WELCOME TO CLINICAL CENTER GRAND ROUNDS. TODAY WE HAVE A VERY EXCITING DUO FROM NIDDK WHO IS GOING TO TELL US HOW TO LOOSE WEIGHT, BE PHYSICALLY FIT. SO OUR FIRST SPEAKER IS DR. KEVIN HALL, SENIOR INVESTIGATOR IN THE LABORATORY OF BIOLOGICAL MODELING, INTEGRATIVE PHYSIOLOGY SECTION OF NIDDK. DR. HALL EARNED HIS Ph.D. IN PHYSICS FROM McGILL, IN MONTREAL. CANADA. AND HIS THESIS INVOLVED MATHEMATICS MODELING IN THE DEVELOPMENT OF ALGORITHM FOR THE DIAGNOSIS AND CONTROL OF A VARIETY OF ABNORMAL HEART RHYTHMS. AFTER OBTAINING HIS DEGREE, HE JOINED A BIOTECH COMPANY, LED A TEAM OF SCIENTISTS AND ENGINEERS IN THE DEVELOPMENT OF COMPUTATIONAL MODELS OF HUMAN METABOLISM AND THE PATHOSIZOLOGY OF TYPE II DIABETES. HE CAME TO THE NIH IN JULY, 2003, A TENURED TRACK INVESTIGATOR IN THE LABEL OF BIOLOGICAL MODELING. IN 2010, HE BECAME A TENURED SENIOR INVESTIGATOR. TODAY, HIS LAB STUDIES THE REGULATION OF BODY WEIGHT AND METABOLISM. THE MODELS HE HAS DEVELOPED HAVE BEEN USED TO QUANTIFY THE ENERGY IMBALANCE UNDERLYING THE OBESITY EPIDEMIC, AND TO PREDICT HOW INTERVENTIONS WILL IMPACT BODY WEIGHT AND FAT TISSUE COMPOSITION IN INDIVIDUALS AS WELL AS ENTIRE POPULATIONS. DR. HALL IS THE CREATOR OF THE BODY WEIGHT SIMULATOR, AN ONLINE TOOL THAT HELPS RESEARCHERS UNDERSTAND HOW DIET AND EXERCISE CONTRIBUTE TO WEIGHT LOSS. HIS LABORATORY IS ALSO DEVELOPED ON THE BODY WEIGHT SIMULATOR FOR SMART PHONES AN TABLET USERS. HE HAS RECEIVED 2 NIH DIRECTOR'S AWARDS, THE FIRST IN 2012 FOR RECOGNITION OF HIS CONTRIBUTION TO THE TRANSNIH COLLABORATIVE ON THE HBO DOCUMENTARY ENTITLED THE "THE WAIT OF THE NATION CONFRONTING AMERICA'S OBESITY EPIDEMIC." IN 2013, AGAIN, FOR RECOGNITION OF HIS CONTRIBUTION TO THE CREATION OF THE BODY WEIGHT SIMULATOR. HE ALSO RECEIVED A 2013 NIDDK DIRECTOR'S AWARD OF OUTSTANDING CONTRIBUTIONS TO DEVELOPMENT AND PATENTING OF INVENTIONS THAT HAVE HELPED WITH -- TO ACHIEVING THE NIDDK MISSION. HIS OTHER HONORNIZECLUDE AN HHS INNOVATIVE HONORABLE MENTION, THE LILY SCIENTIFIC ACHIEVEMENT AWARD FROM THE OBESITY SOCIETY, AND THE AMERICAN PHYSIOLOGICAL SOCIETY ARTHUR C TUYTON AWARD FOR EXHENCE. SO WE'RE LUCKY TO HAVE DR. HALL AS A MEMBER OF OUR TEAM. HE'S GOING TO PRESENT THE CALCULUS OF CALORIES, WHAT MATHEMATICS CAN TEACH US ABOUT OBESITY. WELCOME. THANK YOU VERY MUCH. IT'S A REAL HONOR TO PRESENT TO YOU TODAY AND CLINICAL CENTER GROUND ROUNDS. I NEVER MONTHLIEN WHEN I GOT MY Ph.D. THAT I WOULD BE DOING SUCH A THING. IT'S BEEN A WILD RIDE HEAR AND I HOPE TO SHEAR OUR RESEARCH FINDINGS WITH YOU TODAY. SO I HAVE NOTHING TO DISCLOSE. THE OBJECTIVE OF THIS TALK ARE -- I WANT TO UNDERLIE WHAT'S GOING ON WHEN PEOPLE ARE MAKING WEIGHT LOSS PREDICTIONS USING CLASSICAL RULE OF 3500-CALORIES PER POUND. WHAT ARE THE ASSUMPTIONS UNDERLYING THAT RULE OF THUMB, AND WHY ARE THEY FLAWED? AND THEN I'LL DESCRIBE HOW MORE SOPHISTICATED MATHEMATICS MODELING CAN HELP TO UNDERSTAND THE DIE DIES OF HUMAN -- DYNAMICS OF HUMAN METABOLISM IN OBESITY AND SHOW HOW TO APPLY A WEB BASED TOOL TO ACHIEVE AND MAINTAIN WEIGHT LOSS GOAL. A WHAT IS A 3500-CALORIE PER POUND RULE? I BECAME AWARE OF THIS WHEN I WAS SITTING WITH A DIETITIAN AT THE CLINICAL CENTER, AND THEY WERE BASICALLY DESIGNING A WEIGHT LOSS PROGRAM. AND BASICALLY, THE IDEA WAS THAT -- I ASKED THE DIETITIAN AFTER, WHERE DID YOU GET THESE RECOMMENDATIONS FOR PRESCRIBING A DIET INTERVENTION TO GIVE RISE TO A KNOWN AMOUNT OF WEIGHT LOSS? ONE OF THE MANY PUBLICATIONS THAT SHE POINTED ME TO WAS THIS PRACTICAL GUIDE TO THE IDENTIFICATION OF VALUATION AND TREATMENT OF OVERWEIGHT AND OBESITY IN ADULTS FROM THE NHLBI EDUCATION INITIATIVE IN 2000O IT'S VERY CLEAR A REDUCTION OF 500 TO 1,000 KILACALORIES PER DAY WILL PRO TO US A RECOMMENDED WEIGHT LOSS OF 1-2 POUNDS PER WEEK. IF YOU DO THE MATH, YOU CAN SEE THAT 500-CALORIE A DAY REDUCTION, 7 DAYS, 3500-CALORIES, A POUND OF WAIT LOSS IN A WEEK. THIS IS THE 3500 KILACALORIE PER POUND RULE. IF YOU GOOGLE HOMMOCKS ARE IN A POUND YOU'LL SEE 8 MILLION HITS, ALL SAYING THIS IS HOW MANY CALORIES ARE IN A POUND. IT SEEMS ODD TO ME. THAT'S 50 POUNDS IN A YEAR IF I KIT 500 CALORIES A DAY. IF I CUT THAT PERMANENTLY, AFTER THREE YEARS, I'M GOING TO DISAPPEAR. SO THERE IS SOMETHING WRONG WITH THIS NOTION, JUST ON ITS FACE. AND SO I REALLY TRIED TO FIGURE OUT WHAT -- WHERE DID THIS NUMBER COME FROM? IT'S IN A VARIETY OF NUTRITION TEXTBOOKS, THE DIETITIAN INFORMED ME THEY'RE TESTED ON THIS IDEA, HOW TO MAKE PREDICTIONS FOR HOW A DIET INFLUENCES BODY WEIGHT. I FOUND AFTER A MONTH OR SO OF SEARCHING, A 1953 PAPER BY A GENTLEMAN NAMES MAX, WHO BASICALLY HAD DONE AN EXPERIMENT WHERE HE WAS INTERESTED TO SEE HOW MANY CALORIES WERE STORED IN A POUND OF ADIPOSE TISSUE, A POUND OF HUMAN FAT TISSUE. HE CAME UP WITH 3500 CALORIES PER POUND ONCE HE TOOK INTO ACCOUNT THE TRY GUYS RIDE, PRONE, WATER IN A TYPICAL AMOUNT OF TISSUE T WAY THAT THAT STORED CALORIES IN ADIPOSE TISSUE GOT TRANSLATED INTO PRACTICE WAS THIS IDEA THAT THERE ARE TWO ASSUMPTIONS. ONE, WHEN HE LOOSE WEIGHT YOU'RE ONLY LOSING ADIPOSE TISSUE. WE FLORIDA THAT'S NOT TRUE. I USE LEAN TISSUE AS WELL T SECOND MORE SERIOUS ASSUMPTION, IF I CUT CALORIES IN MY DIET NOTHING HAPPENS TO THE NUMBER OF CALORIES THAT I'M BURNING. IT STAYS THE SAME. WE KNOW THAT THAT'S NOT TRUE. COMPLEX DYNAMIC RELATIONSHIP. SO AS A PHYSICIST, I SET OUT TO TRY TO UNDERSTAND WHAT IS A REALISTIC DYNAMIC MODEL OF HOW ENERGY METABOLISM CHANGES, HOW BODY COMPPITION CHANGES WHEN YOU MANIPULATE DIETS. BOTH THE NUMBER OF CALORIES AS WELL AS CASH FOR CLUNKERS FAT AND -- CARBOHYDRATE FAT AND PROTEIN IN THE DIET. AFTER A LENGTHY LITERATURE SEARCH I BUILT A MODEL. THIS IS THE MODEL EQUATION. IT'S A PRETTY -- IT'S NOT THAT COMPLICATED A MODEL COMPARED TO WHAT I WAS DOING IN INDUSTRY BEFORE COMING TO THE NIH, BUT IT'S REALLY TRYING TO SIMULATE MECHANISTICALLY WHAT WE KNOW ABOUT IF YOU CHANGE THE CARBOHYDRATE AND FAT CONTENT OF THE DIET, HOW DOES THAT IMPACT ENDOCRINE PHYSIOLOGY, INSULIN HAS A BIG ROLE IN DRIVING METABOLISM FLUXES IN THE REGULATION THROUGHOUT THE BODY. THIS MODEL IS TRYING TO SYNTHESIZE AND INTEGRATE A WHOLE SWATH OF INFORMATION FROM REALLY WELL CONTROLLED HUMAN STUDIES THAT HAVE BEEN CONDUCTED OTHER THECADES. SO I'M NOT GOING INTO DETAIL ABOUT THIS MODEL. DOES IT MAKE ANY REALISTIC PREDICTIONS? CAN WE MAKE USE OF THIS MODEL? AND THE WAY YOU PLAY THAT GAME IS SAY I BUILT A MODEL USING THIS WHOLE SET OF DATA AND NOW I I WANT TO VALIDATE THE MODEL. YOU COMPARE MODEL PREDICTIONS WITH DATA FROM COMPLETELY INDEPENDENT EXPERIMENTS, AND THE ONLY THING YOU'RE ALLOWED TO CHANGE IS THE INITIAL CONDITIONS OF THE MODEL TO MATCH THE CONDITIONS OF THE EXPERIMENTS UNDER STUDY. IF I'M STUDYING A LEAN MAN I START WITH THE BODY COMPOSITION OF A LEAN MAN. THE RESTING METABOLISM RATE, TYPICAL OF A LEAN MAN. YOU FEED THE MODEL WITH WHAT WAS FED IN THAT CONTROL FEEDING EXPERIMENT. YOU COMPARE THE RESULTS. THE MODEL RESULTS TO THE RESULTS OF THE EXPERIMENT, SEE HOW WELL YOU DO. WE'VE DONE THIS NOW, THIS PAIR OF AMERICAN JOURNALISTS PHYSIOLOGY PAPERS FOR MORE THAN A DOZEN KINDS OF EXPERIMENTS, OVER-FEEDING, UNDER-FEEDING EXPERIMENTS, MEN AND WOMEN, LEAN, OBESITY, DIFFERENT MICRONUTRIENTS. ONE VALIDATES EXPERIMENT THAT WAS CONDID YOU GETED PIE FOLKS IN NEW YORK, THAT WASN'T IN THESE TWO PAPERS. THIS IS A CLASSIC NEW ENGLAND JOURNAL PAPER FROM 1995 BY SEVERAL, WHERE THEY DID THIS REMARKABLE LONG TERM STUDY IN OBESITY SUBJECTS. WHAT I'M PLOTTING IS THE ENERGY IN-TAKE. WHAT THEY DID, THEY BROUGHT THE PEOPLE IN FOR UPWARDS OF ALMOST NINE MONTHS. AND FED THEM THIS LIQUID DIET OF ABOUT 800 CALORIES PER DAY. THEY START OFF, EATING -- BEFORE THEY COME INTO THE STUDY, ABOVE 3,000 CALORIES A DAY, OBESITY. THEY CUT THEM ON A LIQUID DIET TO LESS THAN A THOUSAND CALORIES A DAY, UNTIL THEY LOSE TEN PERCENT OF THEIR BODY WEIGHT. THEN THEY RAMP THEM BACK UP ON THE SAME LIQUID CALORIES TO MAINTAIN THEIR BODY WEIGHT AT THIS 10% WEIGHT LOSS TO ACHIEVE A STEADY STATE. THEY DO IT ALL OVER AGAIN UNTIL THEY ACHIEVE 20% WAIT WEIGHT LOSS. WHAT WE DID IN OUR MODEL, WE BASICALLY STARTED THE MODEL AS THE AVERAGE OBESE SUBJECT AND THEN FED THEM THIS ENERGY INTAKE. AND SO HERE IS WHAT WE GOT. CURVES ARE THE MODEL PREDICTIONS, THE DATA POINTS ARE THE DATA FROM THE EXPERIMENT. AND WHAT I WANT TO POINT OUT IS I'M PLOTTING THE TOTAL ENERGY EXPENDITURE, THE TOTAL NUMBER OF CALORIES BEING BURNED. YOU CAN SEE THIS ASSUMPTION THAT NOTHING HAPPENED TO THE TOTAL NUMBER OF CALORIES BURNED WHEN YOU GO ON A DIET IS FALSE. THERE IS THIS DRAMATIC DROP TRANSIENT. AND THEN AS YOU KIND OF MAINTAIN THE ENERGY IN-TAKE TO MATCH THE EXCLUSIVE, THERE IS -- EXPENDITURE, THERE IS INCREASE. THEY DIDN'T AFTER MEASURE OF TOTAL ENERGY EXPENDITURE BUT THEY HAD A MESH OF RESTING ENERGY EXPENDITURE. YOU CAN SEE THE MODEL PREDICTIONS MATCH THE EXPERIMENT SO THERE IS GREATER SUPPRESSION DURING DYNAMIC WEIGHT LOSS THAN DURING WEIGHT STABILITY. AND AGAIN, THEY DID NOT HAVE MEASUREMENTS OF PHYSICAL ACTIVITY, ENERGY EXPENDITURE OVER TIME BUT THE MODEL MAKES PREDICTION ABOUT WHAT THAT LOOKS LIKE. SO AGAIN, WE'RE NOT FITTING THE MODEL TO THESE DATA, WE'RE JUST FEEDING THE MODEL WITH WHATEVER WAS FED IN THAT EXPERIMENT, AND LOOKING TO SEE HOW WELL THE MODEL CAPTURES THESE RESULTS. AND THEN WHAT DOES THAT DO IN TERMS OF BODY WEIGHT AND COMPOSITION? YOU CAN SEE THAT THE MODEL IS LOSING THE RIGHT AMOUNT OF WEIGHT, STABLE AT THAT PERIOD OF TIME, AND LOSING THE RIGHT COMPOSITION OF WEIGHT COMING FROM FAT MASS, CHANGES, AS WELL AS FAT FREE MASS CHANGES. THERE IS SOME REDUCTION IN FAT FREE MASSING IN CONTRAST TO THE ASSUMPTION OF THAT 3500 CALORIES PER POUND RULE. WE THEN -- BY THE WAY, THIS IS THE PREDICTION OF THE 3500 CALORIES PER POUND RULE. WE'RE TALKING 30-KILOGRAMS OFF PIE TEND OF THE EXPERIMENT WHICH IS NOT A VERY GOOD PREDICTION AT ALL. SO AS WAS MENTIONED IN THE INTRODUCTION, IN 2011, PUBLISHED A PAPER IN THE LANCET WHERE WE BASICALLY SIMPLIFIED THAT MODEL. AND GENERATED AND ONLINE PREDICTION TOOL THAT URL, AND WHAT IT ALLOWS YOU TO DO IS YOU COME IN AND YOU ENTER SOME BASELINE INFORMATION ABOUT YOUR INITIAL WEIGHT, YOUR GENDER, YOUR HEIGHT, AND ANSWER A COUPLE OF QUESTIONS ABOUT YOUR PHYSICAL ACTIVITY AT WORK AND DURING LEISURE TIME. THIS IS A 110-KILO MALE WHO IS RELATIVELY INACTIVE, AND TO MAINTAIN THEIR INITIAL WEIGHT, THIS IS THE BASELINE INFORMATION, THIS PERSON WOULD BE -- NEED TO EAT ABOUT 3,000 CALORIES PER DAY. YOU PROBABLY CAN'T SEE IT. THEN WHAT YOU CAN DO IS ENTER IN YOUR GOAL. THIS PERSON'S GOAL WAS TO WEIGH 80-KILOGRAMS IN SIX MONTHS. THEN THE MODEL TELLS YOU TWO THINGS. ONE, WHAT YOU HAVE TO DO TO YOUR DIET TO ACHIEVE THAT GOAL IN THE 6 MONTH TIMEFRAME. PERHAPS MORE IMPORTANTLY, WHAT YOU HAVE TO DO PERMANENTLY, AFTER YOU ACHIEVE YOUR GOAL, TO MAINTAIN THAT WEIGHT LOSS. THAT'S A MAJOR PROBLEM THAT WE'LL TALK ABOUT LATER, ACHIEVE WEIGHT LOSS IS ACTUALLY NOT THE DIFFICULT PART. MAINTAINING THAT WEIGHT LOSS IS THE DIFFICULT PART. SO WE PUBLISHED THIS PAPER IN 2011, AND THE ONLINE APPLICATION THAT WENT ALONG WITH IT. AND IT'S REALLY INTENDED FOR RESEARCHERS BUT WHAT'S BEEN SURPRISING IS THAT SINCE THE PUBLICATION OF THIS PALM, WE'VE HAD MORE THAN 100 MILLION UNIQUE USERS OF THIS MODEL. SO CLEARLY, NOT JUSTRISHERS ARE USING THE -- RESEARCHERS ARE USING THE MODEL. ONE PERSON CONTACTED ME RECENTLY, A WEIGHT LOSS PHYSICIAN IN CEDAR RAPIDS. AND HE SAID I'VE REALLY INTERESTED IN USING THIS MODEL, AND WE HAVE BEEN LOOKING AT SOME OF OUR PATIENTS WHO HAVE BEEN PRESCRIBED MALE REPLACEMENT DIET -- MEAL REPLACEMENT DIET. THESE ARE ADHERENT FOLKS. AND IT WOULD BE INTERESTING TO COMPARE YOUR MODEL PREDICTIONS IN THIS SORT OF REAL WORLD SETTING WITH WHAT WE'RE SEEING. I AM ASHOWING YOU AN EXAMPLE OF TWO SUBJECTS, THE DATA POINTS ARE THESE OPEN CIRCLES. THE BEST ESTIMATE IS THE BLACK SOLID CURVE AND THE CONFIDENCE INTERVAL OF THE PREDICTION IN DASHED. YOU CAN SEE THAT MATCHING RELATIVELY WELL FOR THESE INDIVIDUAL SUBJECTS. WHEN YOU TAKE A LOOK AT ALL 60 OF HIS SUBJECTS AND YOU COMPARE THE WEIGHT LOSS PREDICTIONS OF THE MODEL WITH THE WEIGHT LOSS PREDICTIONS OF THE DATA, THESE ARE HIGHLY CORRELATED AND ARE DOING A PRETTY GOOD JOB OF MATCHING REAL WORLD WEIGHT LOSS IN THESE VERY ADHERENT PATIENTS IN BRADY'S PRACTICE. SO THIS IS ONE SO THE OF POTENTIAL CLINICAL APPLICATION, MAKING REALISTIC WEIGHT LOSS PREDICTIONS IF YOU'RE ADHERENT TO A PARTICULAR INTERVENTION. MY LAB IS CALLED THE LAB OF INTEGRATED PHYSIOLOGY, BECAUSE WHAT I LIKE TO THINK IS THAT MATHEMATICS MODELS CAN HELP YOU PUT TOGETHER VARIOUS DIFFERENT DATA SOURCES A QUANTITATIVE WAY AND MAKE INFERENCES ABOUT THINGS THAT WERE NOT MEASURED. ONE OF THE THINGS THAT WAS SURPRISING TO ME, ONE DAY I CAME HOME AND TURNED ON THE TELEVISION, WATCHING THIS PROGRAM CALLED "THE BIGGEST LOOSER" AND I WAS SEEING THE TAIL END OF THIS PROGRAM. PEOPLE WERE LOSING ENORMOUS QUALITIES OF WEIGHT IN A VERY RAPID PERIOD OF TIME. I WAS VERY CURIOUS HOW THEY WERE ACHIEVING THAT. SO I MADE A POINT TO WATCH THE ENTIRE PROGRAM, AND BASICALLY WHAT I SAW WAS A BUNCH OF PEOPLE WITH OBESITY BEING YELLED AT BY TRAINERS ON TREADMILLS. AND DOING VARIOUS CHALLENGES. WHAT WAS NOT CLEAR, WAS HOW MUCH THEY WERE EATING. IT'S HARD TO MAKE A TELEVISION SHOW WATCHING PEOPLE NOT EAT. SO I WAS REALLY INTRIGUED BY THIS. I CONTACTED THE PHYSICIAN WHO IS IN CHARGE OF THE CARE OF THESE FOLKS, THIS IS ROB WHO IS THE MIDDLE THORON THIS PAPER WE PUBLISHED. I ASKED HIM SOME QUESTIONS ABOUT WHAT'S HAPPENING TO HOW MANY CALORIES THESE BURNING ARE BURNING, THE RESTING METABOLISM RATE, THE BODY COMPOSITION. HE WAS MAKING REALLY GOOD MEASUREMENTS OF BODY COMPOSITION CHANGES BUT HAD NO MEASUREMENTS OF METABOLISM AT ALL. AND SO I CONVINCED ERIC FROM THE PENTINGTON CENTER, AND HIS POSTDOC, TO PAIR UP WITH MY POSTDOC, AND GO OUT AND STUDY THESE FOLKS. WHILE THEY WERE PARTICIPATING IN THIS PROGRAM. AND SEE IF WE COULD MAKE SENSE OF WHAT WAS GOING ON METABOLISMICALLY. AND BUILD A MODEL. SO EXPERIMENT WAS PUBLISHED. SO WHAT HAPPENS? SO AGAIN, THIS IS THE SAME PATTERN, THE SIMULATIONS ARE THE CURVES, THE DATA ARE THE BOXES. AND WHAT YOU CAN SEE IS THAT WHEN THEY'RE ISOLATED ON THE RANCH FOR APPROXIMATELY 13 WEEKS THEY'RE LOSING A GREAT QUANTITY OF WEIGHT, VERY QUICKLY. THEY'RE LOSING A POUND A DAY, WHICH IS REMARKABLE. AND THE VAST MAJORITY OF IT IS COMING FROM BODY FAT. SO THE GREEN CURVE AND THE BOXES HERE ARE THE FAT CHANGES. THEN THEY GO HOME, SO THEY'RE ISOLATED ON A RANCH AWAY FROM THEIR NORMAL DAILY ACTIVITIES, DOING ALL THIS EXERCISE. AND THEN THEY'RE INSTRUCTED TO GO HOME AND TRY TO KEEP IT UP AND DO WHATEVER YOU'RE DOING. AND THE RATE OF WEIGHT LOSS CUTS IN HALF BUT THEY'RE STILL LOSING ABOUT A HALF A POUND A DAY WHICH IS STILL REMARKABLE. TO PERT UNDERSTAND THE ENERGY BALANCE, WE GAVE A DOSE OF DOUBLERY LABELED WATT ARAT BASELINE BEFORE AT THE KNEW THEY MADE IT ON TO THE TELEVISION PROGRAM. 6 WEEKS INTO THE PROGRAM, AND THEN AT THE VERY END OF THE PROGRAM. AND SO WHAT YOU CAN SEE IS THAT THERE IS SUBSTANTIAL INCREASE IN THE TOTAL NUMBER OF CALORIES BEING BURNED. AND THAT THAT NUMBER GOES DOWN QUITE A LOT BY TEND. AND THE CURVES HERE ARE THE MATHEMATICS MODEL SIMULATION. SO EXERCISE, THE CALORIES BURPED IN EXERCISE IS RAMPING UP SO BY THIS PERIOD OF TIME THEY'RE DOING IN EXCESS OF 2,000 CALORIES PER DAY OF EXERCISE. AND THAT TRANSLATES TO ABOUT THREE HOURS OF VIGOROUS ACTIVITY PER DAY, SUPERVISED ON THE RAMP FOR THE MOST PART MUCH AND -- RANCH FOR THE MOST PART. THAT IS MATCHING THE SUPERVISED EXERCISE. WHEN THEY GO HOME, THE EXERCISE CALORIES ARE GOING DOWN A LOT. BUT WHAT YOU HAVE TO REMEMBER IS THAT THE NUMBER OF CALORIES THAT ARE EXTENDED DURING EXERCISE IS NOT JUST DUE TO THE -- DUE TO THE EXERCISE IN PROPORTION TO THE WEIGHT ITSELF. MOST EXERCISES ARE WEIGHT BEARING. DO THE SAME INTENSITY OF RUNNING FOR THE SAME AMOUNT OF TIME, ONCE YOU'VE LOST 60-KILOS LIKE THESE GUYS HAVE DONE, COSTS YOU GREATLY. SO EVEN THIS NUMBER LOOKS LIKE A MUCH SMALLER NUMBER IN TERMS OF CALORIES PER DAY, THESE FOLKS HAVE LOST ABOUT 60-KILOS OF BODY WEIGHT. THIS WHOLE PERIOD OF TIME AVERAGES OUT TO ABOUT ONE HOUR EVERY DAY OF VIGOROUS EXERCISE. RESTING METABOLISM RATE, DESPITE THIS VIGOROUS EXERCISE STILL DROPPED A LOT. IN THE MODEL PREDICTS THAT VALUE. AND THE INTERESTING THING IS WHAT WE DIDN'T MEASURE, MOST PEOPLE IN DOING SORT OF OBESITY RESEARCH, HAVE A VERY DIFFICULT TIME MEASURING IS ENERGY INTAKE. HOW MANY CALORIES ARE PEOPLE EATING? BECAUSE IF YOU ASK THEM TO JUST REPORT WHAT THEY'RE EATING, WE KNOW THAT THOSE RESULTS ARE NOT VALID. THEY TEND TO UNDER-REPORT. MORE OBESITY YOU ARE, THE MORE YOU UNDER-REPORT. THERE ARE VARIOUS REASONS WHY. WE CAN USE A MODEL AND WE KNOW WE HAVE TO CONSERVE ENERGY TO ASK THE QUESTION, GIVEN THESE CHANGES IN NORTH AMERICA EXPENDITURES AND THE CHANGE -- ENERGY EXPENDITURE. CAN WE INFER HOW MANY CALORIES A DAY THESE PEOPLE WERE EATING. YES, WE CAN MAKE A PREDICTION. THEY WERE EATING ABOUT 3700 CALORIES PER DAY, TO MATCH THE WEIGHT CHANGES AND BODY COMPOSITION CHANGES THEY WOULD HAVE TO BE EATING ABOUT 1300 CALORIES A DAY DURING THE 13 WEEKS THEY WERE ON THE RANCH. THINK ABOUT THAT IN TERMS OF DOING GREATER THAN 2,000 CALORIES A DAY OF EXERCISE, ONLY EATING 1300 CALORIES A DAY. THEN THEY BUMP UP WHEN THEY GO HOME TO ABOUT 1900 CALORIES A DAY ON AVERAGE. THIS IS AN EXAMPLE OF WHERE YOU CAN USE THE MODEL TO INTEGRATE QUANTITATIVELY DIFFERENT SETS OF PHYSIOLOGICAL INFORMATION TO INFER THINGS THAT WOULD BE VERY DIFFICULT TO MEASURE OTHERWISE, IN THIS CASE, ENERGY INTAKE. SO WE CAN APPLY THE SAME IDEA, WE VALIDATED IT ANOTHER STUDY. WE CAN APPLY THIS SAME IDEA TO UNDERSTANDING OTHER BODY WEIGHT TRAJECTORIES. THIS S IN PARTICULAR, THE BODY WEIGHT TRAJECTORY THAT INTRIGUES ME THE MOST. PRACTICALLY WHAT HAPPENS EVERY TIME YOU DO AN INTERVENTION TO TREAT OBESITY, OTHER THAN BARIATRIC SURGERY. EVEN DRUGS, YOU GET THE SAME PATTERN. PEOPLE LOSE WEIGHT FOR A PERIOD OF TIME. THIS IS DATA FROM LAURA'S GROUP AT DUKE. THIS PATTERN IS REPRO TO USED HUNDREDS OF TIMES, PROBABLY, IN THE LITERATURE. PEOPLE LOSE WEIGHT FOR 6-8 MONTHS, PLATEAU, THEY DON'T LOSE MORE, THEN SLOWLY OVER THE SUBSEQUENT YEARS REGAIN WEIGHT. NOW, THERE IS A SORT OF STORY THAT PEOPLE TELL ABOUT WHAT THE SOURCE OF THIS PATTERN IS. IT GOES LIKE THIS. PEOPLE GO ON A DIET. AND THEIR METABOLISM STARTS TO SLOW DOWN. I SHOWED YOU THAT'S TRUE. IT DOES SLOW DOWN. AND THEN EVENTUALLY, THEIR METABOLISM SLOWS DOWN ENOUGH TO MATCH THE NUMBER OF CALORIES THAT THEY'RE EATING. AND SO THEY REACH A PLATEAU. AND NOW THEY'RE ON THIS DARN DIET AND NOT LOSING MORE WEIGHT SO THEY'RE NOT GETTING MORE BANG FOR THEIR BUCK. THEY SHOULD RELAX, WHAT MOTIVATION DO THEY HAVE TO STAY ON AND THEY RELAX THEIR ADHERENCE AND GAIN THE WEIGHT. WE ASKED THE QUESTION, GIVEN THIS PLATEAU AND REGAIN, WHAT TOES THE MODEL SAY HAPPENED? AND IT COMES UP WITH A VERY DIFFERENT STORY. IT SAYS THAT THERE IS A TRANSIENT PERIOD WHERE YOU DRAMATICALLY REDUCE YOUR CALORIES, AND THEN THERE IS A PERIOD WHERE YOU'RE PROGRESSIVELY LOSING ADHERENCE TO THE DOW THE. NOW, THE CALORIES YOU'RE BURNING SLOWS DOWN, NOT ALL THE WAY TO WHERE YOU STARTED. BY THE TIME THE TWO CURVES CROSS THAT'S THE PLATEAU. YOU'RE ALMOST ALL THE WAY BACK UP TO WHERE YOU STARTED. IN TERMS OF YOUR ENERGY INTAKE. AND THE ENTIRE PERIOD OF TIME THAT THIS BLACK CURVE IS BELOW THE BLUE CURVE YOU'RE LOSING WAIT, BURNING MORE CALORIES THAN YOU'RE EATING. INTERESTING, WHAT DOES THE SUBCONSCIOUS OR CONSCIOUS PHYSIOLOGY GOING ON HERE WHERE YOU'RE PROGRESSIVE LEE LOSING ADHERENCE OWE THE TIE THE BUT YOU STEP ON THE SCALE AND LOSING WEIGHT? AND THEN THE MODEL PREDICTS THAT BY ABOUT TEN MONTH YOU'RE BACK UP ALL THE WAY TO WHERE YOU STARTED, AND THIS IS NOW THE SLOW POSITIVE ENERGY BALANCE AS YOU REGAIN THE WEIGHT. I JUST PRESENTED A INITIAL PROTOCOL TO THE NIDDK IRB TO REALLY ASSESS THIS. THIS IS JUST A MODEL PREDICTION. SO I DON'T KNOW WHAT THE RESULTS WAS. HOPEFULLY WE'LL BEING TO A STUDY TO REALLY ASSESS THIS IN THE NEAR FUTURE. HERE IS ANOTHER BODY WEIGHT CURVE, THIS TIME IT'S THE AVERAGE ADULT BODY WEIGHT OF US POPULATION AS MEASURED BY INHAIN. CORRESPONDING TO THE GENERATION OF OBESITY. OVER 30 YEARS WE'VE GAINED ON ORDER OF TEN KILOGRAMS ON AVERAGE. SOME PEOPLE GAINING MUCH MORE, SOME PEOPLE MUCH LESS THAN THAT. AVERAGED OVER THE POPULATION. WE CAN BUILD AN AVERAGE MODEL AND ASK THE QUESTION, HOW MUCH WOULD FOOD INTAKE HAVE TO HAVE GONE UP TO EXPLAIN THE INCREASE IN AVERAGE BODY WEIGHT? THIS IS THE ANSWER. THAT THE MODEL PREDICTS. IT SAYS IT'S ABOUT 250 CALORIES A DAY ON AVERAGE. PLOTTING IT ON THIS SCALE. IF YOU LOOK AT WHAT HAPPENED TO THE FOOD SUPPLY OVER THE SAME PERIOD, THIS IS THE UNITED NATIONS FOOD AND AGRICULTURE ORGANIZATION FOOD BALANCE SHEET. YOU CAN SEE THAT NUMBER ONE IT STARTS OFF A LOT HIGHER PER CAPITA IN THE FOOD SUPPLY. THE RATE OF INCREASE IS MUCH GREATER. WELL, SOME OF THAT FOOD IS NOT AVAILABLE TO BE EATEN. IT GETS LOST IN THE TRANSITION FROM FARM TO FORK. SO THE USDA HAS DONE SOME LOSS ADJUSTED FOOD AVAILABILITY BASED ON SIMILAR DATA. THEY CAME UP WITH A CURVE THAT LOOKS HIKE THIS. THAT BRINGS US BACK IN LINE WITH THE MODEL PREDICTIONS IN THE 70 SAID BUT THE RATE OF INCREASE IS MUCH HIGHER. WE CAN TURN THE MODEL AROUND AND RUN IN THE OTHER DIRECTION AND FEED IT THIS FOOD INTAKE TO SEE HOW FAR OFF THE BODY WEIGHT IS. IF WE THINK WE HAVE AN OBESITY PROBLEM NOW, IF WE HAD EATEN THE FOOD THAT WAS LOST WE WOULD BE ON AVERAGE 100-KILOS. THAT WOULD BE THE AVERAGE BODY WEIGHT. SO CLEARLY, SOMETHING IS GOING ON HERE TO WHERE IS THIS MISSING FOOD GOING? AND SO WE STARTED TO THINK ABOUT THIS. THIS IS THE FOOD AVAILABLE TO BE EATEN IN THE FOOD SUPPLY. THIS IS THE ACTUAL FOOD INTAKE PREDICTED BIOMODEL. THE DIFFERENCE BETWEEN THESE CURVES MUST HAVE BEEN WASTED SOMEWHERE ALONG THE SUPPLY CHAIN. WE CAN PLOT THAT DIFFERENCE. IT SAYS THAT BASICALLY, IN THE 19 P 70s REMEMBERS YOU'RE LOSING ABOUT 900 CALORIES PER PERSON PER DAY. NOWITE MORE LIKE 1400 CALORIES PER PERSON PER DAY, 50% INCREASE OVER THE PAST 30 YEARS. IF YOU PLOT THE USDA, IT MATCHES WHAT WE HAD IN THE 1970s, ABOUT 25% TOO LOW NOW. ACTUALLY I TAKED TO THE PERSPECTIVE IN CHARM -- PERSON IN CHARGE AT THE USDA. SHE REVEALED DURING THE LAWFIRM PERIOD OF TIME THEY DIDN'T -- LARGE PERIOD OF TIME THEY DIDN'T HAVE UPDATED LOSS ESTIMATES. THEY WERE USING THE LOSS ESTIMATES THAT WERE INITIALLY CALCULATED IN 1970. JUST LAST WEEK, THE USDA PUBLISHED A NEW LOST ESTIMATE FOR 2010, BUMPS UP TO 1300 CALORIES A DAY. SHE AGREED THEY MIGHT HAVE BEEN MISESTIMATING THE LOSS. AND SHE HAD A GOOD IDEA. WHY DON'T YOU GO LOOK AT THE FOOD THAT'S IN LANDFILLS? BECAUSE THE EPIDEMIOLOGY CALCULATES THIS -- EPA CALCULATES THIS, MAYBE YOU CAN CALCULATE A PRACTICE CAPITA VALUE. WE DID THAT. THE SOLID FOOD WASTE IN MUNICIPAL LANDFILLS HAVE GONE UP IN PARALLEL. THERE IS EXACTLY PARALLEL 50% INCREASE IN PRACTICE CAPITA SOLID FOOD WASTE IN MONTREAL LANDFILLS. MUNICIPAL LAPPED FILLS. THIS AMOUNT OF FOOD WASTE IS NOT A SMALL NUMBER WHEN YOU CALCULATE IT OVER THE COURSE OF THE POPULATION. IF WERE TO BRING FOOD WASTE BACK TO LEVELS IN THE 1970s, SO NOT ELIMINATE, JUST GET IT BACK TO 900 CALORIES PER PERSON PER DAY. IF WE MADE THAT AVAILABLE IT WOULD BE ENOUGH TO FEED 60 MILLION PEOPLE OR ALLEVIATE HUNGER OF 600 MILLION PEOPLE. WE DID THIS IN THE ARTICLE ABOUT THE RESOURCES IMPLICATIONS OF PRODUCING ALL THIS FOOD NEVER EATEN, 25% OF THE U.S. FRESH WATER SUPPLY TO PRODUCE FOOD THAT'S NEVER EATEN. IT'S SHOCKING QUANTITIES OF WATER AND OIL. ABOUT 4% OF THE TOTAL U.S. OIL PRODUCTION JUST TO PRODUCE THE FOOD ON THE FARM THAT NEFF GETS EATEN. MORE THAN ALL THE OFF SHORE DRILLING COMBINED. IT GAVE US THE IDEA THAT THIS PUSH HYPOTHESIS FOR THE U.S. OBESITY EPIDEMIC. THERE HAS BEEN A VARIETY OF IMPROVEMENTS IN AGRICULTURE RESEARCH AND POLICY, AND I DON'T KNOW IF THERE ARE IMPROVEMENTS IN POLICY. AND VARIOUS SUBSIDIES ALLOWED FOR INCREASED PRODUCTION OF FOOD. THAT'S DRIVEN THE PRICE OF FOOD DOWN. FOOD MARKETS HA INCREASED, MORE CHEAP FOOD IS AVAILABLE T REMARKABLE THING IS THAT MORE THAN TIRED OF THAT EXCESS FOOD WENT IN THE TRACK, THE OTHER THIRD GENERATED THE OBESITY EPIDEMIC. SO I'VE GOTTEN FAR AFIELD FROM THE PHYSIOLOGY OF BODY WEIGHT CHANGE HERE, BUT I DON'T KNOW IF WE CAN ADDRESS THESE SITUATIONS AT THE NIH BUT WHAT WE CAN DO IS ASK THE QUESTION, WHY WERE SOME PEOPLE SO MUCH MORE SUSCEPTIBLE TO THE CHANGING FOOD ENVIRONMENT THAN OTHERS? AND OUR RESEARCH GROUP HAS BEEN FOCUSED ON THE METABOLISM FOR THE MOST PART. IN RECENT YEARS WE'VE COLLABORATED WITH FOLKS AT NIMH, ALEX MARTIN'S GROUP, KYLE SIMONS, NOW AT THE LAUREATE INSTITUTE FOR BRAIN RESEARCH. PART OF A LARGER STUDY WE'RE INVESTIGATING HOW PEOPLE ARE RESPONDING TO FOOD IMAGES AND DOING BRAIN IMAGING. THIS IS ONE OF OUR TASKS WE'VE DONE. WITH WE'VE ASKED PEOPLE TO LOOK AT PICTURE OF FOODS IN THE MAGNET. AND ASSESS HOW PLEASANT WOULD IT BE TO EAT THIS FOOD RIGHT NOW? AND THE QUESTION IS, WHAT PARTS OF THE BRAIN ARE SUPPORTING INFERENCES ABOUT THE NECESSARIANTNESS OF THAT FOOD? -- PLEASANTNESS? WE DO AN UNLESS -- ANALYST WHERE WE LOOK AT THE MODULATION OF THE BRAIN ACTIVITY IN RELATION TO THE PLEASANTNESS RATING. WHAT REGIONS OF THE BRAIN ARE SUPPORTING PLEASANTNESS INFERENCES IN THIS GRADED WAY IS THIS WHAT WE CAME UP WITH TWO REGIONS. THE VENTRAL PAL TEMPERATURE, WHICH IS AN INTERESTING REGION. IT'S THE FIRST TIME IT'S BEEN IDENTIFIED IN HUMANS BUT VERY CLASSIC HE DONIC HOT SPOT IN THE RODENT LITERATURE. AND ONE THAT WAS EXPECTED FOR A WIDE -- LONG PERIOD OF TIME, THE OR TRAL FRONTAL COACH TEXT. KYLE SIMONS, THIS IS HIS PAPER PLUSHED LAST YEAR IN BRAIN STRUCTURE AND FUNCTION. SINCE HE MOVED TO THE LAUREATE INSTITUTE WE REPLICATED THIS STUDY IN A SEPARATE COHORT AT THE LAUREATE INSTITUTE. ONE OF THE CHALLENGES OF THE FMRIRISM IS REPLICATION SO WE'RE PROUD THIS PAPER HAS THE SAME DATA IN TWO COHORTS IN THESE GROUPS. WANT TO CLOSE BY THANKING THE VARIOUS FOLKS INVOLVED IN THIS RESEARCH OVER THE YEARS. IN PARTICULAR, RAMPING UP TO DO CLINICAL RESEARCH HAS BEEN A CHALLENGE AND FUN RIDE. I WANT TO THANK THE FOLKS AT THE METABOLIC CLINICAL RESEARCH UNIT, THE NURSING STAFF AND VOLUNTEER STUDY SUBJECTS. AND MY COLLABORATORS. THANK YOU VERY MUCH. [APPLAUSE] DR. KRISTINA ROTHER A STAFF CLINICIAN COMPLETED HER RESIDENCY IN PEDIATRICS AT THE MAYO CLINIC, THE MASSACHUSETTS GENERAL HOSPITAL AND CHILDREN'S HOSPITAL. IN 2008. DOCTOR ROTHER EARNED THE MASTER OF HEALTH SCIENCES AND CLINICAL RESEARCH THROUGH THE COLLABORATION BETWEEN THE CLINICAL CENTER AND DUKE UNIVERSITY MEDICAL CENTER. ALSO THE PRINCIPLE INVESTIGATOR ON A BENCH TO BEDSIDE STUDY. DR. ROTHER IS AN ACTIVE FACULTY MEMBER OF THE PEDIATRIC ENDOCRINE SOCIETY, THE DOCTOR'S MAYO SOCIETY, THE MASSACHUSETTS MEDICAL SOCIETY AMONG OTHERS. TOGETHER WITH MEMBERS OF HER BRANCH, SHE RECEIVED THE 2012 NIDDK DIRECTOR'S AWARD FOR EXPERTISE IN INTRAMURAL RESEARCH AND SUPPORT OF THE NIDDK MISSION. HER RESEARCH IS FOCUSED ON CELL TRANSPORTATION PLANTATION, AND BETA CELL PRESERVATION, BOTH PEDIATRIC AND AUDIT PATIENTS. ALSO TYPE II DIABETES AND METABOLIC EFFECTS OF ARTIFICIAL SWEETENER. TODAY HER TALK IS ARTIFICIAL SWEETENERS AND OBESITY, MORE THAN AN ASSOCIATION. NHAU. A LATE GOOD MORNING TO THE AUTOPSIES. YOU'VE HEARD A FASCINATING TALK BY KEVIN HALL, BASED ON LOGIC AND MATH MAT BEENS. -- MAT MATHEMATICS. WITH THIS TITLE, I WANTED TO MAKE SURE THAT YOU UNDERSTAND I DO -- I WILL NOT BREAK THE RULES OF THERMODYNAMICS. I ALSO HAVE NO CONFLICTS OF INTEREST. AND THE MAIN LEARNING OBJECTIVES WILL BE TO DISTINGUISH BETWEEN THE DIFFERENT ARTIFICIAL SWEETENERS TO DESCRIBE THEIR MECHANISM OF ACTION AND RECOGNIZE THE DIFFICULTIES IN ESTABLISHING CAUSALITY FOR OBESITY PROMOTING EFFECTS. I'LL DIVIDE UP THE TALK TO THREE PARTS. FIRST, AND OVERVIEW OF THESE ARTIFICIAL SWEETENERS, AND THEN I'LL MENTION SOME STUDIES THAT REPORT AN ASSOCIATION BETWEEN ALSOS -- ARTIFICIAL SWEETENERS, AND OBESITY. AND THE INTERESTING PART IN THE DATA AND CONCEPT REFUTING OR SUPPORTING A CAUSAL ROLE. THE FDA FDA PRESENTLY REGULATES FIVE ARTIFICIAL SWEETENER. THE OLDEST IS SACCHARIN, ABOUT 300 TIMES SWEETER THAN GLUCOSE, A SIMILAR WEIGHT. ASPERTAME IS THE ONE THAT GOT A LITTLE BIT OF BAD REPUTATION BECAUSE IT METABOLIZED INTO ACID AND METHANOL. THE METHANOL IS EXTREMELY SMALL CONCENTRATIONS, AND THERE IS NO TRUE EVIDENCE FOR ANY NEGATIVE HEALTH EFFECTS. ASSUL FAME POTASSIUM, YOU DON'T OFTEN SEE. IT HAS A BITTER TASTE TO IT. AND THEREFORE IT IS MANY OF THE ARTIFICIAL SWEETENERS USED IN A MIXTURE. SUCRALOSE IS PROBABLY PRESENTLY THE MOST COMMONLY USED ARTIFICIAL SWEDENER, YOU FIND IT IN SPLENDA. 600 TIMES MORE SWEET THAN GLUCOSE, AND NEO TAME IS THE STAR. 10,000 TIMES SWEETER WHICH ACTUALLY CAUSES A PROBLEM BECAUSE IT'S SO SWEET THAT I CAN ONLY USE SUCH MINIMAL AMOUNTS IT'S DIFFICULT TO HANDLE. IT HAS A SLOW ON SET OF SWEETNESS. WHEN I SAY THE FDA REGULATES ARTIFICIAL SWEETENERS, THAT INCLUDES THAT THERE ARE DAILY -- ACCEPTED DAILY INTAKE LIMITS. AND THIS MEANS YOU CAN ADD A FOOD ADDITIVE TO YOUR FOOD EVERY DAY FOR YOUR LIFE, AND YOU SHOULDN'T EXPECT ANY NEGATIVE HEALTH EFFECTS SOFT SACCHARIN, THIS IS FIVE MILLIGRAMS PER KILOGRAM. FOR ME THAT MEANS IF YOU LOOK AT THE USUAL SODAS THAT I CAN DRINK THREE SODAS PER DAY BASED ON MY BODY WEIGHT. IF YOU GO DOWN TO SUCRALOSE, FIVE SODAS, IF YOU'RE A PEPSI ONE, OR DIET COKE WITH SPLENDA FAN, NO MORE THAN FIVE SODAS A DAY. I WILL NOT AND SOME WILL BE DISAPPOINTED. WHOLE FOODS, THIS ARE NO ARTIFICIAL SWEETENERS. THERE IS STEVE GRAY. I WILL NOT TALK ABOUT STEEVIA TODAY. I WILL ALSO NOT TALK ABOUT THE SUGAR ALCOHOLS. JUST A HISTORIC NOTE. WE'RE SO CLOSE TO BALTIMORE. SACCHARIN WAS FIRST FOUND BY CONSTANTINE FAHLBERG, A RUSSIAN SCIENTIST. IT'S ONE OF THESE STORIES, HE WORKED LATE. WENT HOME, ATE SOMETHING. AND HAD EXTREMELY SWEET TASTE. TOUCHED SOMETHING ELSE, HE WAS SWEET AGAIN, HE WENT BACK TO THE LAB AND HE FOUND SACCHARIN. NOT THAT HE BOURQUEED ON SWEETENERS. HE WORKED ON COLD TAR DERIVATIVES. IN ALL OF THIS WAS PUBLISHED TOGETHER WITH REMSEN IN 1877, COMING FROM JOHNS HOPKINS UNIVERSITY. THE STORY DIDN'T END VERY WELL BECAUSE FAHLBER WENT TO PATENT SACCHARIN AND GERMANY STARTED PRODUCING IT. REMSEN NEVER SAW A PENNY AND LATER CALLED FAHLBERG A SCOUNDREL. THAT SOMETIMES HAPPENS IN SCIENCE. WELL, FAHLBERG NAMED THIS SWEET STUFF SACCHARIN. HERE, YOU HAVE TO ALLOW ME A COMPARISON TO DNA STRUCTURES. WHEN DNA IS VERY MUCH CONSERVED, WE THINK THAT THERE IS SOME IMPORTANCE TO IT. I THINK I CAN CONVINCE YOU SUGAR IS CONSERVED COMING FROM SAN CITE TO THESE FOREIGN WORDS. FAHLBERG CALLED IT SACK RELATIONSHIP BECAUSE IT'S SO CLOSE TO HIS RUSSIAN WORD FOR SUGAR. GOING BACK TO PHYSIOLOGY, WE PERCEIVE SEVERAL TASTES IN OUR TASTE THAT CONTAIN TASTE BUDS. EACH ONE OF THESE BUDS CONTAINS ABOUT 80 CELLS, AND ONE SPECIFIC CELL IS RESPONSIBLE FOR ONE SPECIFIC TASTE. WE PERCEIVE THE TASTES OF SALT, SOUR, SWEET, BITTER AND MOMMY. MOMMY IS THE SAVORY TASTE FROM GLUT MEAN. THE THREE TASTE RECEPTORS, SWEET, BITTER AND UMAMI, SHARE THIS SIMILAR STRUCTURE. P # TRANSMEMBRANE RECEPTORS. THE ONLY THING IS THEY DIFFER IN THEIR SUBUNITS. SO WHAT HAPPENS, YOU GET A DROP OF SWEETENERS ON YOUR TONGUE, SWEET TASTE RECEPTORS ARE ACTIVATED, THEN VIA CRANIAL NERVES, THE MESSAGING IS SENT UP TO THE BRAIN SWEETNESS. THE INTERESTING THING, WE FEEL SWEET TASTE RECEPTORS NOT ONLY ON THE TONGUE AND THE FAN X BUT WE HAVE THEM THROUGHOUT THE BODY. YOU CAN SEE THEY ARE EXPRESSED IN THE LUNGS, IN THE LIVE, AND PANCREATIC BETA CELLS IN THE GUT. IF YOU'RE A FLY, YOU HAVE THEM ON YOUR WINGS AND THE TIP OF YOUR FEET. NOW, LET'S GO TO THE GUT OF HUMAN, WE HAVE CERTAIN END TRO CIN CELLS. THESE END DRO CIN CELLS EXPRESS TASTE RECEPTORS. WHEN COLUMBUS DOES OR AN -- GLUCOSE OR AN ARTIFICIAL SWEETENER ACTIVATES A TASTE RECEPTOR, THAT DOES NOT ALOUETTENESS TO YOUR BRAIN. WHAT IT DOES, IT LEADS TO DECREATION IN THAT CELL. THIS IS ONE OF THE -- GLP1, WHICH IS VERY IMPORTANT FOR THE REGULATION OF THIS SPEED WHICH WHICH YOU EMPTY NOUR STOMACH. DECREASES APPETITE, AND INCREASES INSULIN. SO SWEETENERS SIGNALED TO THE BRAIN FROM THE TONGUE AND PHARYNX. LET ME COME TO THESE STUDIES THAT REPORT AN ASSOCIATION BETWEEN ARTIFICIAL SWEETENER AND OBESITY. KEVIN ALREADY MENTIONED THE HOT TOPIC, NAMELY IN TODAY'S JAMA, THE LATEST NUMBERS CAME OUT OVER ALL OBESITY PREVALENCE IN -- ACCORDING TO INHAIN STATE. 34.9 IN ADULTS. THIS IS BASICALLY THE SAME AS IN 2003. SO THIS IS ASSESSED IN TWO YEAR INTERVALS. AND THE OBESITY RATE HAS NOT CHANGED IN ADULTS, HAS GONE UP IN WOMEN ABOVE 60 AND HAS DECREASED AS KEVIN MENTIONED, INTHE VERY YOUNG, IS-2 YEAR -- 0-2 YEARS. THIS IS ABOUT ASSOCIATION. THIS IS THE CURVE THAT SHOWS YOU HOW MANY PEOPLE -- AGAIN, BASED ON NHANES DATA, CONSUME AN ARTIFICIALLY SWEETENED DRINK ON FOOD PER DAY. AND INHAINS IS BASED ON FOOD RECALL, DIETARY RECALL OF ONE DAY. SO [INDISCERNIBLE] HERE IN THE AUDIENCE, SHE PUT TOGETHER THE LATEST DATA. AND FOUND THAT 32% OF ALL ADULTS ON A GIVEN DAY, IN 2010, CONSUMED SOMETHING THAT IS SWEETENED WITH AN ARTIFICIAL SWEETENER. UNDER, I HAVE IN COLOR, THE INTRODUCTION OF SPECIFIC ARTIFICIAL SWEETENERS TO OUR FOOD CHAIN. AND SO THIS MAKES A VERY NICE PARALLEL CURVE. I WANT TO JUST AS YOU ALL KNOW, MAKE YOU AWARE OF THE FACT THAT ASSOCIATION REALLY DOESN'T STAND FOR CAUSATION, BECAUSE I DON'T THINK ANYBODY WOULD ARGUE THAT BECAUSE YOU DRINK MORE BOTTLED WATER, I GAIN WEIGHT. OTHER THAN IF THERE IS BPA IN THE PLASTIC. BUT THAT'S NOT WHAT I WANT TO TALK ABOUT TODAY. SO ONE OF THE MOST IMPORTANT STUDIES THAT IS CITED FOR THIS STRONG ASSOCIATION BETWEEN ARTIFICIAL SWEETENERS AND OBESITY, COMES FROM THE SAN ANTONIO HEART STUDIES. YOU MAY KNOW THAT THIS IS A LARGE STUDY, NATURAL HISTORY STUDIES STARTED IN 1979, THAT INCLUDED FM -- ANGLO AMERICANS AND EMBASSIENS, MOSTLY MEXICAN AMERICANS, IN ORDER TO FIND OUT WHAT THE DRIVING FACTORS WERE FOR DIABETES AND CARDIOVASCULAR RISK. WHAT DOES SHARON FOWLER HAS TON IN THIS 2008 PUBLICATION, SHE HAS DIVIDED INDIVIDUALS INTO VARIOUS GROUPS OF ARTIFICIAL SWEETENER CONSUMPTION. SO ON THE Y AXIS, YOU HAVE THE BMI CHANGE FROM THE START OF THE STUDY, AND HERE, YOU HAVE VARIOUS GROUPS ACCORDING TO IN-TAKE OF ARTIFICIAL SWEETENER BEVERAGES PER WEEK. AND THEN THEY LOOKED AGAIN 7-8 YEARS LATER. AND FOLLOWED WHAT THE PROGRESS WAS, WHAT BMI CHANGE WAS. I WANT TO MAKE AN EXAMPLE. SO IF YOU'RE ABOUT MY HEIGHT, HEAVIER, 155-POUND, A BMI OF 25, AND YOU DO NOT CONSUME ARTIFICIAL SWEETENERS, THEN YOU ARE IN THIS FIRST GROUP HERE. YOU ARE EXPECTED TO GAIN ABOUT 1BMI POINT. YOU END UP AT 26. SO THAT MEANS YOU GAINED 6 POUNDS. BUT IF YOU DRINK JUST ONE SODA A DAY, YOU END UP A LITTLE HEAVIER, FOUR POUND HEAVIER. THE POINT I WANT TO MAKE IS THAT THERE IS A CLEAR CUT STATISTICAL RELATIONSHIP BETWEEN SWEETENER INTAKE AND BMI THAT IS NOT TRAUMATIC. BUT IT'S CLEAR CUT. SO NOW LET ME COME TO SOME OF THE DATA AND CONCEPTS REFUTING AND SUPPORTING. NOT ONLY BECAUSE I'M A PEDIATRICIAN, I MAKE THAT LITTLE SIMPLE, BUT I WANT TO START WITH SHOWING IN VITRO DATA, AND THEN GOING TO SOME ANIMAL STUDIES, AND THEN TELL YOU ABOUT SOME CLINICAL TRIALS. THE CLINICAL TRIALS I REALLY WANT TO POINT OUT IS VERY IMPORTANT TO DISTINGUISH IN WHOM YOU USE THE ARTIFICIAL SWEETENERS, AND IN WHICH CONTEXT. STARTING WITH IN VITRO STUDIES, THESE HAVE SHOWN TO STIMULATE ADPO GENUS IN 3T3-L1 CELLS. IF YOU ADD THEM TO MATURE CITES YOU HAVE DECREASED LIPOYLSIS. SUCCEED RA LOWS AND SACCHARIN, WHEN THEY'RE ADDED TO A MOUSE INSULIN THEY ARE SHOWN INFLAMMATORY CREASE -- SHOP TO INCREASE INSULIN SECRETION. DURING THIS LECTURE, THE POSSIBLE -- THE POSSIBILITY THAT HYPER INSUL THEMIA IS DRIVING OBESITY WAS DISCUSSED, AND HYPOINSUL EMIA COULD BE INDUCED BY VARIOUS FACTORS IN OUR NUTRITION, AMONG THEM, ARTIFICIAL SWEETENERS. THEN SOMETHING FOR THE DENTIST. SUCRALOSE, MORE THAN SACCHARIN, THEY ARE BACTERIAIO STATIC. THIS HAS BEEN TESTED IN PERIODONTAL DISEASE CAUSING BACTERIA. EVEN IF YOU DON'T GIJEST DIET SODA, YOU PROBABLY HAVE IT IN YOU RIGHT NOW BECAUSE YOU BRUSHED YOUR TEETH. IT TASTES LIKE STRAWBERRY, OR SOMETHING, IS ARTIFICIAL SWEETENER. AND THEN DR. GALLON MENTIONED BEFORE THE SUPPRESSION, THERE WAS A TALK ABOUT THE INFLUENCE OF THE MICROBIOME IN OBESITY. SO SOME ARTICLE SWEETENERS HAVE ALSO BEEN SHOWN TO SUPPRESS THE INTESTINAL MICRO FLOORA, SO FAR ONLY IN RAT. ONE OF THE PUBLICATIONS MENTIONED HERE. AND SO THE QUESTION IS OPEN WHAT HAPPENS IN HUMANS. IT'SNISTING TO KNOW THAT LACTATING RATS CONCENTRATE ACE SUL FAME POTASSIUM IN BREAST MILK. WE HAVE DATA THAT MIRROR THE FINDINGS IN RATS, NAMELY, WITH THE HELP OF SOME GENEROUS VOLUNTEERS, WE'VE SAMPLED BREAST MILK SAMPLES AND FOUND HIGHER POTASSIUM CONCENTRATIONS IN HUMAN BREAST MILK COMPARED TO WHAT YOU EXPECT IN HUMAN PLASMA. IN ADDITION, WE FIND SACCHARIN AND SUCCEEDRO LOWS, AND YOU MAY ASK THE QUESTION, WHAT DOES THIS MEAN. I CAN ONLY ANSWER, THE OFF SPRING EXPOSED DURING PREGNANCY HAD HIGHER PREVIOUSRANCE FOR SWEETERS, WHETHER YOU GAVE THEM WHEN THEY WERE 6 MONTHS OLD, ARTIFICIAL SWEETENER OR REGULAR SUGAR. THEY LIKED IT BETTER. SWEETNESS WAS IMPORTANT. SO IS THIS SOMETHING THAT ALSO HAPPENS IN OUR INFANTS? WE DON'T KNOW. BUT I WANT TO SAY INFANT MICROBIOME STUDIES SHOULD BE EASIER THAN IN ADULTS. IT'S THE DIAPERS WE NEED TO SAMPLE. SO GOING TO THE RANDOMIZED ACUTE INTERVENTION STUDIES IN HUMANS, AS I MENTIONED BEFORE, I THINK IT'S IMPORTANT TO KNOW IN WHICH COHORT YOU DO THE STUDIES, AND IN WHICH CONTEXT YOU GIVE THE ARTIFICIAL SWEETENERS. SO LET'S START WITH ADOLESCENCE AND YOUNG ADULTS. WHAT WE HAVE DONE IS WE HAVE CONDUCTED ORAL GLUCOSE TOLERANCE TESTS IN MANY HEALTHY AND VOLUNTEERS WITH TYPE ONE DIABETES. AS YOU CAN SEE, THE SUBJECTS WERE BETWEEN 12 AND 25 YEARS OF AGE. BEFORE THEY INGEST -- BEFORE THEY GET THE ORAL FLY DOES TOLERANCE, DOWN HERE, THESE ARE ORAL GLUCOSE TOLERANCE TESTS, OVER THREE HOURS. BEFORE THEY START THE TEST THEY GET A CLASS OF WATER OR SOME DIET SODAERS IN RANDOMIZED ORDER. WHAT WE FOUND IN THESE OTHER RED LINES, IF YOU GAVE DIET SODA BEFORE THE ORALGLUCOSE TOLERANCE TEST, WE FOUND MORE GOP1. THIS WAS CLEARLY STATISTICALLY SIGNIFICANT, THE AUC WAS 34% HIGHER IN THE HEALTHY VOLUNTEERS, EVEN HIGHER, 43%, IN THE INDIVIDUALS WITH TYPE ONE DIABETES. IN GPO ONE IS THE ONE THAT BEFORE MENTIONED IN THE CONTEXT OF DECREASED GASTRIC EMPTYING, DECREASED APPETITE, AND THE NUTTRA SUITICAL COMPANIES HAVE BEEN THINKING ABOUT USING THIS CONCEPT, SO THERE ARE -- CALLED NUTTRA SUITICALS, THEY'RE NOT REALLY DRUGS. THEY'RE MEDICATION MADE FROM FOOD STUFFS THAT ARE SUPPOSED TO SUPPRESS YOUR APPETITE. SO THE FIRST RESULTS HAVE BEEN ACTUAL HEY PRESENTED AT THE OBESITY SOCIETY LAST YEAR. NOW, WHEN YOU USE SUCRALOSE ALONE, WE DIDN'T REPRODUCE OUR RESULTS. AND IF YOU USED SUCRALOSE AND POTASSIUM ALONE, OTHERS HAVE NOT SHOWN GOP1 INCREASES. THIS NEEDS TO BE CONFIRMED AND WE'RE DOING THIS RIGHT NOW. BUT IN SAM KLEIN'S GROUP, THIS IS [INDISCERNIBLE] AT WASH YOU, THEY HAVE DONE AN INTERESTING STUDY. I WANT TO POINT OUT IN WHOM. THESE WERE BLACK WOMEN, TYPICALLY DIDN'T USE ARTIFICIAL SWEETENERS, AND THEY WERE QUITE HEAVY. BMI OF 40. IN THESE WOMEN, IF YOU PRETREATED THEM WITH SUCRALOSE, THEY ACTUALLY HAD HIGHER GLUCOSES AND INSULIN. THIS IS WHAT YOU DON'T WANT. WHEN YOU'RE OVERWEIGHT AND MAYBE GOING TOWARD PREDIABETES, AND YOU THINK YOU SHOULD REALLY AVOID SUGAR IN YOUR DRINK SUINGRA LOWS, YOU MAY END UP WITH HIGHER GLUCOSE AND INSULIN. SMALL STUDIES, 17 INDIVIDUALS, NEEDS TO BE CONFIRMED T SUMMARY OF THE RANDOMIZED ACUTE INTERVENTIONS, WE HAVE SHOWN THAT ADOLESCENCE AND YOUNG ADULTS WITH OR WITHOUT TYPE 1 DIABETES HAVE MORE GLP1. OTHERS HAVE NOT CONFIRMED THE DATA. MIDDLE-AGED, MOSTLY BLACK, HIGHER INSULIN AND GLUCOSE. THESE ARE ACUTE STUDIES. WHAT HAPPENS IF YOU GIVE PEOPLE ARTIFICIAL SWEETENERS IN THE LONG RUN? EXACTLY THAT HAS BEEN PUBLISHED LAST YEAR IN THE SAME ISSUE, TWO GREAT STUDIES. ONE FROM DAVID'S GROUP IN BOSTON. AND THE OTHER ONE, A TRIAL OF SUGAR-FREE OR SWEETENED BENCHES IN BODY WEIGHT IN CHILDREN. IN THE FIRST TRIAL, IN WHICH OVERWEIGHT OBESE ADOLESCENTS IN 9th AND 10th GRADE WERE ENROLLED, THEY HAD TO HABITUALLY CONSUME SUGAR SWEETENED BEVERAGES. WHAT THEY, THEN, DID, ONE GROUP GOT -- INSTEAD OF WHAT THEY USED, NAMELY THE SUGAR SWEETENED BEVERAGES, THEY GOT DIET SODAS DELIVERED TO THE HOUSE. THE OTHER GROUP SO SUPERMARKET GIFT CARDS. THEY WERE NOT INSTRUCTED TO BUY ANYTHING SPECIFIC. NOW, THE REPLACEMENT 0 -- IT REALLY WAS A REPLACEMENT. LED ANNIVERSARY ONE YEAR, TO A VITALLY -- TO A SLIGHTLY LESS WEIGHT GAIN. IT MEANS IT WAS STILL WEIGHT GAIN IN BOTH GROUPS. ONE GAINED A LITTLE LESS, 1.9-KILOGRAMS. AWFUL TWO YEARS, THERE WAS NO MORE DIFFERENCE. ALL THIS EFFORT TO REPLACE THE DRINKS AT HOME, DELIVERED IT TO HOME, AND ULTIMATELY YOU END UP WITH VERY LITTLE DIFFERENCE. HOW ABOUT THE KIDS? THE YOUNGER KIDS? THESE WERE NOW KIDS AGE OF 8, ELEMENTARY SCHOOL KIDS, ALMOST 3 TIMES, 641 KIDS, HABITUALLY CONSUMED SUGAR SWEETENED BEVERAGES. THEY HAD TO BE CONSUMERED. OTHERWISE IT'S NOT ETHICAL TO PUT SOMEBODY ON SUGAR SWEETENED BEVERAGES. SO THESE KIDS WERE RANDOMIZED, IN THE BEGINNING THEY ALL DRANK SUGAR SWEETENED. THEN THEY WERE RANDOMIZED AND GOT, IN SCHOOL, ALSO OVER THE WEEKENDS AT HOME, EITHER THE SUGAR SWEETENED BEVERAGE OR AN ARTIFICIALLY SWEETENED BEVERAGE. THEY DID THIS FOR ONE AND A HALF YEARS. SO TRULY LONG DURATIONS. IN ORDER TO EXPLAIN THE OUTCOME, I WANT TO BRIEFLY MENTION THAT THEIR OUTCOME WAS BMI-Z SCORE. CHILDREN GAIN WEIGHT AND GROW AND THAT'S NORMAL. SO IF YOU GO, ACCORDING TO THIS ORANGE ARROW, AND YOU GAIN ACCORDING TO THE ORANGE ARROW, YOU STAY ON THE 50th PERCENTILE. YOU'RE SMACK IN THE MIDDLE WHICH MEANS THE DIFFERENCE IN BMI IS 0. SO IF KIDS GROW ALONG THAT CURVE YOU EXPECT, NO CHANGE. THE KIDS IN THIS STUDY STARTED OUT VERY CLOSE TO 0. YOU SEE .05 ABOVE 0 OR MINES .01. THEY ENDED UP MUCH HIGHER IN THE SUGAR GROUP COMPARED TO THE SUGAR-FREE GROUP, THERE WAS 1 KILOMETERO GRAM DIFFERENCE IN WEIGHT AFTER 18 MONTHS. I REALLY WANT TO POINT OUT WHAT YOU EXPECT, IF YOU STAY ON THE 50th PERCENTILE OR WHEREVER YOU STARTED TO GROW ALONG YOUR OWN PERCENTILE, YOU SHOULD HAVE NO INCREASE. SO THE KIDS IN THE SUGAR SWEETENED GROUP REALLY INCREASED. AND THE KIDS IN THE ARTIFICIAL SWEETENER GROUP INCREASED A BIT. THE PROBLEM IN MY EYES IS THAT YOU SHOULD HAVE A GROUP WHERE YOU KNOW IF YOU DON'T DO ANYTHING, WHERE THEY END UP. OF COURSE THIS IS GREAT EFFORT TO INCLUDE SUCH A GROUP. IN THE INTERPRETATION OF THE PRESENT TIME FOR ME IS THAT KIDS WHO CONTINUE TO DRINK REGULAR SODA IN SCHOOL GAIN MORE WEIGHT. BECAUSE EVEN REPLACEMENT OF THE SUGAR SWEETENED BEVERAGE WITH AN ARTIFICIAL SWEETENER DIDN'T DO ANYTHING TO GAIN WEIGHT. I WANT TO MENTION THE SAME PRINCIPLE KEVIN HAS STARTED TO TALK ABOUT, NAMELY REWARD. IN THIS FOOD NAVIGATORS, THIS IS LITERATURE THAT SAID THAT THE BRAIN CANNOT BE FOOLED INTO THINKING 0-CALORIES SWEETENERS ARE PROVIDING US WITH ENERGY, WARNED RESEARCHERS. THAT AWE PEERS TO BE CORRECT. THAT BEAUTIFUL STUDY DONE BY FRANK, ORIGINALLY CAME FROM GERMANY, WORKED WITH WALTER K, IN EXCELLENT INVESTIGATOR IN EATING DISORDER, WHAT THEY DID, THEY TOOK 12 HEALTHY WOMEN, NORMAL WEIGHT. AND THEY PUT A DROP OF SUGAR ON THEIR TONGUE IN A FUNCTIONAL MRI, IN THE MRI SCANNER. AND ONE TIME THE DROP CONTAINED SUCRALOSE, THE OTHER TIME IT CONTAINED SUCROSE. WHAT I WANT TO POINT OUT IS THE DIFFERENCE OF ACTIVATION OF CERTAIN BRAIN AREAS, WHICH KEVIN HAS TOLD YOU, CAN ACTUALLY BE REPEATED. THERE IS CLEAR LAY A DIFFERENCE IN THE ACTIVATION. ONE OF THE IMPORTANT -- THE IMPORTANT FACTORS ARE DOPAMINE, IN REGARD TO SIGNALING REWARD. THERE IS LESS DOPAMINE RECEPTOR ACT VACCINE WITH THE -- ACTIVATION WITH THE SUCRALOSE. WETH WHEN WE INGEST SOMETHING SWEET. IT DOESN'T CONTAIN CALORIES. SO IN SUMMARY, I THINK I WANT TO TURN THIS AROUND. I THINK I HAVE NOT PROVIDED ANY CONVINCING EVIDENCE THAT ARTIFICIAL SWEETENERS PREVENT OR ALLEVIATE OBESITY. BUT AT LEAST IN VITRO, AND ALSO IN ANIMALS AND SOME HUMAN STUDIES SHOW THAT THERE IS PLAUSIBLE REASON TO BELIEVE THAT THEY COULD PLAY A ROLE THROUGH PROMOTION OF ADPO GENESIS, MORE INSULIN IS HE CESSION AND LESS REWARD -- SECRETION AND LESS REWARD. ON THE OTHER HAND, THIS MAY BE MORE GUT HORMONE SECRETION, GOES IN THE DIRECTION OF APPETITE SUPPRESSION. SO CLEARLY, WE NEED TO SORT THIS OUT. I HOPE I'LL BE REINVITED AND CLARIFY THIS THE ETHICS TIME A LITTLE BETTER. PROMISE WE KEEP WORKING ON THE BREAST MILK ISSUE AND THE MICROBIOME. WITH THAT, I WANT TO THANK OUR COLLABORATORS AND YOU IN THE AUDIENCE. THANK YOU. [APPLAUSE]