTUAL DRUG, 752 00:33:59,880 --> 00:34:01,120 LEPTIN AND HOW MUCH WAS JUST 753 00:34:01,120 --> 00:34:03,760 RELATED TO STUDY PARTICIPATION. 754 00:34:03,760 --> 00:34:06,600 IN ADDITION, AS IN MOST STUDIES, 755 00:34:06,600 --> 00:34:08,040 WE OBSERVED GREATER IMPROVEMENTS 756 00:34:08,040 --> 00:34:10,840 IN METABOLIC PARAMETERS IN THE 757 00:34:10,840 --> 00:34:11,960 PATIENTS WITH THE MOST EXTREME 758 00:34:11,960 --> 00:34:14,120 BASELINE DISEASE AND THIS COULD 759 00:34:14,120 --> 00:34:14,960 SIMPLY REPRESENT PROGRESSION TO 760 00:34:14,960 --> 00:34:16,360 THE MEAN AND HAVE NOTHING TO DO 761 00:34:16,360 --> 00:34:19,120 WITH LEPTIN TREATMENT. 762 00:34:19,120 --> 00:34:20,880 FURTHERMORE, LEPTIN ASSAYS ARE 763 00:34:20,880 --> 00:34:23,760 POORLY STANDARDIZED AND SO 764 00:34:23,760 --> 00:34:24,760 VARIABILITY IN THE ASSAY ITSELF 765 00:34:24,760 --> 00:34:26,080 MAY HAVE CONTRIBUTED TO OUR LACK 766 00:34:26,080 --> 00:34:28,800 OF ABILITY TO DETECT THE LEPTIN 767 00:34:28,800 --> 00:34:32,320 CUT POINT AND FINALLY LEPTIN IS 768 00:34:32,320 --> 00:34:33,440 ACUTELY REGULATED BY ENERGY 769 00:34:33,440 --> 00:34:35,840 BALANCE AS WELL AS BEING 770 00:34:35,840 --> 00:34:36,960 REGULATED IN THE LONG TERM BY 771 00:34:36,960 --> 00:34:38,680 FAT MASS AND THUS THE DIET THAT 772 00:34:38,680 --> 00:34:41,080 PATIENTS WERE CONSUMING OVER THE 773 00:34:41,080 --> 00:34:42,960 DAYS PROCEEDING THE MEASUREMENT 774 00:34:42,960 --> 00:34:45,080 OF THEIR SERUM LEPTIN COULD HAVE 775 00:34:45,080 --> 00:34:47,640 AFFECTED THAT MEASUREMENT. 776 00:34:47,640 --> 00:34:49,680 THUS FAR, I'VE SHOWN YOU DATA ON 777 00:34:49,680 --> 00:34:52,120 HOW SERUM LEPTIN CONCENTRATION 778 00:34:52,120 --> 00:34:54,360 DOES OR DOESN'T PREDICT EFFECTS 779 00:34:54,360 --> 00:34:58,800 OF LEPTIN TREATMENT ON APPETITE, 780 00:34:58,800 --> 00:35:05,120 DIABETES AND DYSLIPIDEMIA AND 781 00:35:05,120 --> 00:35:06,360 ABOUT ANOTHER COMPLICATION? 782 00:35:06,360 --> 00:35:08,360 I'LL SHOW YOU DATA THAT SUGGESTS 783 00:35:08,360 --> 00:35:13,360 THAT LEPTIN'S EFFECTS ON 784 00:35:13,360 --> 00:35:14,280 STEATO-HEPATITIS MAY EXTEND 785 00:35:14,280 --> 00:35:15,000 ACROSS A BROADER RANGE 786 00:35:15,000 --> 00:35:17,560 POTENTIALLY ALLOWING US TO 787 00:35:17,560 --> 00:35:20,680 EXTEND EFFICACY TO PATIENT WITH 788 00:35:20,680 --> 00:35:23,760 HIGHER LEPTIN LEVELS AND COMMON 789 00:35:23,760 --> 00:35:24,040 CONDITIONS. 790 00:35:24,040 --> 00:35:26,640 A GROUP AT THE UNIVERSITY OF 791 00:35:26,640 --> 00:35:32,320 MICHIGAN SHOWED LEPTIN TREATMENT 792 00:35:32,320 --> 00:35:36,320 IMPROVED HISTOLOGY OF 793 00:35:36,320 --> 00:35:39,080 NON-ALCOHOL NASH IN TWO COHORTS. 794 00:35:39,080 --> 00:35:41,360 SHE TESTED EFFECTS OF LEFTIN IN 795 00:35:41,360 --> 00:35:46,840 SIX MEN WITH NON-ALCOHOLIC 796 00:35:46,840 --> 00:35:48,600 STEATOHEPATITIS IN THE LOWEST 797 00:35:48,600 --> 00:35:50,680 QUARTILE TO THEIR BODY MASS AND 798 00:35:50,680 --> 00:35:52,560 TERMED THIS LOW LEPTIN NASH. 799 00:35:52,560 --> 00:35:54,280 THE MEAN CONCENTRATION IN THE 800 00:35:54,280 --> 00:35:57,240 PATIENTS WAS 7 NANOGRAMS PER ML 801 00:35:57,240 --> 00:36:00,880 WITH A RANGE OF 3.6 UP TO 10.9. 802 00:36:00,880 --> 00:36:03,640 IN ALL SIX SUBJECTS HISTOLOGIC 803 00:36:03,640 --> 00:36:07,560 NASH SCORES IMPROVED AFTER SIX 804 00:36:07,560 --> 00:36:09,480 MONTHS OF LEPTIN ADMINISTRATION. 805 00:36:09,480 --> 00:36:11,560 SHE ALSO STUDIED 15 SUBJECTS 806 00:36:11,560 --> 00:36:13,440 WITH PARTIAL LIPODYSTROPHY WITH 807 00:36:13,440 --> 00:36:15,960 A MEAN SERUM LEPTIN OF 16.2 808 00:36:15,960 --> 00:36:21,120 RANGE FROM 14.8 UP TO 67.1. 809 00:36:21,120 --> 00:36:23,360 THOUGH IMPROVEMENTS IN NASH 810 00:36:23,360 --> 00:36:25,080 HISTOLOGY AFTER LEPTIN TREATMENT 811 00:36:25,080 --> 00:36:26,960 WERE MORE VARIABLE IN THE 812 00:36:26,960 --> 00:36:29,760 COHORT, AGAIN, THERE WAS 813 00:36:29,760 --> 00:36:31,360 STATISTICALLY SIGNIFICANT 814 00:36:31,360 --> 00:36:35,560 IMPROVEMENT SUGGESTI INING LEPTIN 815 00:36:35,560 --> 00:36:39,840 MIGHT IMPROVE NASH EVEN IN 816 00:36:39,840 --> 00:36:41,760 PATIENTS WITH QUITE HIGH SERUM 817 00:36:41,760 --> 00:36:42,880 CONCENTRATIONS AND WELL LOOKED 818 00:36:42,880 --> 00:36:45,760 AT THE MECHANISMS IN WHICH IT 819 00:36:45,760 --> 00:36:49,080 IMPROVES NASH IN PATIENTS WITH 820 00:36:49,080 --> 00:36:49,560 LIPODYSTROPHY. 821 00:36:49,560 --> 00:36:52,040 THIS WAS DONE BY A MEDICAL 822 00:36:52,040 --> 00:36:53,440 STUDENT IN MY LAB WITH 823 00:36:53,440 --> 00:36:56,360 COLLABORATION WITH THE 824 00:36:56,360 --> 00:36:58,320 UNIVERSITY OF MISSOURI. 825 00:36:58,320 --> 00:37:03,160 TO UNDERSTAND HOW LEPTIN 826 00:37:03,160 --> 00:37:06,560 IMPROVES STEATOHEPATITIS WE HAVE 827 00:37:06,560 --> 00:37:13,920 TO UNDERSTAND HOW LIPPED LIPIDS 828 00:37:13,920 --> 00:37:16,400 ACCUMULATE IN THE LIVER LIPE OL 829 00:37:16,400 --> 00:37:20,880 SIS CAN BE TAKEN UP BY THE 830 00:37:20,880 --> 00:37:26,000 LIVER. 831 00:37:26,000 --> 00:37:27,560 TRIGLYCERIDES CAN BE TAKEN UP 832 00:37:27,560 --> 00:37:31,760 AND ONCE IN THE HEPATOSITE LDL 833 00:37:31,760 --> 00:37:46,960 CAN CONTRIBUTE TO STEATO 834 00:37:46,960 --> 00:37:47,960 STEATOHEPATIT 835 00:37:47,960 --> 00:37:48,320 STEATOHEPATITIS. 836 00:37:48,320 --> 00:37:49,640 WHAT ARE THE MECHANISMS WHERE IT 837 00:37:49,640 --> 00:37:53,520 CAN REDUCE ACCUMULATION? 838 00:37:53,520 --> 00:37:56,840 OUR GROUP DEMONSTRATED LEPTIN 839 00:37:56,840 --> 00:38:07,760 REDUCES FOOD INTAKE AND REDUCES 840 00:38:07,760 --> 00:38:12,440 ADIPOCYTE TO REDUCE TRIGLYCERIDE 841 00:38:12,440 --> 00:38:14,080 ACCUMULATION. 842 00:38:14,080 --> 00:38:14,880 RODENT DATA SUPPORT ADDITIONAL 843 00:38:14,880 --> 00:38:17,680 ROLES OF LEPTIN TO ENHANCE THE 844 00:38:17,680 --> 00:38:21,840 LDL EXPORT FROM THE LIVER AND 845 00:38:21,840 --> 00:38:29,520 DECREASE STEATOLIPOGENESIS. 846 00:38:29,520 --> 00:38:31,640 WE STUDIED WHETHER IT REDUCED IT 847 00:38:31,640 --> 00:38:34,240 IN PATIENTS WITH LIPODYSTROPHY. 848 00:38:34,240 --> 00:38:41,320 WHAT IS DE NOVO LIPOGENESIS. 849 00:38:41,320 --> 00:38:43,360 THEY'RE CARBOHYDRATE PRECURSORS. 850 00:38:43,360 --> 00:38:47,160 IT OCCURS PRIMARILY IN THE LIVER 851 00:38:47,160 --> 00:38:51,960 WITH A MINOR CONTRIBUTION FROM 852 00:38:51,960 --> 00:38:54,360 ADIPOSE TISSUE. 853 00:38:54,360 --> 00:39:01,280 CARBOHYDRATES STIMULATE THROUGH 854 00:39:01,280 --> 00:39:04,000 CRHEBP AND INSULIN IS THOUGHT TO 855 00:39:04,000 --> 00:39:08,400 BE NECESSARY IN INSULIN 856 00:39:08,400 --> 00:39:11,480 RESISTANT STATES THROUGH 857 00:39:11,480 --> 00:39:15,720 INCREASED EXPRESSION OF SREBP1 A 858 00:39:15,720 --> 00:39:17,440 MAJOR TRANSCRIPTION FACTOR. 859 00:39:17,440 --> 00:39:22,400 WHY DO WE CARE ABOUT DE NOVO 860 00:39:22,400 --> 00:39:23,080 LIPOGENESIS. 861 00:39:23,080 --> 00:39:25,560 THIS ILLUSTRATE THE RELATIVE 862 00:39:25,560 --> 00:39:26,440 CONTRIBUTIONS OF DIFFERENT 863 00:39:26,440 --> 00:39:30,960 SOURCES OF DLDD TRIGLYCERIDE IN 864 00:39:30,960 --> 00:39:32,920 PATIENTS WITH LOW LIVER FAT 865 00:39:32,920 --> 00:39:33,920 COMPARED TO THOSE WITH HIGH 866 00:39:33,920 --> 00:39:35,320 LIVER FAT ON THE RIGHT. 867 00:39:35,320 --> 00:39:38,560 THE ONLY SIGNIFICANT DIFFERENCE 868 00:39:38,560 --> 00:39:41,080 BETWEEN THE TWO GROUPS IS 869 00:39:41,080 --> 00:39:43,080 TRIGLYCERIDES DERIVED FROM DE 870 00:39:43,080 --> 00:39:44,680 NOVO LIPOGENESIS. 871 00:39:44,680 --> 00:39:48,360 THE AMOUNT OF THE LDL 872 00:39:48,360 --> 00:39:55,240 TRIGLYCERIDE DERIVED WAS 250% 873 00:39:55,240 --> 00:39:56,920 HIGHER IN SUBJECTS WITH HIGH 874 00:39:56,920 --> 00:40:00,120 LIVER FAT SHOWING A ROLE OF 875 00:40:00,120 --> 00:40:02,720 INCREASED DE NOVO LIPOGENESIS IN 876 00:40:02,720 --> 00:40:05,640 THE PATHOGENESIS OF LIVER 877 00:40:05,640 --> 00:40:08,320 DISEASE AND IN THE REPORT OF 878 00:40:08,320 --> 00:40:12,200 THREE PATIENTS DE NOVO 879 00:40:12,200 --> 00:40:13,000 LIPOGENESIS WAS INCREASED 880 00:40:13,000 --> 00:40:16,360 SUGGESTING IT MAY PLAY A ROLE IN 881 00:40:16,360 --> 00:40:19,120 LIPODYSTROPHY ASSOCIATED FATTY 882 00:40:19,120 --> 00:40:21,080 LIVER DISEASE AS WELL AS OBESITY 883 00:40:21,080 --> 00:40:22,000 RELATED FATTY LIVER DISEASE. 884 00:40:22,000 --> 00:40:23,960 WE HYPOTHESIZED IT WOULD BE 885 00:40:23,960 --> 00:40:27,680 ELEVATED IN PATIENTS WITH 886 00:40:27,680 --> 00:40:29,200 LIPODYSTROPHY AND DECREASED 887 00:40:29,200 --> 00:40:39,040 AFTER ADMINISTRATION RESULTING 888 00:40:39,040 --> 00:40:54,960 IN STEATOLIPO GENESIS AND WE 889 00:40:54,960 --> 00:40:55,560 ENRICHED THE BODY WATER POOL AND 890 00:40:55,560 --> 00:40:56,200 IN THE MORNING BLOOD WAS DRAWN 891 00:40:56,200 --> 00:41:00,800 AND THE INCORPORATION INTO RDLs 892 00:41:00,800 --> 00:41:02,400 WAS ANALYZED AND THESE DATA WERE 893 00:41:02,400 --> 00:41:05,120 USED TO CALCULATE THE PERCENTAGE 894 00:41:05,120 --> 00:41:09,440 OF TRIGLYCERIDE IN VLDL THAT 895 00:41:09,440 --> 00:41:11,960 DERIVED FROM DE NOVO LIPO 896 00:41:11,960 --> 00:41:12,560 GENESIS. 897 00:41:12,560 --> 00:41:14,880 OUR SUBJECT'S AGES RANGE FROM 14 898 00:41:14,880 --> 00:41:17,120 TO 65 YEARS OLD AND THE MAJORITY 899 00:41:17,120 --> 00:41:17,680 WERE FEMALE. 900 00:41:17,680 --> 00:41:19,920 BECAUSE MOST PATIENTS IN THIS 901 00:41:19,920 --> 00:41:22,640 GROUP HAD PARTIAL LIPODYSTROPHY, 902 00:41:22,640 --> 00:41:24,760 THE MEAN LEPTIN LEVEL PRIOR TO 903 00:41:24,760 --> 00:41:30,400 TREATMENT WAS 9.5 NANOGRAMS PER 904 00:41:30,400 --> 00:41:32,280 ML WHICH OVERLAPS LEVELS IN THE 905 00:41:32,280 --> 00:41:33,160 GENERAL POPULATION. 906 00:41:33,160 --> 00:41:37,000 THE HIGHEST LEVEL WAS 32 907 00:41:37,000 --> 00:41:38,720 NANOGRAMS PER ML IN THE OBESE 908 00:41:38,720 --> 00:41:38,920 RANGE. 909 00:41:38,920 --> 00:41:40,360 LEPTIN WAS AT MINISTERED AT A 910 00:41:40,360 --> 00:41:41,800 MEAN DOSE OF ABOUT 8 MILLIGRAMS 911 00:41:41,800 --> 00:41:43,560 PER DAY AND I WANT TO DWELL ON 912 00:41:43,560 --> 00:41:47,200 THAT DOSE FOR A MOMENT . 913 00:41:47,200 --> 00:41:49,320 I MENTIONED PREVIOUS LEPTIN 914 00:41:49,320 --> 00:41:51,120 TREATMENT WORKS AT HORMONE 915 00:41:51,120 --> 00:41:52,360 REPLACEMENT DOSES IN PATIENTS 916 00:41:52,360 --> 00:41:57,560 WITH CONGENITAL LEPTIN 917 00:41:57,560 --> 00:42:00,360 DEFICIENCY AND THE DOSE WAS WELL 918 00:42:00,360 --> 00:42:00,440 A 919 00:42:03,600 --> 00:42:05,240 -- ABOVE THAT. 920 00:42:05,240 --> 00:42:07,720 WE FOUND LEPTIN TREATMENT 921 00:42:07,720 --> 00:42:09,960 LOWERED BODY WEIGHT, IMPROVED 922 00:42:09,960 --> 00:42:12,080 PERIPHERAL AND HEPATIC INSULIN 923 00:42:12,080 --> 00:42:12,840 SENSITIVITY AND IMPROVED 924 00:42:12,840 --> 00:42:16,400 DIABETES CONTROL AS MEASURED BY 925 00:42:16,400 --> 00:42:19,520 HEMOGLOBIN A1C AND LOWERED 926 00:42:19,520 --> 00:42:21,760 HEPATIC CONTENT FROM 17.6% AT 927 00:42:21,760 --> 00:42:24,320 BASELINE TO 10% AFTER SIX 928 00:42:24,320 --> 00:42:26,760 MONTHS. 929 00:42:26,760 --> 00:42:28,360 THIS GRAPH SHOWS THE CHANGE IN 930 00:42:28,360 --> 00:42:31,360 THE PERCENTAGE OF THE LDL 931 00:42:31,360 --> 00:42:35,720 TRIGLYCERIDE THAT DERIVE FROM DE 932 00:42:35,720 --> 00:42:38,360 NOVO LIPOGENESIS TERMED PERCENT 933 00:42:38,360 --> 00:42:38,520 DNL. 934 00:42:38,520 --> 00:42:43,200 AFTER SIX MONTHS THE PERCENT OF 935 00:42:43,200 --> 00:42:45,680 LEPTIN OF TRIGLYCERIDES 936 00:42:45,680 --> 00:42:47,920 DECREASED FROM 21% AT BASELINE 937 00:42:47,920 --> 00:42:50,920 DOWN TO 7% AFTER LEPTIN 938 00:42:50,920 --> 00:42:51,840 TREATMENT. 939 00:42:51,840 --> 00:42:53,560 FOR COMPARISON IN LEAN HEALTHY 940 00:42:53,560 --> 00:42:57,120 INDIVIDUALS, DE NOVO LIPOGENESIS 941 00:42:57,120 --> 00:43:00,680 CONTRIBUTE 5% TO 10% OF THE 942 00:43:00,680 --> 00:43:03,160 TRIGLYCERIDE HERE INDICATED BY 943 00:43:03,160 --> 00:43:08,880 THE RED SHADING. 944 00:43:08,880 --> 00:43:10,640 AND THIS SHOWS THE AMOUNT BEFORE 945 00:43:10,640 --> 00:43:13,680 AND AFTER LEPTIN TREATMENT. 946 00:43:13,680 --> 00:43:16,680 REMARKABLY ABSOLUTE DE NOVO 947 00:43:16,680 --> 00:43:19,000 LIPOGENESIS DECREASED IN ALL 948 00:43:19,000 --> 00:43:23,040 SUBJECT S WITH A MEAN 88% 949 00:43:23,040 --> 00:43:26,160 REDUCTION FROM 54 TO 86 POINTS 950 00:43:26,160 --> 00:43:28,160 COMPARABLE TO THE NORMAL LEVEL 951 00:43:28,160 --> 00:43:32,000 OF 4 MILLIGRAMS SEEN IN LEAN 952 00:43:32,000 --> 00:43:33,240 HEALTHY INDIVIDUALS AS INDICATED 953 00:43:33,240 --> 00:43:36,280 BY THE RED SHADING. 954 00:43:36,280 --> 00:43:38,400 AS SHOWN IN THE LEFT HAND GRAPH, 955 00:43:38,400 --> 00:43:40,720 SERUM LEPTIN WAS NOT CORRELATED 956 00:43:40,720 --> 00:43:43,360 WITH DE NOVO LIPO GENESIS AT 957 00:43:43,360 --> 00:43:44,760 TREATMENT PRIOR TO LEPTIN 958 00:43:44,760 --> 00:43:46,720 TREATMENT HOWEVER, AS SEEN IN 959 00:43:46,720 --> 00:43:48,520 THE RIGHT HAND GRAPH LOWER SERUM 960 00:43:48,520 --> 00:43:52,320 LEPTIN LEVELS WERE ASSOCIATED 961 00:43:52,320 --> 00:43:54,960 WITH LOWER AMOUNTS OF DE NOVO 962 00:43:54,960 --> 00:43:56,360 LIPO GENESIS AFTER SIX MONTHS OF 963 00:43:56,360 --> 00:43:57,520 TREATMENT AND THIS IS CONSISTENT 964 00:43:57,520 --> 00:44:00,360 WITH WHAT A TOLD YOU SO FAR 965 00:44:00,360 --> 00:44:02,200 ABOUT LEFTIN BIOLOGY. 966 00:44:02,200 --> 00:44:04,560 THE MORE LEPTIN DEFICIENCY A 967 00:44:04,560 --> 00:44:06,680 PATIENT THE GREATER RESPONSE TO 968 00:44:06,680 --> 00:44:08,000 LEPTIN THERAPY INDICATED HERE BY 969 00:44:08,000 --> 00:44:10,760 LOWER DNL AT SIX MONTHS HOWEVER, 970 00:44:10,760 --> 00:44:15,720 ALL PATIENTS SHOWED IMPROVEMENTS 971 00:44:15,720 --> 00:44:18,200 IN DE NOVO LIPOGENESIS WITH 972 00:44:18,200 --> 00:44:21,160 LEVELS UP TO 32 NANOGRAMS BY ML. 973 00:44:21,160 --> 00:44:28,040 THIS SUGGESTS LEPTIN MAY IMPROVE 974 00:44:28,040 --> 00:44:30,080 NON-ALCOHOLIC LIVER DISEASE BY 975 00:44:30,080 --> 00:44:33,360 LOWERING THIS IN EVEN NON LEPTIN 976 00:44:33,360 --> 00:44:35,520 PATIENTS AND WHEN DEFINING 977 00:44:35,520 --> 00:44:38,960 CONDITIONS WE CAN LIKELY EXTEND 978 00:44:38,960 --> 00:44:42,680 RESPONSIVENESS FOR PATIENTS WITH 979 00:44:42,680 --> 00:44:45,520 LOWER LEPTINS IN THE OVER WEIGHT 980 00:44:45,520 --> 00:44:45,720 RANGE. 981 00:44:45,720 --> 00:44:49,960 WE DON'T KNOW IF THOSE WITH 982 00:44:49,960 --> 00:44:51,520 HIGHER LEPTIN WOULD ALSO HAVE 983 00:44:51,520 --> 00:44:53,960 IMPROVEMENTS IN NON-ALCOHOL 984 00:44:53,960 --> 00:44:55,520 FATTY LIVER DISEASE. 985 00:44:55,520 --> 00:44:58,760 TO RECAP WE HAVE SEEN LEPTIN 986 00:44:58,760 --> 00:45:00,080 ADMINISTRATION HAS DRAMATIC 987 00:45:00,080 --> 00:45:04,080 THERAPEUTIC AFFECTS IN PATIENTS 988 00:45:04,080 --> 00:45:06,600 WITH LEPTIN DEFICIENCY INCLUDING 989 00:45:06,600 --> 00:45:09,760 STATES OF LEPTIN DEFICIENCY AND 990 00:45:09,760 --> 00:45:15,040 STARVATION AND GENERALIZED 991 00:45:15,040 --> 00:45:15,720 LIPODYSTROPHY. 992 00:45:15,720 --> 00:45:16,960 CLINICAL EFFECTS INCLUDE 993 00:45:16,960 --> 00:45:18,840 REVERSAL OF ADAPTATION TO 994 00:45:18,840 --> 00:45:21,000 STARVATION SUCH AS DECREASING 995 00:45:21,000 --> 00:45:22,680 APPETITE AND INCREASING THYROID 996 00:45:22,680 --> 00:45:24,800 HORMONES AND PERMITTING NORMAL 997 00:45:24,800 --> 00:45:27,920 PUBERTY AND REPRODUCTION. 998 00:45:27,920 --> 00:45:29,360 STUDIES OF PATIENT WHO'S HAVE 999 00:45:29,360 --> 00:45:32,360 SEVERE INSULIN RESISTANCE HAVE 1000 00:45:32,360 --> 00:45:34,240 SHOWN METABOLIC BENEFITS ON 1001 00:45:34,240 --> 00:45:39,040 LEPTIN ON INSULIN SENSITIVITY, 1002 00:45:39,040 --> 00:45:53,400 DIABETES AND DISDYSLIPODEMIA AND 1003 00:45:53,400 --> 00:45:57,200 THOSE WITH HYPOTHALAMIC 1004 00:45:57,200 --> 00:46:00,040 AMENORRHEA HAVE MORE MODEST 1005 00:46:00,040 --> 00:46:01,440 BENEFITS FROM LEPTIN 1006 00:46:01,440 --> 00:46:01,800 ADMINISTRATION. 1007 00:46:01,800 --> 00:46:03,640 HOWEVER, BENEFITS OF LEPTIN 1008 00:46:03,640 --> 00:46:05,000 ADMINISTRATION MAY EXTENT TO 1009 00:46:05,000 --> 00:46:07,640 PATIENTS WITH HIGHER LEPTIN 1010 00:46:07,640 --> 00:46:12,360 CONCENTRATIONS FOR EFFECTS ON 1011 00:46:12,360 --> 00:46:15,640 STEATOHEPATITIS AND DE NOVO 1012 00:46:15,640 --> 00:46:15,960 LIPOGENESIS. 1013 00:46:15,960 --> 00:46:18,760 BEFORE WE CONCLUDE I WANT TO 1014 00:46:18,760 --> 00:46:21,800 MENTION TWO IMPORTANT STUDIES. 1015 00:46:21,800 --> 00:46:23,600 FIRST, SUB GROUP OF A STUDY OF 1016 00:46:23,600 --> 00:46:25,800 LEPTIN TREATMENT IN PATIENTS 1017 00:46:25,800 --> 00:46:27,160 WITH OBESITY SHOWED THOSE WITH 1018 00:46:27,160 --> 00:46:30,280 THE LOWEST SERUM LEPTIN LEVELS 1019 00:46:30,280 --> 00:46:33,520 DID HAVE MODEST BUT CLINICALLY 1020 00:46:33,520 --> 00:46:34,880 MEANINGFUL WEIGHT LOSS. 1021 00:46:34,880 --> 00:46:37,240 WE CAN CALL THESE PATIENTS LOW 1022 00:46:37,240 --> 00:46:39,160 LEPTIN OBESITY. 1023 00:46:39,160 --> 00:46:41,760 FINALLY, IN PATIENTS WITH 1024 00:46:41,760 --> 00:46:43,720 OBESITY WHOSE LEPTIN LEVELS WERE 1025 00:46:43,720 --> 00:46:46,840 REDUCED BY DIETING, LEPTIN 1026 00:46:46,840 --> 00:46:51,240 ADMINISTRATION RESTORED THE 1027 00:46:51,240 --> 00:46:52,240 METABOLIC ADAPTATIONS INCLUDING 1028 00:46:52,240 --> 00:46:53,600 INCREASED THYROID HORMONES AND 1029 00:46:53,600 --> 00:46:55,440 PUTTING THE PATIENTS INTO THE 1030 00:46:55,440 --> 00:47:00,360 LOW LEPTIN OBESITY CATEGORY. 1031 00:47:00,360 --> 00:47:03,920 IN CONCLUSION, LOW LEPTIN IS A 1032 00:47:03,920 --> 00:47:05,480 SIGNAL OF LONG-TERM ENERGY 1033 00:47:05,480 --> 00:47:09,960 DEFICIENCY AND MEDIATES 1034 00:47:09,960 --> 00:47:13,080 METABOLIC ADAPTATION. 1035 00:47:13,080 --> 00:47:16,920 MOST THE BIOLOGICAL ACTIONS ARE 1036 00:47:16,920 --> 00:47:20,040 IN THE TRANSITION FROM LEPTIN 1037 00:47:20,040 --> 00:47:21,200 DEFICIENCY TO SUFFICIENCY AND 1038 00:47:21,200 --> 00:47:21,760 UNDERSTANDING THE BIOLOGY 1039 00:47:21,760 --> 00:47:24,360 REQUIRED THE STUDY OF PATIENTS 1040 00:47:24,360 --> 00:47:26,440 WITH RARE DISEASES CAUSING 1041 00:47:26,440 --> 00:47:27,480 LEPTIN DEFICIENCY. 1042 00:47:27,480 --> 00:47:31,160 LEPTIN HAS LIMITED BIOLOGICAL 1043 00:47:31,160 --> 00:47:33,040 ACTIONS IN THE TRANSITION FROM 1044 00:47:33,040 --> 00:47:36,640 SUFFICIENCY TO ACCESS AND THE 1045 00:47:36,640 --> 00:47:38,120 ACTS MAY REQUIRE PHARMACOLOGIC 1046 00:47:38,120 --> 00:47:39,880 IN ADDITION TO PHYSIOLOGIC 1047 00:47:39,880 --> 00:47:42,600 DOSING OF LEPTIN. 1048 00:47:42,600 --> 00:47:44,360 I'D LIKE TO ACKNOWLEDGE THOSE 1049 00:47:44,360 --> 00:47:45,840 WHO CONTRIBUTED TO THE WORK AND 1050 00:47:45,840 --> 00:47:48,400 PHIL GORDON AND THE MEMBERS OF 1051 00:47:48,400 --> 00:47:51,720 MY LAB, COLLABORATORS BOTH NIH 1052 00:47:51,720 --> 00:47:53,720 AND OUTSIDE OF NIH, DRUG 1053 00:47:53,720 --> 00:47:55,160 COMPANIES THAT PROVIDED US WITH 1054 00:47:55,160 --> 00:47:56,760 LEPTIN OVER THE YEARS AND NONE 1055 00:47:56,760 --> 00:47:57,920 OF THIS WOULD HAVE BEEN POSSIBLE 1056 00:47:57,920 --> 00:48:00,400 WITHOUT OUR PATIENTS AND THEIR 1057 00:48:00,400 --> 00:48:03,240 FAMILIES. 1058 00:48:03,240 --> 00:48:08,680 THANK YOU VERY MUCH. 1059 00:48:08,680 --> 00:48:12,400 >> DR. BROWN, THANK YOU VERY 1060 00:48:12,400 --> 00:48:13,880 MUCH FOR YOUR PRESENTATION 1061 00:48:13,880 --> 00:48:16,480 OFFERING US INSIGHTS INTO LEPTIN 1062 00:48:16,480 --> 00:48:19,320 BIOLOGY AND PHYSIOLOGY AS WELL 1063 00:48:19,320 --> 00:48:22,560 AS THE BENEFITS OF IT IN LEPTIN 1064 00:48:22,560 --> 00:48:23,400 RESPONSIVE CONDITIONS ESPECIALLY 1065 00:48:23,400 --> 00:48:25,560 WITH LIPODYSTROPHY. 1066 00:48:25,560 --> 00:48:28,360 WE HAVE A COUPLE QUESTIONS THAT 1067 00:48:28,360 --> 00:48:30,200 HAVE COME IN. 1068 00:48:30,200 --> 00:48:34,920 ONE, WHY ARE PATIENTS WITH 1069 00:48:34,920 --> 00:48:39,920 OBESITY POTENTIALLY RESISTANT TO 1070 00:48:39,920 --> 00:48:45,640 APPETITE- SUPPRESSING EFFECTS OF 1071 00:48:45,640 --> 00:48:45,880 LEPTIN? 1072 00:48:45,880 --> 00:48:50,560 >> LEPTIN MAY BE REALLY REALLY 1073 00:48:50,560 --> 00:48:53,160 IRRELEVANT WHEN YOU'RE IN THE 1074 00:48:53,160 --> 00:48:56,000 OBESE STATE AND HAVE MANY LEPTIN 1075 00:48:56,000 --> 00:48:58,440 AROUND AND IT PLAYS A ROLE AS A 1076 00:48:58,440 --> 00:49:00,360 SIGNAL IN STARVATION. 1077 00:49:00,360 --> 00:49:02,520 WHY CAN'T HIGH LEPTIN SUPPRESS 1078 00:49:02,520 --> 00:49:04,120 APPETITE IN STATES OF OBESITY? 1079 00:49:04,120 --> 00:49:06,920 SOME PEOPLE CALLED IT LEPTIN 1080 00:49:06,920 --> 00:49:08,760 RESISTANCE. 1081 00:49:08,760 --> 00:49:15,000 IT MAY SIMPLY BE WE'RE ABOVE THE 1082 00:49:15,000 --> 00:49:16,440 AADAPTIVE LINEAR RESPONSE AND 1083 00:49:16,440 --> 00:49:17,680 MAY BE BEYOND THAT. 1084 00:49:17,680 --> 00:49:20,160 THERE'S BEEN REALLY INTERESTING 1085 00:49:20,160 --> 00:49:25,960 STUDIES IN RECENT YEARS FROM A 1086 00:49:25,960 --> 00:49:28,480 GROUP SUGGESTING YOU CAN RESTORE 1087 00:49:28,480 --> 00:49:30,760 LEPTIN SENSITIVITY BY 1088 00:49:30,760 --> 00:49:31,720 SUPPRESSING LEPTIN LEVELS. 1089 00:49:31,720 --> 00:49:33,200 THAT'S ONLY BEEN SHOWN IN MICE 1090 00:49:33,200 --> 00:49:39,160 NOT IN HUMANS. 1091 00:49:39,160 --> 00:49:39,960 >> THANK YOU. 1092 00:49:39,960 --> 00:49:42,000 AND ALONG THOSE LINES ARE THERE 1093 00:49:42,000 --> 00:49:44,360 ANYTHING WE CAN DO TO REVERSE 1094 00:49:44,360 --> 00:49:46,240 THE LEPTIN RESISTANCE YOU 1095 00:49:46,240 --> 00:49:46,720 MENTION? 1096 00:49:46,720 --> 00:49:48,760 >> THE SUPPRESSING LEPTIN LEVELS 1097 00:49:48,760 --> 00:49:50,760 AS I MENTIONED HAS BEEN SHOWN IN 1098 00:49:50,760 --> 00:49:52,960 RODENT MODELS. 1099 00:49:52,960 --> 00:49:59,720 THAT'S BEEN DONE WITH DIFFERENT 1100 00:49:59,720 --> 00:50:02,160 METHODS AND OTHER INVESTIGATORS 1101 00:50:02,160 --> 00:50:05,680 HAVE TRIED GIVING LEPTIN IN 1102 00:50:05,680 --> 00:50:08,800 COMBINATION WITH OTHER 1103 00:50:08,800 --> 00:50:09,640 APPETITE-SUPPRESSING HORMONES. 1104 00:50:09,640 --> 00:50:11,760 THE ONE THAT MADE IT FURTHEST IN 1105 00:50:11,760 --> 00:50:16,400 THE CLINICAL WAS LEPTIN IN 1106 00:50:16,400 --> 00:50:22,360 COMBINATION WITH AN ANALOG OF AN 1107 00:50:22,360 --> 00:50:22,680 ANALIN. 1108 00:50:22,680 --> 00:50:26,640 THAT WAS SUCCESSFUL IN REDUCING 1109 00:50:26,640 --> 00:50:28,320 OBESITY BUT THOSE WERE 1110 00:50:28,320 --> 00:50:29,760 TERMINATED EARLY IN THE PROCESS 1111 00:50:29,760 --> 00:50:35,800 BECAUSE A SUBSET OF PATIENTS 1112 00:50:35,800 --> 00:50:36,760 DEVELOPED NEUTRALIZING 1113 00:50:36,760 --> 00:50:39,160 ANTIBODIES AND PUT THEM IN A 1114 00:50:39,160 --> 00:50:40,840 WORSE CLINICAL SCENARIO PRIOR TO 1115 00:50:40,840 --> 00:50:46,040 GETTING EXPOSED TO THE DRUG. 1116 00:50:46,040 --> 00:50:46,920 >> THANK YOU. 1117 00:50:46,920 --> 00:50:48,400 ANOTHER QUESTION DOES IT MAKE 1118 00:50:48,400 --> 00:50:51,200 SENSE THEN TO MEASURE LEPTIN 1119 00:50:51,200 --> 00:50:52,760 LEVELS IN OBESITY TO DETERMINE 1120 00:50:52,760 --> 00:50:56,960 IF AN INDIVIDUAL BELONGED TO A 1121 00:50:56,960 --> 00:50:58,520 LOW-LEPTIN OBESITY GROUP? 1122 00:50:58,520 --> 00:51:01,080 >> INTERESTING QUESTION. 1123 00:51:01,080 --> 00:51:04,360 THERE'S THERAPEUTIC IMPLICATION 1124 00:51:04,360 --> 00:51:07,720 FOR UNDERSTANDING IF A PATIENT 1125 00:51:07,720 --> 00:51:11,800 HAS CONGENITAL LEPTIN DEFICIENCY 1126 00:51:11,800 --> 00:51:14,960 AND MEASURING IT UNDER THAT 1127 00:51:14,960 --> 00:51:16,360 CIRCUMSTANCE WILL BE 1128 00:51:16,360 --> 00:51:17,440 INFORMATIVE. 1129 00:51:17,440 --> 00:51:18,520 I'LL HAVE AN OBESITY PATIENT 1130 00:51:18,520 --> 00:51:21,520 WITH A LOW LEPTIN LEVEL. 1131 00:51:21,520 --> 00:51:23,720 USUALLY THEY COME FROM FAMILIES 1132 00:51:23,720 --> 00:51:25,760 WITH A HISTORY OF CONSANGUINITY 1133 00:51:25,760 --> 00:51:28,240 AND THEY'LL BE UNCOMMON. 1134 00:51:28,240 --> 00:51:31,520 NOW, THE PATIENTS WHO HAVE 1135 00:51:31,520 --> 00:51:33,600 RELATIVELY LOW LEPTIN OBESITY, 1136 00:51:33,600 --> 00:51:35,360 ONE CONCERN IS WHAT WAS THE 1137 00:51:35,360 --> 00:51:36,920 PATIENT EATING OVER THE LAST FEW 1138 00:51:36,920 --> 00:51:37,120 DAYS? 1139 00:51:37,120 --> 00:51:39,760 IF THE PATIENT WAS DIETING SAY 1140 00:51:39,760 --> 00:51:44,280 OVER THE THREE-DAY PERIOD PRIOR 1141 00:51:44,280 --> 00:51:46,800 TO COMING TO SEE YOU MAY GET A 1142 00:51:46,800 --> 00:51:48,320 LOW LEPTIN LEAVE OUT OF THAT 1143 00:51:48,320 --> 00:51:49,760 SEEMS OUT OF PROPORTION LOW 1144 00:51:49,760 --> 00:51:51,240 COMPARED TO THEIR OBESITY BUT 1145 00:51:51,240 --> 00:51:52,880 MAY BE REFLECTING THEIR DIETARY 1146 00:51:52,880 --> 00:51:55,080 STATE OVER THE LAST FEW DAYS AND 1147 00:51:55,080 --> 00:51:57,400 MAY NOT HAVE MUCH IMPLICATIONS 1148 00:51:57,400 --> 00:51:58,880 WITH HOW TO RESPOND TO LEPTIN 1149 00:51:58,880 --> 00:51:59,240 TREATMENT. 1150 00:51:59,240 --> 00:52:00,960 I DON'T THINK WE REALLY KNOW THE 1151 00:52:00,960 --> 00:52:09,200 ANSWER TO THAT AT THIS STAGE. 1152 00:52:09,200 --> 00:52:11,160 >> THANK YOU. 1153 00:52:11,160 --> 00:52:12,280 THAT APPEARS TO BE THE LAST 1154 00:52:12,280 --> 00:52:17,640 QUESTION THAT WE'VE GOTTEN FROM 1155 00:52:17,640 --> 00:52:20,040 THE NIH COMMUNITY VIEWING 1156 00:52:20,040 --> 00:52:20,320 AUDIENCE. 1157 00:52:20,320 --> 00:52:22,880 DR. BROWN, THANK YOU FOR THE 1158 00:52:22,880 --> 00:52:23,240 PRESENTATION. 1159 00:52:23,240 --> 00:52:26,280 IT WAS VERY CLEAR, CONCISE AND 1160 00:52:26,280 --> 00:52:26,600 COMPREHENSIVE. 1161 00:52:26,600 --> 00:52:27,720 THANK YOU VERY MUCH. 1162 00:52:27,720 --> 00:52:29,360 TO EVERYONE ELSE, THANK YOU. 1163 00:52:29,360 --> 00:52:31,840 YOU HAVE A GREAT AFTERNOON AND 1164 00:52:31,840 --> 00:52:33,360 WE'LL SEE YOU NEXT WEEK. 1165 00:52:33,360 --> 00:52:33,920 THANK YOU VERY MUCH. 1166 00:52:33,920 --> 00:52:34,160 BYE-BYE. 1167 00:52:34,160 --> 00:00:00,000 >> THANK YOU.