Demystifying Medicine 2017: Obesity: Brown and Other Fat

January 9, 2020 0 By Ewald Bahringer


I’M JOHN HANOVER, I LECTURED A FEW WEEKS AGO AND WIN ASKED ME TO PROCTOR THIS SESSION OF DEMYSTIFYING MEDICINE. IT’S PARTICULARLY APPROPRIATE I COME FROM THE INSTITUTE THAT BOTH REBECCA AND AARON COME FROM AND IT’S AN AREA OF INTEREST OF MINE TOO. SO THE TOPIC TODAY WILL BE ON OBESITY AND THE KINDS OF FAT, THE EVER INCREASING NUMBER KINDS OF FAT THAT MAKES UP THE OBESITY PHENOTYPE. FOR THOSE THAT WENT TO MEDICAL SCHOOL AND GRADUATE SCHOOL IN THE 1960S AND 70S THE DIP LO SIGHT WAS A STORAGE RESERVOIR. AND THAT’S HOW IT WAS TAUGHT IN MEDICAL SCHOOL AND THAT’S HOW IT WAS UP UNTIL FAIRLY RECENTLY WITH THE DISCOVERIES ASSOCIATED WITH HYPOTHALAMIC INPUT INTO THE KINDS OF NAT WE PRODUCE AND THE MECHANISMS OF WHAT THE FAT TISSUE WAS DOING. TODAY WHAT WE’LL BE HEARING ABOUT ARE THE SORT OF MANY AND VERY TALENTS OF THE ADIPOST ORGAN NOW. I THINK WE WILL HEAR THAT AND YOU SHOULDN’T THINK OF FAT AS ONE THING. IT’S REALLY–BECAUSE OF ITS ROLE IN THERMOGENESIS, IT’S A QUITE DISCIPLINARY VERGS AND EXTREMELY EXCITING AREA OF RESEARCH. WE WILL HEAR FROM TWO OF THE STRONGEST ADVOCABULARY KAILTS IN THE INTRA MURAL PROGRAM. AARON CYPESS AND REBECCA BROWN. I WANT TO INTRODUCE THEM INDIVIDUALLY. AARON WILL BEGIN TODAY’S SESSION. SO AARON IS CURRENTLY THE ACTING CHIEF OF THE TRANSLATIONAL PHYSIOLOGY SECTION AT OUR INSTITUTE. HE ACTUALLY HAS A CHEMISTRY DEGREE FROM PRINCETON. HE DID HIS M. D. AT CORNELL AND CORRECT ME IF ANY OF THIS IS WRONG, AND HAS DOCTOR AT ROCK ROCKEFELLER HE WAS AN ASSISTANT AT DIABETES, HE HAD THE PRIVILEGE OF WORKING WITH MY GOOD FRIEND RON WHO TAUGHT MANY OF US ABOUT INSULIN RESISTANCE IN THE METABOLIC FIELD AND HIS FOCUS IN HIS OWN RESEARCH IS ON THE MECHANISMS OF EPIDEN O GENESIS AND THE ROLES OF BROWN FAT IN OBESITY. WITH THAT I WILL TURN IT OVER TO DARREN. –AARON AND OUR SECOND SPEAKER WILL BE REBECCA. SHE WILL TAKE A SECOND APPROAH BUT YOU NEED TO STAY TODAY BECAUSE YOU WILL LEARN A LOT ABOUT ADIPOSE TISSUE.>>THANK YOU VERY MUCH, JOHN, THAT WAS A GREAT INTRODUCTION TO WHAT WE’RE TALKING ABOUT TODAY BECAUSE THIS ISSUE OF WHAT I WAS TAUGHT IN MEDICAL SCHOOL FOR ME IN THE EARLY 90S–OKAY, GO AHEAD. WHAT HAPPENED IN THE EARLY 90S AND WHERE WE ARE TODAY IS REALLY THE GREAT TRANSITION WITHIN THE BROWN AND OTHER FAT IS MORE OF A BROWN VIEW TOWARDS THINGS AND AS YOU LISTEN TO DR. BROWN, YOU WILL HEAR A DIFFERENT SIDE AND IT’S ALL COMPLIMENTARY. I WILL HAVE TO PUT THE CONFLICT OF INTEREST DISCLOSURE. I WILL BE TALKING ABOUT MIRABEGRON, AND WHICH IS HIGHER THAN THE FDA’S HIGHEST APPROVED DOSAGE OF 50-MILLIGRAMS FOR TREATING OVERACTIVE BLADDER AND I HAVE NO OBLIGATIONS ECTOMYOSINNIVES WITH THE PHARMACEUTICALS. SO WE WANT TO DISTINGUISH BETWEEN BROWN AND WHITE TISSUE. AND THEN WE WILL IDENTIFY BROWN FAT FUNCTION AND WHY YOU NEED IMAGING AND THEN WE WILL LIST THE INTERVENTIONS ALREADY SHOWN TO INCREASE THE MASS AND ACTIVITY AND AT THE END HOPEFULLY, BASED ON CURRENTLY AVAILABLE DATA, TELL BE A TREATMENT TARGET FOR OBESITY AND DIABETES. OKAY, WE ALWAYS SHOW THIS SLIDE BUT I THINK IT’S RELEVANT FOR TWO REASONS, ONE YOU COULD BELIEVE THAT TOO MUCH FAT IS HIGHLY MORBID. THESE ARE THE RATES OF OBESITY FROM 94 TO 2007. THEY’RE MOVING UP. THAT AS DR. MICHAELS TOLD ME WHEN I STARTED MEDICAL SCHOOL, 50% OF THE DETAILS THAT WE WILL TEACH YOU HERE WILL BE WRONG IN 20 YEARS. HE WAS WRITE. AND THAT IS PROMOTIONAL A HIGHER NUMBER WHEN IT COMES TO ADIPOSE TISSUE. IN PARTICULAR, THERE ARE AT LEAST TWO TYPES OF FAT. ONE, WE RIKE TO THINK OF AS WHITE ADIPOSE TISSUE AND THAT IS INVOLVED AS ENERGY STORAGE AS YOU HEARD THEN THERE’S BROWED ADIPOSE TISSUE AND BAT WHICH IS INVOLVED IN ENERGY COMSUMPTION. TO PUT IT IN PERSPECTIVE, WHAT ADIPOSE TISSUE, 50-GRAMS, 2-OUNCES HOLDS ROUGHLY 300 TO 500-CALORIES, THE WE DID THE EQUATION AND A TYPICAL 80 KILOGRAM PERSON HAS ABOUT 170,000 PIECES OF TOAST IN THEM IN TERMS OF ENERGY. JUST TO SEE HOW LONG CAN YOU GO ON THE ENERGY THAT YOU STORED IN YOUR BODY. NOW WHITE FAT GETS A BAD RAP BECAUSE TOO MUCH CAUSES ALL SORTS OF METABOLIC DISEASES IN CANCERS HOWEVER, NOT HAVING ENOUGH AS YOU WILL HEAR ABOUT FROM DOCTOR BROWN IS ALSO A PROBLEM BUT IT’S ALSO A LOT OF THINGS AS WE WILL GET INTO. BROWN ADIPOSE IS ENERGY EXPENDITURE, AND ONE-300 KCAL,. THIS NUMBER COULD BE AN ORDER OF MAGNITUDE TOO LOW AND AN ORDER OF MAGNITUDE TOO HIGH AND WE WILL FIND OUT WHAT THOSE NUMBERS. NOW THIS IS ACHIEVED IN BROWN ADIPOSE TISSUE, THROUGH THE EXPRESSION OF ACTIVATION OF UNCOUPLING PROTEIN WONDER WHICH LEAD THE GENERATION OF HEAT ALSO KNOWN AS THERMOGENESIS AND I WILL SHOW YOU AT A MECHANISTIC LEVEL HOW THAT OCCURS. NOW ONE THINK THIS I WAS TOLD OR LED TO BELIEVE OR JUST STUCK IN MY HEAD WAS THAT THE AMOUNT OF WHITE FAT AN ADULT HUMAN HAS IS FIXED AND THAT THE CELLS GET LARGER, SMALLER BUT THERE’S NOT MUCH TURNOVER OVER TIME. THAT IS NOT TRUE IN THE ANIMAL MODEL. THIS IS THE MOUSE RAISED AT 28-DEGREES AND THIS IS DISSECTED OUT BY THE UNIVERSITY OF ANCONA AND YOU CAN SEE THAT A LOT OF THE ADIPOSE TISSUE IS WHITE. IT’S ACTUALLY A BIT MISLEADING BECAUSE THE TISSUE IN HUMANS IS YELLOW. THE BROWN AND PRINCIPAL ADIPOSE TISSUE, DEPO IN A RODENT. NOW THE KEY THING TO APPRECIATE IS THAT 28-DEGREES IS ROUGHLY THERMONEUTRALLITY FOR A MOUSE. SO IT DOESN’T NEED TO STAY WARM BY EXPENDING ENERGY. BUT TAKE THE SAME MOUSE AND PUT AT 6-DEGREES CELSIUS, LITTLE OVER 40-DEGREES FARENHEIT AND KEEP IT THERE FOR 10 DAYS AND THAT SHATTER PERIOD OF TIME THERE’S PROFOUND BROWNING OF THE ADIPOSE TISSUE DEPOT, YOU CAN SEE THE FAT, ALL THESE WHITE CELLS ARE NOW BROWN. ONE OF THE QUESTIONS THAT OBVIOUSLY HAS BEEN EXCITING WITHIN THE FIELD IS DO THOSE WHITE CELLS BECOME BROWN? IS THERE TRANSDIFFERENTIATION? SOME WILL SAY YES AND SOME WILL SAY AINGRILY, ARE SAYING ABSOLUTELY NO, THEY ARE COMING FROM THE BROWN SELLS WITHIN THE DEPOT. I WOULD LIKE TO POINT OUT THAT THESE ARE BROWN ADIPO SIGHTS, THEY LOOK DROWN BECAUSE THERE’S A LOT OF MITOCHONDRIA, A LOT OF IRON IN THESE CELLS AND THAT MAKES THEM LOOK BROWN. IN ADDITION TO THERE’S A LOT OF BLOOD GOING THROUGH SO THAT DOES LOOK LIKE BROWN ADIPOSE WHEN YOU SEE IT IN A MOUSE. THESE CELLS, THESE ADIP O SIGHTS THAT GROW WITHIN THE DEPOTS ARE OFTEN CALLED BEIGE BECAUSE IF YOU MIX BROWN WITH WHITE, YOU GET SOMETHING THAT’S BEIGE COLORED. THEY’RE ALSO BRIGHT FROM BROWN WITHIN RIGHT. WHICH SIDE OF THE ATLANTIC YOU ARE DETERMINES WHICH TERM YOU’LL USE BUT THAT’S CHANGING. SO THERE’S BROWN ADIOSIGHTS AND THERE’S SHIFTING THERMOGENESIS. SO A MOUSE BEFORE IT STARTS TO SHIVER, IT CAN TURNOT PROPERTIES WITHIN THE BROWN ADIPOSE TISSUE AND STAY WARM WITHOUT THE NEED TO SHIVER. THERE’S SOMETHING CALLED DIET INDUCED THERMOGENESIS. THIS IS A MORE CONTROVERSIAL CONCEPT BUT THE NOTION IS THAT AT LEAST FOR A PERIOD OF TIME WHEN AN ANIMAL BEGINS TO WAY MORE THAN A SET POINT OF THE HYPOTHALAMUS AND OTHER PARTS OF BRAIN WOULD LIKE IT TO BE. BROWN TISSUE IS ENGAGED AND THE EXCESS ENERGY THAT’S STORED IN FAT IS BURNED OFF. THIS THERMOGENESIS IS ATTRIBUTED TO BROWN ADIPOSE TISSUE AND THE THING TO KEEP IN MIND IS THAT ONE SEES IN THE MOUSE, THERE ARE THESE TWO PHYSIOLOGICAL PROCESSES BY WHICH ENERGY IS TAKEN AND CONSUME INDEED A SAFE AND REGULATED MATTER. AND BROWN ADIPOSE TISSUE HAS BEEN IN MAMMALS FOR AT LEAST 50 MILLION YEARS. SO IF THERE WERE IN HUMANS THAT WOULD BE USEFUL TO HAVE AS WE’LL TALK ABOUT MORE. NOW HOW DOES BROWN FAT CONSUME FUEL TO GENERATE HEAT? IN THE RESPONSE, THE EPINEFF RIN IS RELEASED BY THE SYMPATHETIC NEURONS AND THAT LEADS TO THE ENDOGENOUS LIPITS, PROFOUND UPTAKE OF GLUCOSE WHICH WE’LL TALK ABOUT MORE LATER, ON THE FATTY ACIDS, THOSE GO INTO THE CELLS AND ULTIMATELY INTO THE MITOCHONDRIA, THE TCA CYCLE AND SPLIT INTO THE INTERMEMBRANE SPACE AND MOVE DOWN THE TRANSPORT CHAIN MEETING OXYGEN TO MAKE WATER AND THEN THE PROTONS WILL GO DOWN THE ATPACE TO MAKE ATP. YOU LEARN ABOUT THIS IN BIOCHEMIST RADIOY. THIS IS THE STANDARD PROCESS. HOWEVER, WHAT THAT DOES IS THAT IS ALLOWS THE PROTONS TO COME THROUGH, NOT SO MUCH AS A CHANNEL BUT AS A FATTY ACID TRANSPORT. DEPENDENT TRANSPORTATION MECHANISM FOR PROTONS COME BACK INTO THE MATRIX AND LEADS TO HEAT, SO THE ADIPOSE TISSUE IS EXCIDING BECAUSE IT CAN BE INVOLVED IN CONSUMING FUEL TO GENERATE HEAT AND POTENTIALLY TREATING OBESITY. BUT THERE’S ANOTHER REASON WHY IT MAY BE INTERESTING PHYSIOLOGICALLY AND THAT’S IN TERMS OF BEING A FUEL SINK. TAKE A COLD MOUSE AND THAT WAS DONE WITH ALEXANDER BARTEL, AND IN THESE COLD ACCLIMATED MICE, THE BROWN FAT WAS MAYBE FIVE% OF THE TOTAL BODY WEIGHT. NOT A LOT BUT WHEN THOSE ANIMALS WERE FED TRI GLYCERIDES, MORE THAN 50% OF THE TRI GLYCERIDES AND MORE THAN 75% OF THE GLUCOSE INGESTED WAS CONSUMED BY THE BROWN ADIPOSE TISSUE IN THE PROCESS OF KEEPING THE ANIMALS WARM. POSSIBLE THAT THE TISSUE IN THE RIGHT CIRCUMSTANCE COULD BE USED TO TREAT HYPER GLYCEMIA, AND OTHER KINDS OF METABOLIC DISEASE. SO ENCH RNLGY BALANCE NUMBER ONE. BETA BOLLIC REGULATION NUMBER TWO AND NUMBER THREE ISLET POTENTIAL ENDOCRINE ROLES FOR THE TISSUE. THIS IS VERY, VERY FRESH INFORMATION. I MEAN, YOU BEING–THINK ABOUT IT IN 1992 WHEN I STARTED MEDICAL SCHOOL, WHITE FAT STORY
STORED CALORIES AND NOW WE HAVE THE ADIPOSE ORGAN. WELL, BROWN FAT IS COMING ON LINE, IT’S IDENTIFIED AS THE YFORT OF MICHIGAN AND BINDING WITH THE ERBFOUR, BINDS TO THE LIVER AND DECREASE IN DE NOVO LIPO GENESIS WITH A DECREASE IN OXIDATION DISP INCREASE IN INSULIN SENSITIVITY. IN ADDITION A ARTICLE THAT WAS PUBLISHED LAST MONTH IN NATURE BY RON KAHN’S GROUP, THEY FOUND RNA’S TO REGULATE THE LIVER TO SUPPRESS FGF21. SO THIS IS OTHER – WAY IT MIGHT BE AN ENDOCRINE ORGAN AND HERE IS A FIGURE FROM A PAPER THAT WAS PUB LIBRARY FOUNDATIONED YESTERDAY ONLINE SAYING THAT THE DIABETES CENTER AND THEY FOUND THAT THE ADIPO SIGHTS ARE RELEASING A MOLECULE IN RESPONSE TO COLD THAT COULD BE HAVING BOTH AUTOCRINE AND ENDOCRINE ROLES IN INCREASING FATTY ASIT UPTAKE AND FATTY ACID OXIDATION. SO THIS IS EXPLODING. ALL NEW, STUDIES TO SUGGEST THAT BROWN ADIPOSE TISSUE IS VERY IMPORTANT AND PHYSIOLOGICALLY RELEVANT ENDOCRINE ORGAN AS WELL. SO WHAT ABOUT HUMANS. WELL THE STORY TELLERS YOU IS IS–WELL, THE STORY IS MORE COMPLICATED. THERE WAS A LOT OF INFORMATION IN TBO THOUSAND TWO, IN NUCLEAR MEDICINE IN PARTICULAR, THERE WAS THE INTRODUCTION CLINICALLY OF A NEW METHOD OF STUDYING CANCER AND THAT IS THE PET CT SCAN. THOSE THAT ARE NOT FAMILIAR, THAT STANDS FOR STRUCTURE, SHOWN AS A CT SCAN OF A 32 YEAR-OLD MAN, THIS IS WHAT WE CALL A CORONA LIMIT, HERE’S NECK, HEART, LUNGS. LIGHTER THINGS LIKE WHITE BONES HERE ARE DENSER MATERIAL, DARK MEANS THAT IT’S VERY LIGHT MATERIAL, SUCH AS AIR IN THE LUNGS AND THE FAT IS HERE, ALONG THE SIDES SOMEWHERE IN BETWEEN. NOW THE PET STANDS FOR POSITRON EMISSION TOMOGRAPHY. THIS IMPLIES METABOLIC FUNCTION, METABOLICALLY TISSUES THAT TAKE UP GLUCOSE SUCH AS TUMOR TISSUE WILL BE SHOWN AS TAKING UP AN ENORMOUS AMOUNT OF GLUCOSE, HEART HERE, BRAIN HERE AND IN% THIS PERSON, HE HAD PROG KINS DISEASE AND HE HAS UPTAKE IN SHOULDER REGION. NOW THIS FTION A PROBLEM UNTIL THE ABILITY TO FUSE THOSE SCANS AND THE PET C. T. SHOWN HERE AND THAT GIVES YOULET METABOLIC ACTIVITY OF EACH TISSUE AND IT TURNS OUT THAT ALL THIS UPTAKE IS NOT FORTUNATELY TUMOR OCCURRENCE BUT RATHER ACTIVATED ADIPOSE TISSUE. SO THERE WAS THE FTG ADDED ADIPOS TISSUE O IN ONE OF MY EARLIER GRANT APPLICATIONS, FAT. I WAS BT TRYING TO BE CHEEKY BUT THAT’S WHAT IT WAS. IT GOT ME IN TROUBLE. I PROPOSED INFORMATION THAT THERE COULD BE BROWN ADIPOSE FAT IN YOU HAD HANS. I BELIEVE THERE’S NO SIGNIFICANT BROWN FAT IN HUMANS THAT WE SEE IS NOT BROWN FAT, AND THE RESPONSE WAS YES, THAT’S PRETTY MUCH IT, I BE VERY SURPRISED IF THOSE PET IMAGES WERE BROWN FAT DEPOSITS AND THAT’S FROM A K. O. L. KEY OPINION LEADER, PROFESSOR OF MEDICINE AT HARVARD AND ENDOCRINOLOGYST AND HE WAS ABSOLUTELY CONVINCED THERE WAS NO FAT IN HUMAN BEINGS. WELL, IT TURNS OUT THAT IN THE REALM OF NUCLEAR MEDICINE IT WAS THE EXACT OPPOSITE, I SAID IN THOSE FTG PET SCANS, YOU VERY OFTEN SEE FALSE-POSITIVE SIGNALS FROM BROWN FAT? HOW DO WE KNOW THAT IT’S BROWN FAT? BECAUSE EVERYONE SAYS SO. THEY WERE GETTING TISSUE THAT WAS SUPPOSED TO BE A THYROID GLAND, IT WAS BROWN FAT AND THE PATHOLOGIST WAS LIKE, ALL RIGHT, WELL IT’S WHAT YOU THOUGHT IT WAS SO THIS DOESN’T HAPPEN ONLY IN OUR FIELD BUT THIS I THINK IS A FAIRLY COMMON PHENOMENON AT EDGES OF CLINICAL MEDICINE AND RESEARCH. ONE SET’VE GROUP THINKS THAT SOMETHING DOES EXIST OR BEHAVES AN ENTIRELY DIFFERENT GROUP. IT HAS NEW INFORMATION THAT PAY ATTENTION THAT LEAD TO THE OPPOSITE CONCLUSION. YOU TRY TO RECONCILE THE INFORMATION WITH DATA. IN OUR CASE, WHAT WE WERE ABLE TO DO IS WE IDENTIFIED A WOMAN WHO HAD A PET CTSCAN. SHOWN IS HER IMAGING, SHE HAD A TUMOR, THIS IS THE IMAGE HERE, CAN YOU SEE THE GLUCOSE UPDATE HERE, THIS IS THE CT SCAN AND THIS IS THE TUMOR. IT LOOKS LIKE FAT, THE LIVER HERE, MUCH SMALLER AND HERE’S THE HEART. SO THIS FDG ADIPOSE TISSUE. NOW, PATHOLOGY DEPARTMENTS YOU SUBMIT THE SAMPLE AND IT’S STORED AS A LIBRARY. SO WENT TO THE LIBRARY, TOOK OUT THE TISSUE AND THEN IN A COLLABORATION, SECTIONED IT AND IT LOOKS EXACTLY LIKE THE BROWN ADIPOSE TISSUE THAT ONE WOULD SEE IN A MOUSE AND IT’S STAINED VERY AVIDLY FOR UCP ONE. THIS WAS THE FIRST DEMONSTRATION THAT WHAT WAS BEING SEEN IN THE IMAGES WAS WHAT WAS EXPECTED THEM TO BE BASED ON HIOF THEOLOGY. AND NOW WITH THAT PROOF, IT TURNS OUT THAT WE AND FOUR OTHER GROUPS THROUGHOUT THE ENTIRE WORLD WERE WORKING ON THIS QUESTION AT THE EXACT SAME TIME. WE’RE ALL TOLD THAT BROWN FAT DIDN’T EXIST, WE DIDN’T BELIEVE IT AND BACK IN 2009, ALMOST EXACTLY EIGHT YEARS AGO, THREE PAPERS WERE PUBLISHED IN THE NEW ENGLAND JOURNAL OF MEDICINE AND TWO OTHERS AND OTHER JOURNALS WERE ABLE TO SHOW THAT YES THERE IS BROWN ADIPOSE IN HUMANS AND IT MAY BE BIOLOGICALLY RELEVANT. WHAT DID WE LEARN? STRUCTURALLY IN REGIONS OF THE BODY, AND BEFORE WE HAVE TO RELY ON BIOPSIES WHICH IS NOT RELIABLE WHEN IT COMES TO BEING ABLE TO UNDERSTAND THE WHOLE BODY FUNCTION. IT PROTECTS AGAINST COLD ACUTELY. THERE’S NONTRIBUTE THERMOGENESIS AND WE’RE TRYING FIGURE THIS OUT TODAY. PEOPLE THAT ARE PROTECTED FROM BROWN FAT ARE MORE OFTEN FEMALE, YOUNGER, LEADER AND NOT TAKING BETA BLOCKER MEDICATION. SO THERE’S A LOT THAT’S LOADED IN THERE AND THAT’S BEEN BORN OUT BY THE PROSPECTIVE STUDIES I’LL TALK ABOUT. MOST IMPORTANTLY NEARLY EVERY ADULT HUMAN HAS BROWN FAT. EVERYBODY IN THIS ROOM, PROBABLY. ALL RIGHT, SO THE NEXT QUESTION TO US BECAME THESE: GOING BACK TO ISSUES I BROUGHT UP ORIGINALLY. TO WHAT EXTENT DOES ADULT B. A. T. CONTRIBUTE TO INCREASED ENERGY EXPENDITURE. SECONDLY WHO YOU DOES BAT’S UPTAKE OF PLACENTAS MA GLUCOSE AND TRI GLYCERIDES IMPACT WHOLE BODY FUEL METABOLISM? , AND THISHED HOW DOES ACTIVATED BAT WORK WITH THEM? TD ONLY WAY TO STUDY THE FULL BODY TISSUE IS PET, CT AND MRI, AND ULTRA SOUND. WE HAVE TO LOOK AT HUMAN, RODENT AND INVITRO MODELS, MOTE I DON’T MEANICS AND GENOMICS AND THESE TWO COME TOGETHER, BEING ABLE TO ALLOW US TO GO BACK TO THE BED AND LOOK FOR THERAPEUTICS. I WILL SHOW YOU ABOUT COLD ACTIVATION AND DRUGS AND HORMONES IN PARTICULAR, THE BETA THREE AGANISTS. THE FIRST THING I WAS TALKING ABOUT, I WANT TO LOOK AT THIS, THIS IS THE FAVORITE TEXTBOOK IN MEDICAL SCHOOL. FRANK NETTER’SAT LAS PINTAS OF HUMAN ANATOMY. IT’S BEAUTIFUL, IT’S EXQUISITE, I STILL LOOK AT ITED BUT IT’S INCOMPLETE. CAN YOU LOOK AT THE BONES IN BODY, THE MUSCLES ARE DEFINED VERY WELL, TOO, BUT THERE’S SOMETHING MISSING, WHERE’S THE FAT? RIGHT? MY HOPE IS THAT WITHIN 15-20 YEARS WHEN YOU BUY THE MOST RECENT VERSION OF NETTER’S IT WILL HAVE A NEW SET OF PAGES TO TALK ABOUT THE ADIPOSE TISSUES IN THE BODY. YOU WILL GET A FAT MAP AND TOWARD THAT END, WE ARE WORKING ON THIS AND WE ARE DOING THIS IN COLLABORATION WITH KAHN CHEN, AND WE’RE WORKING WITH BROOKS BRUTUS ITNER, SO SHOWN HERE IS A PERSON WITH A LOT OF BROWN FAT, 500-GRAMS OF BROWN ADIPOSE TISSUE AND BROOKS WAS ABLE TO SEGGREGATE IT INTO SIX DEFINED DEPOTS, CERVICAL IN DARK BLUE, SUPER RACLAFFICULAR, AUXILIARY, ANTERIOR MEDIAL, BUT THE PARASPINAL DOWN THE BACK AND THE PERO TONE EEL FAT HERE, AND THIS THE FIRST TIME ANYBODY’S BEEN ABLE TO PUT A CHARACTERIZATION WITH IT. NOTICE THAT IT’S MOSTLY IN THE POSTERIOR REGIONS OF THE BLD. NOT A LOT OF BROWN FAT IN THE ANTERIOR REGIONS, THAT RELATES TO WHAT BROWN FAT IS SUPPOSED TO DO WHICH IS GENERATE HEAT AND GET IT INTO THE BLOOD TO GET TO THE REST OF THE BODY. HOW MUCH BROWN FAT COULD A PERSON HAVE? THAT IS WORK THAT’S UNPUBLISHED AND HOPEFULLY WILL BE PUBLISHED SOON? YOU CAN SEE WE LOOKED AT 20 MEN AND THE COLORED PORTIONS, THE AMOUNT OF BROWN FAT IN EACH OF THESE DEPOTS, AND A WHITE BOX IS THE AMOUNT OF WHITE FAT IN THE DEPOTS AND THE KEY THING TO APPRECIATE ON AVERAGE IS ABOUT A THOUSAND GRAMS OF FAT IN THESE DEPOTS AND THE BROWN FAT IS ROUGHLY 240-GRAMS OF IT, DELIVER ABOUT 20-25%. AND FOUR% OF THE TOTAL BODY FAT MASS IS IN THIS ENTIRE DEPOT. SO WE’RE TALKING ABOUT A SMALL PORTION WITHIN THE ENTIRE FAT OF THE BODY BUT IT MAY BE IMPORTANT METABOLICALLY. AS AN EXAMPLE,ER’S A 19 YEAR-OLD MAN, 2.3 BMI, THE RED IS THE ADIPOSE TISSUE, THE BLUE IS THE REMAINING WHITE FAT IN THOSE REGIONS, WELL, COULD YOU TURN THAT BROWN FAT, THE WHITE FAT TO BROWN. IS THAT POSSIBLE? AND WE’RE LOOKING AT THIS IN COLLABORATION WITH CARL AT NICHD, CAN YOU SEE THIS WOMAN, 64 YEARS OLD, VERY LOW BMI, AND THIS PARAGANG LIAISONONA IS RING LEVELS THAT ARE BY DEFINITION PHYSIOLOGICAL BECAUSE SHE’S MAKING IT BUT CERTAINLY NOT NORMAL WHEN THE TYPICAL RANGE IS 112 TO 750. THAT LED TO PROFOUND BROWNING OF THE ADERKS IPOSE TISSUE IN THE REGION WHERE THE TUMOR WAS SO HER WHITE PLUS BROWN IN THE BODY WAS 460. HER ACTIVE IS 300. 65% OF THOSE REGIONS ARE NOW BROWN BECAUSE SHE’S BEING CHRONICALLY EXPOSED TOCCATA COLA MINES WHICH CAUSE BROWN FAT TO GROW. CAN YOU SEE IN THIS REEVENLGION, 175-GRAMS OF TOTAL FAT, AND BROWN FAT IS 90% OF THAT REGION. SO IS IT POSSIBLE TO TURN YOUR WHITE INTO BROWN AT LEAST IN THOSE PLACES, WE THINK YES. SO LET’S MOVE ON TO THERAPEUTICS. CO-EXPOSURE IS THE WAY THAT THEY RUN OUT OF ADIPOSE TISSUE BECAUSE IT’S THESTST TO WORK WITH–IT’S THE EASE
ESTFOCUSED–EASY ESTTO WORK WITH. 19, 24, 19, 27. CAN YOU SEE THE BROWN FAD AT THE RED, AND IF THAT INKREETIONED, AND TERMS OF METABOLIC ACTIVITY, WENT BACK TO WHERE IT WAS AT THE ORIGINAL ROOM TEMPERATURE AND THEN WHEN IT’S WARM, THE BROWN FAT IS GONE, SO THIS TISSUE IS PLASTIC, IT CAN BOTH INCREASE AND DECREASE METABOLIC ACTIVITY, BASED ON CHRONIC STIMULATION. IN ADDITION, COLD EXPOSURE WAS TESTED OUT BY THE NETHERLANDS. THEY LOOKED AT EIGHT SUBJECTS WITH TYPE TWO DIABETES, 14-15-DEGREES CELSIUS AND THEY HAVE 56-58-DEGREES FAHRENHEIT. IT LED TO AN INCREASE IN ACTIVITY. SHOWN HERE, HERE, AND HERE, AND LED TO AN INCREASE IN GLUCOSE FUSION RATE MEANING THERE WAS AN INCREASE IN SENSITIVITY WHOLE BODY RNGHTS COLD EXPOSURE AND IT APPEARS TO BE THAT THE INCREASE OF MASSIVE BROWN FAT AND AUGMENT ENERGY EXPENDITURE AS OPPOSE TO METABOLIC DISEASE. THE BIPG PROBLEM, IS HOW MUCH OF THIS COLD EXPOSEDDURE THAT LEADS TO IT IS INCREASE IN GLUCOSE UPTAKE, WE DON’T KNOW THAT. THAT REMAINS UNKNOWN, IT’S PROMISING AND IDENTIFYING STUDIES TO DO. SO WE LIKE TO USE THE APPROACH FOR THIS REASON. FOR ONE THING, THERE’S POTENTIAL FOR MORE SPECIFIC TARGET, COLD EXPOSURE WORKS ON THE ENTIRE BODY. ANIMAL MODELS SHOWN THEY’RE EFFECTIVE AND IF I TOOK A POLL IN THIS ROOM. WOULD YOU RATHER SIT IN A ROOM THAT’S COLD WITH A T-SHIRT AND SHORTS FOR FOUR-SIX HOURS EVERY DAY FOR A MONTH OR TAKE TWO-TO PILLS IN THE MORNING EVERY DAY FOR A MONTH. WHO WOULD CHOOSE THE COLD? WHO WOULD TAKE AND–ALL RIGHT, FINE. I THINK THE PHARMACOLOGICAL WINS. THIS IS COMBINED WITH THE MEDICATIONS TO GET THE EFFECT WE WANT TO SEE. AND THE BETA THREE ADA NERNLGIC RECEPTOR, BETA ONE IS ON THE HEART, BETA TWO IS ON THE LUNGS AND BETA THREE IS EXPRESSED BY HUMAN BROWN AND WHITE FAT AND WHAT APEERPS TO BE FROM CHRISTIE’S PAPER BACK IN 2009 IS THAT THERE’S MORE EXPRESSION IN THE BROWN FAT THAN WHITE FAT. WE LOOKED AT A SIMILAR ISSUE IN MOUSE VERSUS HUMAN TISSUE. HERE’S BETA THREE RECEPTOR, NECK FAT WHERE THERE’S A LOT OF FAT, LOT OF BETA RECEPTOR AND A LOT LESS IN THE SUPERFICIAL NECK NAT OF A HUMAN. WHEREAS NOTICE THAT THE BROWN AND WHITE AND BROWN FAT OF A MOUSE HAVE A SIMILAR EXPRESSION OF THE BETA THREE RECEPTOR. I DON’T HAVE TIME TO GO INTO THOSE TODAY BUT SHERYL CHETO, IN OUR GROUP ADENTIFIED THE PROBLEM WITH THIS TISSUE. THE BETA THREE RECEPTOR IS MUCH HIGHER EXPRESSED IN MOUSE BROWN FAT AND WHITE FAT THAN IN HUMAN BROWN FAT AND WHITE FAT AND THE FAILURE OF USING DRUGS RELATE TO THESE AS I’LL SHOW YOU IS IN FACT THAT THE MICE ARE DIFFERENT FROM HUMANS AND WHILE THAT MAY BE OBVIOUS, KNOWING WHAT THE DIFFERENCES ARE IN EACH PARTICULAR CIRCUMSTANCE HAS BEEN A CHALLENGE AND THIS IS SEVERAL BILLION DOLLAR CHALLENGE BECAUSE DRUG VS BEEN DEVELOPED AND FAILED, NOT REALIZING THE IMPLICATIONS OF THE DIFFERENCE BETWEEN MICE AND MEN AND WOMEN. SO IT TURNS OUT THAT THE BETA THREE CAN BE USED WIDELY IN HUMAN. SO THERE WERE OVER 43 MILLION AFFECTED BY OVERACTIVE BLADDER AND THESE NUMBERS ARE FROM THE THE–COMPARE THAT TO 26 MILLION PEOPLE IN AMERICA WITH TYPE ONE AND TWO DIABETES. NOW, BESIDES ADIPOSE TISSUE, THERE ARE BETA THREE RECEPTORS AND URINARY BLADDEROT MUSCLE, AND ACTIVATION RELAXS THE BLADDER. SO THAT’S VERY EXCITING AND IT TURNS OUT THAT IN 2012, FDA APPROVED A BETA THREE ADDER NERNLGIC RECEPTOR CALLED MIRAGRON, FOR THE TREATMENT OF OVERACTIVE BLADDERS. THIS IS A MOLECULE. NOT A FANCY ONE. THIS PORTIONOT LEFT BIEBDS TO THE RECEPTOR AND THIS PORTION HERE IS ON THE RIGHT IS WHRA ACHIEVES ELECTIVITY OVER THE BETA ONE AND TWO RECEPTORS SO YOU COULD GIVE THIS DRUG, RELAX THE BLADDER AND NOT CAUSE THE HEART RATE TO GO UP. SO WE FIRST NEEDED TO PROVE THIS WOULD WORK. SO THIS WAS PROOF OF CONCEPT STUDY DESIGN AND THIS IS LAUREN WEINER WHO WORKED WITH ME AND WE RECRUITED 20 THREEN HEALTHY MEN AND THE REASON WHY WE DID MEN IS THAT THERE FTION SAFETY OF THIS IN WOMEN AND EACH OF THEM WAS TREATED WITH PLACEBO AND THIS IS HIGHER THAN THE DOSE THAT APPROVED AND THE REASON WE DID THIS IS WE KNEW 200-MILLIGRAMS WOULD BE SAFE, RELATIVELY SO AND MORE LIKELY TO GIVE US A SIGNAL BECAUSE IF WE MISS A SIGNAL BECAUSE WE CHOSE THE WRONG DOSE WE WOULD MISS THE WHOLE POINT ENTIRELY. WE ALSO EXPOSED OUR SUBJECTS TO MILD COLD, VITAL SIGNS, EXPENDITURE, AND WE MEASURED THE BROWN FAT METABOLIC ACTIVITY USING THE FTG MET CT, WELL, MIRABEGRON INCREASED AND 13% ABOVE BASE LINE. MORE WITH THE COLD EXPOOEDURE AND IN ADDITION AS WE SAW IN THE FDA LITERATURE, AT PEAK CONCENTRATION, THE SIGNIFICANCE TOLL-LIKE RECEPTORIC BLOOD PRESSURE HAD GONE UP, NOT MUCH CHANGE IN DIASTOOL DNAIC AND INCREASE IN HEART RATE. SO AS I SAY, DON’T DO THIS ON YOUR OWN, I HAVE SAID CAN I TAKE MY MIRABEGRON TO TREAT OBESITY, AND THE ANSWER IS A FLAT NO. BUT IT IS INTERESTING PHYSIOLOGICALLY. WELL, HOW DID IT DID ON THE BROWN FAT. I’VE BEEN BURNED SEVERAL TIMES BY THINGS I THOUGHT ACCOUNTED ACTIVATE THE BROWN FAT AND IT DOESN’T. THIS IS A BODY MASS INDEX OF 23 AND YOU CAN SEE HERE THE FTG, WHEN HE TOOK IT, HERE’S HEART, KID MES AND BRAINS AND THIS IS WHAT THE BROWN TISSUE. WHEN HE WAS EXSUPPOSED TO MILD COLD, IT WAS WICKED ACTIVE, YOU SEE IT ALL OVER THE PLACE HERE, PARAPINE SPINAL AND INTO THE KIDNEYS. IN ADDITION, YOU CAN SEE THAT HIS HEART IS NO LONGER THERE, HE HAS A HEART, WE THAN BUT THIS IS AN EXAMPLE, THE HEART CHOSE TO USE GLUCOSE BECAUSE IT WASN’T MUCH FATTY ARK SIDES IN THE BLOOD. WHEN A HEALTHY HEART HAS FATTY ACIDS AVAILABLE, SO THE HEART DISAPPEARS BECAUSE IT CHAINCHS FUEL SELECTION, INTERESTING PHENOMENON THAT WE’RE TRYING TO STUDY FURTHER. SO THIS IS WHAT THE COLD DID, WHAT HAPPENED WITH MIRABEGRON WE FOWNTD BROWN FAT WHERE WE DIDN’T KNOW IT WAS AT THE TIME. SO THIS WAS A USEFUL TOOL AND POSSIBLY A THERAPEUTIC OPTION ULTIMATELY BECAUSE THE BETA THREE IS ABLE FOE BE USED NOW IN HUMANS. SO WE WANT TO NOW TREAT PEOPLE AND MAKE MORE OF THIS TISSUE, SO WE CAN UNDERSTAND IT. REMEMBER WE DON’T HAVE THAT MUCH IN HUMANS. WE NEED MORE. WE WANT TO UNDERSTAND A LOT MORE ABOUT THE–THIS. THIS HAS BEEN SPEARHEADED BY ALLISON BASKIN, ALONG WITH BROOKS. THANKS, GUYS. SO WE STUDIED AGAIN, 12 YOUNG HEALTHY MEN, ALL WITH CONFIRMED BROWN FAT. EACH TREATED WITH MIRABEGRON AT ZERO, THE FDA APPROVED DOSE WHICH WE KNOW WORK AS A POSITIVE CONTROL. THIS TIME WE DID STANDARD MONITORING, ZERO BLOOD DRAWS WITH THE PKD STUDIES TO FIND OUT HOW MUCH WAS IN THE BLOOD, AND WHERE IT WAS PEAKING AND THEN WE DID PET CT AND M. R., AND THIS WAS DONE IN COLLABORATION WITH OCMAN GAREEB, AND IT SHOWED A LARGE NUMBER OF PEOPLE WE WOULD LIKE TO STUDY AND UNDERSTAND. NOW THE DIFFERENCE BETWEEN FAT ACTIVITY AND BROWN AND ZERO, IS WHAT WE FOUND IS THAT YOU CAN SEE IN RED HERE, IS THE–THIS IS CONCENTRATION IN THE BLOOD. THIS IS DONE IN COLLABORATION WITH PETER WALTER WHO RUNS THE MASS SPEC AT NIDDK, THE RED IS 250, THE BLACK AND 50, AND THE BLUE IS ZERO. EVEN THOUGH 200 IS FOUR TIMES 50, THE EXPOSURE OF A PERSON TO THE DRUG IS MUCH HIGHER THAN FOUR TIMES THE 200-MILLIGRAM DOSE AND YOU CAN SEE HERE THAT WE DID THE FG AND PET CT TO GET THE MAXIMAL EFFECT, AND WE’RE NOT LOOKING AT THE BEST EFFORT, BECAUSE THE CONCENTRATION IS A BIT LOWER. SO IN ADDITION TO THE FACT THAT 200 IS WAY MORE EXPOSURE THAN 50, WHICH IS AGAIN APPROVE DOSE, THE CONCENTRATIONS IN THE BLOOD ARE VERY, VARIABLE WITH 200-MILLIGRAMS AND 50-MILLIGRAM WHICH IS MEANS YOU COULD GIVE THE DRUG TO SOMEBODY, THE DRUG WON’T GET IN MUCH AND MAY NOT HAVE AN EFFECT AND THIS IS STILL SOMETHING WE WILL DEAL WITH TODAY. NOW, IT WAS VERY CLEAR THOUGH, AS YOU SEE IT WOULD BE A DOSE RESPONSE BETWEEN THE DRUG CONCENTRATION AND BROWN FAT ACTIVATION, YOU CAN SEE HERE AT 0-MILLIGRAMS, THERE’S NO BROWN FAT, AT 50-MILLIGRAMS, THERE’S BROWN FAT AND THE BLACK AREAS HERE, 200-MILLIGRAMS IS BROWN FAT ACTIVITY. I WILL SHOW YOU, THESE GREEN DWOTS ARE WHAT WE CALL FID USUAL MARKERS, AND WE LINE THEM UP USING THE MARKERS HERE SO THIS IS EXPLORATORY, THIS IS THE MAGNETIC RESONANCE IMAGING OF THE FAT AND YOU CAN SEE THE Y HERE IS FAT, AND YOU CAN OVERLAY THE PET CT IMAGE WITH THE MR AND YOU WE CAN FIND OUT WHERE THE BROWN FAT IS, SO THIS IS FURTHER DEPRIVATIONED SO ULTIMATELY SOMEDAY WE CAN USE MR IMAGING AND NO EYE OINIZING RADIOIATION AT ALL AND THIS IS DONE WITH ACMED AND PETER HERSC OVICH. THIS CAUSED INCREASE OF BROWN ADIPOSE TISSUE ACTIVITY IN 19 OF THE 12 AND THIS IS–NINE OF THE 12 AND 50-MILLIGRAMS WORK, ABSOLUTELY? IT DID 2-MILLIGRAMS WORK? YES, WAY BETTER. SO THE KEY THENG HERE IS THAT 50-MILLIGRAMS WORKS BUT IT’S NOT NEARLY AS EEIVELGTIVE AS THE 200-MILLIGRAM DOSE AND THIS WAS BORN OUT IN THE ENERGY EXPENDITURE STUDIES AND WE FOWBD THERE WAS NO INCREASE AT ZERO, A TRIVIAL AMOUNT AT 50 AND SUBSTANTIAL INCREASE WITH 200-MILLIGRAMS THAT WAS SIGNIFICANT. MOAR OVER, IN ADDITION, THEY ACTIVATED THE BROWN FAT AND INCREASED ENERGY EXPENDITURE, WE FOUND A SIGNIFICANT RELATIONSHIP BETWEEN THE CHANGE THIS RESTING ENERGY SHOWN HERE,–OH, SHOWN HERE ON THE Y-AXIS AND THE AMOUNT OF BROWN FAT ACTIVITY WE SAW HERE IN EACH COLOR REPRESENTS THE DIFFERENT DOSE. THIS IS AN IMPORTANT POINT. IT’S NOT JUST THAT THE DRUG INCREASED ENERGY EXPENDITURE, BUT WE BELIEVE THAD THE BROWN FAT WAS RESPONSIBLE FOR SOME OF THAT INCREASE IN ENERGY EXPENDITURE, YOU CAN ACTIVATE BROWN FAT AND YOU MAY BE ABLE TO INVITE–MARILYN CREASE THE OXYGEN CONSUCHGZ AND EXPENDITURE THAT THERE COULD BE EFFECT IN ENERGY BALANCE. SO OUR FINAL SUMMARY. THE DIP O SEATS CAN BE FOUND IN THE SUBSTANTIAL PORTION OF HUMANS. AT LEAST EVERYBODY IN THIS ROOM I WOULD IMAGINE HAS SOME. BOTH COLD AND PHARMACOLOGICAL ACTIVATION OF HUMAN BROWN FAT CAN INTERNAL AUDIT CREASE MASS AND EXPENDITURE BUT THE EXTENT OF WHICH REMAINS UNKNOWN. BROWN FAD MAY IMPACT HUMAN METABOLISM AT THREE DIFFERENT LEVELS. KEY POINT, ENERGY BALANCE AND WEIGHT LOSS POSSIBLY, BUT THAT’S NUMBER ONE. GLUCOSE AND FATTY ACID METABOLISM NUMBER TWO AND NUMBER THREE, ADD HORMONAL REGULATION AND THERE’S STILL AN ENORMOUS ATHAT NEEDS TO BE LEARNED AND IN ORDER TO GET AT THAT A PLUG FOR OUR NEW STUDY, THE PHYSIOLOGICAL RESPONSES AND CHRONIC TREATMENT WITH BETA THREE ADA NERNLGIC RECEPTOR AGANIST. WE WILL RECRUIT HEALTHY MEN AND WOMEN. AND INITIAL STUDIES WILL BE WITH HEALTHY WOMEN, WE WANT TO SEE IF AFTER FOUR WEEKS OF TREATMENT WITH MIRABEGRON, THE BETA THREE AGANIST, CAN WE INCREASE BROWN ACTIVITY AND AS A SIDE POINT TO THAT CAN WE ALSO SEE THE BEGINNINGS OF CHANGING OF METABOLIC BENEFIT FROM CHRONIC ACTIVATION OF BROWN ADIPOSE TISSUE. AND WITH THEY WOULD LIKE TO THANK THE ENORMOUS NUMBER OF PEOPLE WHO HAVE LET ALL OF OUR STUDIES HAPPEN AND SUCCEED IN PARTICULAR JOYCE, ALLISON IN OUR PARTICULAR SECTION. KAHN, OTHERS THAT WE WELCOMER WITH AND ALL OUR COLLABORATORS WITH LAB CORPS, COLLABORATORS ACROSS THE NIH, CRC AND PEOPLE WITH WHOM WE WORK AT HARVARD UNIVERSITY. THANK YOU. [ APPLAUSE ]>>LET’S TAKE A FEW QUESTIONS AND THEN WE’LL TAKE A LITTLEIND- BREAK.>>[INAUDIBLE QUESTION BY AUDIENCE.>>GREAT QUESTION. NO. THE ISSUE OF URINARY REATTENTION IS SIGNIFICANT ONLY IF SOMEONE HAD BASE LINE A BLADDER OUTLET ORBSTRUKS AND THAT IS AN EXCLUSION CRITERION THAT WE USE WHEN RECRUITING PEOPLE BUT THERE WERE NO SYMPTOMS WHATSOEVER RELATED TO BLADDER OUTLET IN THE STUDY THAT WE CONDUCTED.>>[INAUDIBLE QUESTION FROM AUDIENCE ]>>I THINK THEORETICALLY THEY COULD. AND I WANT TO LOOK AT STUDENT STUDENTS IN RODENTS FIRST AND THE REASON I SAY THAT IS THAT EFED RIN, ACTIVATES VERY NICELY. IT ALSO ACTIVATES IN HUMANS AT DOSES THAT ARE–I WOULD NEVER USE BUT HAVE BEEN USED AND SO, WE WANT TO GET A SENSE OF–IS IT POSSIBLE AT A LEVEL THAT MIGHT BE TRANSLATED TO HUMANS SO I THINK IT’S THEORETICALLY POSSIBLE BUT PRACTICALLY MAY NOT BE EFFECTIVE. IN THE BACK?>>[INDISCERNIBLE].>>THE POPULATIONS ARE COUNTRIES OR ETC.ITORIAL REGIONS BECAUSE 20-DEGREES TO SOMEONE WHO LIVES IN ENGLAND IS ACTUALLY QUITE WARM. [LAUGHTER]>>SO THAT’S A GREAT QUESTION. THE FIRST THING IS THAT AND THEY WERE DONE SEQUENTIALLY, IT WAS LIKE ONE RIGHT AFTER THE OTHER. I DON’T KNOW WHAT HAPPENED IN THE OTHER CIRCUMSTANCES WE DON’T KNOW WHAT HAPPENED IN SPECIFICALLY BUT WHETHER WE LOOK AT AND THERE MIGHT BE. IT WAS SOMETHING TO FURTHER LOOK AT. NOW RELATED TO THE OTHER COUNTRY THAT’S ONE OF THE THINGS WE WONDER ABOUT. HOW MUCH BROWN FAT WAS IN A TYPICAL HUMAN BEING WHEN YOU SPENT YOUR TIME IN THE COLD ALL THE TIME? IT MAY BE THAT THAT–THERE WAS NOT 20% BROWN VERSUS WHITE IN THOSE, BUT MIGHT HAVE BEEN CLOSER FROM 80-90 AND THAT WILL BE INTERESTING BECAUSE PEOPLE WERE LEANER AND THEY DIDN’T HAVE ANYTHING TO EAT. YES, IN THE BACK.>>[INDISCERNIBLE]–ARE YOU SAYING THAT DIABETES FOR TYPE ONE OR TYPE TWO? THE TYPE ONE DIABETES IS AN AUTOIMMUNE DISEASE AND IT’S ENTIRELY SEPARATE FROM WHAT WE’RE TALKING ABOUT. TYPE TWO DIABETES, THIS IS A BIG DEBATE BUT I HAPPENED TO BE FOLLOWING MORE ON THE ADIPOSE TISSUE, THE MORE WHITE ADIPOSE TISSUE SOMEBODY HAS, THE MORE THE MILIEU OF THE BODY TRANSITIONS TOWARDS INSULIN RESISTANCE LEADING TO DBTS. THAT’S HOW I WOULD SAY THE MECHANISM OCCURS IN THOSE CIRCUMSTANCES. DID EMPLOY. –>>BUT DIABETES OCCURS LATER ON IN LIFE, IT’S A RANDOM POPS UP AT SOME POINT IN LIFE.>>RIGHT. RIGHT. THERE’S CERTAINLY A PROGRESSION.>>I WANTED TO ASK ABOUT THE SUBJECTIVE EXPERIENCES OF THE HIGH BROWN FAT SUBJECTS. WHETHER THEY FELT HOT OR FELT COLD? THAT KIND OF THING?>>GREAT QUESTION. THE PEOPLE WHO HAVE THE MOST BROWN FAT TOLERATE COLD WELL, SO SOMEONE SAYS OH I’M REALLY COLD, AND DHA MEANS THEY DON’T HAVE A LOT OF BROWN FAT. I WILL TURN TOALISON, I DON’T REMEMBER A SPECIFIC SIGNATURES COMING UP? GET A MIC.>>HI. SO THEY WERE IN THE COLD ROOM FOR THE ONE DAY WHICH WAS OUR POSITIVE CONTROL TO DETERMINE WHETHER OR NOT THEY HAD BROWN FAT BEFORE WE GAVE THEM THE BETA THREE AGANIST. MIRAGBEGRON, LOOKING AT THAT ONE DAY WHERE THEY WERE SUBJECTED TO COLD. THERE DIDN’T SEEM TO BE MUCH OF A REPORTED DIFFERENCE WHEN WE ASK THEM WHETHER OR NOT THEY WERE SHIVERING, HOW COLD THEY WERE BETWEEN THE PEOPLE WITH A LOT OF BROWN FAT.>>SO I DON’T KNOW.>>THE MOST INERVETION PENSIVE SCREENING TOOL, DO YOU FEEL COLD MORE THAN OTHER PEOPLE, PROBABLY WON’T WORK. WE NEED TO DO THE PHYSIOLOGICAL TESTING. [INDISCERNIBLE]>>WE’RE STUDYING BROWN AND WHITE PREADIPOE SIGHTS IN CULTURE TO BE ABLE TO UNDERSTAND THE MECHANISMS BY WHICH THEY’RE ABLE TO GROW AS SCREENING TOOLS TO FIND PERHAPS COMPOUNDS IN THE FUTURE THAT WOULD BE ABLE TO GIVE TO HUMANS AS WAY OF INCREASING BROWN FAT MASS.>>BUT THERE WAS A LOT OF TALK THAT PREMY O SIGHTS CAN BE CONVERTED TO BROWN FAT.>>YES. , IS THAT TRUE OR NOT.>>IT’S COMPLICATED.>>I WOULD SAY THAT WE’RE NOT–WE’RE MATT HOLT LOOKING AT THAT. CAN YOU SOME WILL TRANSFORM A PREMY O SIGHT INTO–AT THE RIGHT STAGE OF PLURIPOTENT CELLSY POTENCY A PRE–LIKE A MYZENCHEMAL CELL, ALSO HAS THE CHANCE GO TO A BROWN ADIPO SIGHT. WE DON’T WORK WITH THOSE BUT IT’S AN INTERESTING POSSIBILITY. IT’S A REASONABLE QUESTION AS TO WHETHER ONE WOULD ACTIVATE THOSE OR NOT AND THERE ARE GRUPS THAT ARE LOOKING AT THAT.>>SO YOU WOULD EXPECT THEIR EXPOSURE TO BE SIMILAR AS THE BETA THREE.>>YES, YES, WE DON’T KNOW OF ANY DIFFERENCE FUNCTIONALLY, FOR EXAMPLE, THE BEIGE AND BROWN, OTHER THAN POTENTIALLY THE ROLE OF FOSTER NURSED FO KRE TINSA TIN CYCLING THAT’S BEEN STUDIED BY DR. BRUCE REGARDING THAT BUT OTHERWISE THERE HASN’T BEEN A LOT OF INFORMATION YET, ON ANYTHING THAT DISTINGUISHES THE BEIGE FROM THE BROWN, SO THERE ARE SIGNALS BUT NOT MUCH.>>SO IF YOU LOOK TO THE METABOLISM OF CELLS IN CULTURE. AND IF THE ACTUAL METABOLIC RATE IS HIGHER IN THE BROWN FAT? AND THEN IF YOU WERE TO CULTURE THEM AT SLIGHTLY LOWER TEMPERATURE, WOULD THAT INCREASE.>>SO THE FIRST ANSWER IS YES, MANY PEOPLE INCLUDING OUR GROUP LED BY SHERYL, IS TRYING TO STUDY THE OXYGEN COMSUMPTION RATES OF THE BROWN ADIPOSIGHTS AND AFTER THEY CULTURE AND THE SIMPLE ANSWER IS YES, THEY HAVE A HIGHER RATE. THAT INVITRO MODEL DOES WORK AND IT CAN HELP US LEARN A LOT ABOUT THE CELL THAT WE CAN’T LEARN FROM HUMAN BASED STUDIES. ONCE AGAIN IT FTION BRUCE’S GROUP THAT PUBLISHED A PAPER IN PNAS, WHERE IF THEY REDUCE IT WITH THE CULTURE DISH, THEY ARE AN INCREASE IN THE THERMOGENESIS, I HAVEN’T SEEN THAT ANYWHERE ELSE SO I DON’T KNOW HOW FAR THAT’S GOTTEN IN HOW FAR THEY PURSUE THE MEDICATION.>>I THINK WE WILL TAKE–THANKS AARON WE WILL TAKE A TWO MINUTE BREAK, FOR ANYBODY WHO NEEDS A TWO MINUTE BREAK. THREE MINUTE BREAK. WE WILL BE NICE AND SAY FIVE MINUTES AND THEN WE WILL INTRODUCE REBECCA. TAKE A QUICK BREAK AND COME ON BACK. OUR NEXT SPEAKER IS REBECCA BROWN AND ONE GREAT THING ABOUT THESE LECTURES IS THEY ALLOW PEOPLE LIKE ME, WHO I GUESS WE’VE BEEN CALLING FIVE OR 10 YEARS–I’VE BEEN HERE SINCE 1979, IT’S HARD FOR ME TO REMEMBER TO LOOK AT THE BACKGROUND OF OUR COLLEAGUES AND REBECCA ATTENDED MAYO MEDICAL SCHOOL AND DID A PEDIATRIC RESIDENCY AT RAINBOW BABIES AND CHILDREN’S HOSPITAL AND SHE ALSO DID PEDIATRIC ENDOCRINOLOGY FELLOWSHIP HERE AT THE NIH DISP I THINK THAT’S WHERE WE MET. AND SHE’S NOW STAYED ON AND BECOME A LASKER CLINICAL INVESTIGATOR EMPLOY ONE OF OUR REALLY STELLAR GROUP OF YOUNG INVESTIGATORS RECRUITED THROUGH THAT MECHANISM. REBECCA’S RESEARCH FOCUSES ON THE BIOLOGY INSULIN RESISTANCE AND LEFT THEM USING PATIENTS WITH RARE FORMS OF SEVERE INSULIN RESISTANCE OF YOU HAD MAN MODELS AND I CAN SAY ON A PERSONAL NOTE MY STUDENT WHO IS NOW AT OXFORD WHO–ROBERT SIMPLE HAD NOTHING BUT KIND THINGS TO SAY ABOUT REBECCA AS A MENTOR. WHEN YOU HEAR THAT FROM A STUDENT, YOU REALIZE YOU’RE DEALING WITH A VERY GOOD MENLTOR, SO I CAN THANK YOU PERSONALLY. THANK YOU.>>THANK YOU FOR THAT VERY NICE INTRODUCTION. IS THE MIC PICKING ME UP OKAY HERE. SO I WAS TELLING AARON AS WE WERE CHATTING BEFORE THE TALKS THAT I GAVE MY TALK THE ASPIRATIONAL TITLE OF WHY IS FAT IMPORTANT AND I’M TALKING ABOUT WHITE FAT HERE BECAUSE I THINK WITH THE HYPE ABOUT THE IMPORTANCE OF BROWN FAT IN THE CONTEXT OF OBESITY AND DIABETES, THAT WE LOSE SIGHT OF THE IMPORTANCE OF WHITE FAT. SO AGAIN AS AARON ALLUDED TO BACK IN 1990S WE LEARNED THAT WHITE FAT WAS NOT MERELY A PASSIVE STORAGE DEPOT BUT AN ACTIVE ENDOCRINE ORGAN AND THIS IS A SLIDE I STOLE MENTIONED EARLIER AND REALLY JUST DEMONSTRATING A FEW OF THE THINGS THAT ARE SECRETED BY WHITE ADIPOSE TISSUE AND THIS IS HYPER GLYCEMIC EFFECTS AND WHAT WE’RE REALLY GOING TO BE FOCUSING ON TODAY, I THINK I WILL USE THE MOUSE HERE IS THE ROLE OF LEAPTIN. SO, I WANTED TO GRIF YOU HISTORIC CONTEXT, SO IT WAS DISCOVERED IN THE CONTEXT OF THE OBOB MOUSE SHOWN HERE WHICH WAS A SPONTANEOUSLY OCCURRING MOUSE MODEL OF OBESITY AND IT WAS KNOWN THAT THE OBESITY PHENOTYPE WAS INHERITED IN THE AUTOSTUDIES OF MULTIPLE ENDOCRINAL RECESSIVE MANNER, BUT NOBODY KNEW WHAT THE GENETIC CAUSE WAS. AND THERE WAS THE INTEREST FROM NIDDK, IN UNCOVERING GENETICS UNDERLYING OBESITY AND SO, IT WAS THOUGHT THIS WAS GOING TO BE A VERY NICE MODEL TO EXPLORE. SO JEFF FREED MAN’S GROUP USED POSITIONAL CLONING IN THE I DAYS OF HIGH THROUGH PUT SEQUENCING IN ORDER TO LEARN THE EFFECTED JEAN WHICH WAS NAMED THE OBESE GENE AND HE CALL TODAY LEAPTIN AFTER THE GREEK WERE LEAPTOSE WHICH MEANS THIN AND IT TURNS OUT THAT MEAS MICE HAVE A NULL NUTATION SO THEY DON’T PRODUCE BRUTUS PTIN AND SO THIS MOUSE EATS TO MUCH AND IT BECOMES OBESE AND IT’S A CIRCULATING PROTEIN AND IF YOU GIVE LEAPTIN BACK, YOU CAN COMPLETELY CORRECT THE PHENOTYPE.–WITH VERY SEVERE
ORN SET OBESITY. CAN YOU SEE HIS EXCESS ADIPOSE TISSUE HERE, AND IT TURNS OUT THAT LEPTIN REPLACEMENT WORKS IN HUMANS AS IT SPECIFIC DETAILS ON IN RODENTS. THIS IS THE SAME CHILD AT AGE SEVEN NOW WAYING LESS AT AGE SEVEN THAN THREE OR FOUR WHICH IS NOT NORMAL PATTERN OF HUMAN GROWTH SO HIS PHENOTYPE HAS BEEN COMPLOATLY CORRECTED WITH REPLACEMENT LEPTIN. SO WHAT DO WE KNOW NOW ABOUT LEPTIN’S ROLE IN THE REGULATION MUCH BODY WEIGHT. SO LEPTIN IS MADE BY ADIPOE SIGHTS AND THE AMOUNT OF LEPTIN WE HAVE CIRCULATING IN OUR BLOOD STREAM IS PROPORTIONAL TO FOUR FAT MASK. SO IF YOU ARE A HEALTHY HUMAN BEING AND YOU HAVE A NORM WILL AMOUNT OF ADIPOSE TISSUE AND YOU WILL HAVE A NORMAL AMOUNT OF LEPTIN. SO LET’S SAY WE PERTERB THAT IN A FASHION. SO NOW THIS HUMAN OR ANY OTHER MAMMAL IS FACED WITH A FAMINE SITUATION, YOU ARE STAEVERRING, YOU LOSE YOUR FAT SOURCE, SO NOW THE LEPTIN CIRCULATE NOTHING YOUR BODY GOES DOWN AND THAT LOAD LEPTIN IS THE MAIN SIGNAL TO OUR BRAINS THAT WE ARE STARVING SO THERE HAS TO BE SOMETHING AS ANIMALS THAT SIGNALS TO US THAT WE NEED TO EAT WHEN WE’RE IN A STAEVERRATION SITUATION. THAT TELLS THE ANIMAL TO GO OUT AND SEEK FOOD. SO NOW LET’S IMAGINE THAT THAT FAMINE SITUATION RESOLVED YOU HAVE THE LOW LEPTIN SIGNALING YOUR BRAIN, YOU GO OUT AND SEEK FOOD. AND YOU REAGAIN YOUR BODY WEIGHT. SO NOW HAVE YOU NORMAL STORES, HAVE YOU NORMAL LEPTIN LEVEL AND HOMEOSTASIS HAS BEEN RESTORED. NOW THIS IS A PROBLEM THAT WE DON’T FACE MUCH IN THE MODERN WORLD. WE’RE MORE OFTEN FACING THE OPPOSITE SCENARIO, SO NOW LET’S TAKE SOMEBODY WHO PERTERBED THEIR EQUIB LIBRARY FOUNDATIONRIUM AND INCREASED FAT STORY TELLERSS, THORS THOSE WILL BE CIRCULING WITH HIGH LEPTIN IN THE PLOOD SO THAT COULD DECREASE RIGHT? SO WE SHOULD RESTORATION OF HOMEOSTASIS AGAIN AND NORMAL FAT STORES SO IF IS TRUE, WHY DO SO MANY SUFFER FROM OBESITY? OKAY, WHY IS LOSING WEALT SO WEIGHT SO DIFFICULT. WE KNOW IF YOU START OFF FROM AN OBESE SITUATION AND YOU LOSE WEIGHT THAT YOU WILL BECOME MORE HUNGRY. OKAY? SO IT TURNS OUT THAT OUR BODIES ARE REALLY MUCH BETTER PROGRAMMED TO RESTORE HOMEOSTASIS FROM A LOSS OF FAT MASS, AND THEN FROM AN INCREASE IN FAT MASS AND I WILL GO THROUGH MORE DETAIL ON THAT. SO THIS IS A VERY TYPICAL PATTERN OF WHAT HAPPEN TO PEOPLE WHEN THEY TRY TO LOSE WEIGHT. THESE ARE DATA FROM WHO PARTICIPATE IN WEIGHT WATCHERS WHICH IS A DIETARY PROGRAM TO LOSE WEIGHT. THIS HAPPENS WITH PRETTY MUCH ANY KIND OF LIFESTYLE MODIFICATION, SO PEOPLE START OFF OVERWEIGHT AND LOSE WEIGHT, THE BODY WEIGHT IS ABOUT SIX MONTHS AND THEN WEIGHT STARTS TO CREEP BACK UP AGAIN. SO KEVIN HALL AND NIDDK TRIED TO FIGURE OUT WHAT WAS LEADING TO THE WEIGHT REGAIN IN THESE INDIVIDUALS. IS IT A LOSS OF WILL POWER AND WHAT’S REALLY HAPPENING. SO HE USED MATHEMATICAL MODELING IN ORDER TO UNDERSTAND HOW MUCH FOOD PEOPLE MUST HAVE BEEN EATING IN ORDER TO OBSERVE THESE CHANGES IN BODY WEIGHT AND WHAT HE CALCULATED IS THAT WHEN YOU START TO LOSE WEIGHT FIRST OF ALL THE AMOUNT OF CALORIES THAT YOUR BODY IS BURNING RAPIDLY DECREASES AND THEN STARTS TO STABILIZE. BUT MORE DRAMATICALLY THE ENERGY INTAKE, THE AMOUNT THAT FOOD DRAMATICALLY DECREASES AND THEN ALMOST IMMEDIATELY AFTER THEY START DIETING THEY GO BACK UP AGAIN AND ACTUALLY BY THE TIME THEY REACHED THEIR WEIGHT AT SIX MONTHS THEY ARE ALMOST BACK TO BASE LINE CALORIC INTAKE. SO WHY IS THAT? SO THERE’S EXPONENTIAL DIET, IS THIS A LOSS OF WILL POWER? WHAT’S GOING ON HERE. PEOPLE’S APPETITES ARE INCREASING. SO AS SOONs YOU REDUCE YOUR CALORIC INTAKE AND YOU LOSE WEIGHT, YOU FEEL HUNGRY AND YOU CAN SEE THAT APPETITE GOES UP AND VERY GRADUALLY STARTS TO DECREASE AS CALORIC INTAKE GETS ABOUT BEING TO BASE LINE AND THERE’S THIS BIG GAP BETWEEN APPETITE ISICALLY INTAKE. –CALORIE INTAKE. AND THIS IS THE PERCEIVED EFFORT THAT PEOPLE ARE PUTTING INTO THE DIET PROGRAM. SO YOU’LL NOTE THAT THIS PERCEIVED EFFORT STILL CONTINUES TO INCREASE THAT GAP BETWEEN CALORIC INTAKE AND APPLICATIONS TIELT EVEN WHEN IT’S BACK TO BASE LINE. SO EVEN ONCE YOU REGAIN YOUR BODY WEIGHT AND YOU ARE CONSUMING AS MANY CALORIES AS DID YOU BEFORE YOU START YOUR DIET PROGRAM, YOU FEEL HUNGRY, TAKEN–THEY DIET PROGRAM. WHY IS THAT? SO WEIGHT LOSS TENDS TO LEAD TO DISCIPLINARY CREASED ENERGY EXPENDITURE, THAT’S ONE OF THE REASONS WHY WE PUT MORE EFFORT INTO OUR WEIGHT LOSS PROGRAMS AND I WILL GO THROUGH DATA ON THAT. SO, THIS CONCEPT, THAT WHEN WE LOSE WEIGHT, WE EXPEND LESS ENERGY IS CALLED MELTA BOLLIC ADAPTATION, AND ADAPTIVE THERMOGENESIS AND THESE ARE NOT HELPFUL IN CONCEPTUALIZING WHAT’S GOING ON HERE SO I WILL TROO I TO WALK YOU THROUGH THERE THIS SO THE AMOUNT OF ENERGY WE BURN RELATES TO ABOUT THE COMPOSITION AND IT’S HIGHLY CORRELATED WITH THE FAT FREE MASS. BASICALLY OUR MUSCLE MASS, SO THAT IF YOU ARE A PERSON WHO IS 60 KILL GRAMS OF LEAN BODY MASS, YOUR RESTING EXPENDITURE, THE ENERGY YOU BURN FROM THE BODILY FUNCTIONS BY BREATHING AND YOUR HEART BEE THING WITH WILL,A ROUND 1600-CALORIES A DAY. IF YOU’RE SMALLER AND YOU ONLY HAVE 40 KILOS OF LEAN MASS YOUR RESTING ENERGY WILL BE AROUND 1200-CALORIES PER DAY, SO WHAT HAPPENS IF YOU START OFF AS 60, AND YOU BECOME A 40 KILOPERSON? WILL YOUR ENERGY CHANGE FROM 1600 TO 1200? THERE’S BAD NEWS, YOUR ENERGY EXPENDITURE WILL GO BELOW 1200- CALORIES PR DAY I’M MAKING THESE UP TO SOME EXTENT IF–BUT I WANT TO GIVE YOU AN IDEA. NOW THESE NUMBERS ARE NOT FAIR, SO YOU TAKE TWO DIFFERENT PEOPLE, YOU START OFF WITH ONE WHO HAS NEVER BEEN OBESE AND THAT RESTING EXPENDITURE IS 1200-CALORIES PER DAY AND NOW YOU TAKE THE PERSON WHO PUT ALL THIS EFFORT INTO THEIR DIET AND EXERCISE PROGRAM AND GOTTEN THEIR LEAN BODY MASS DOWN TO 40 KILOS AND THEY BURN 800-CALORIES PER DAY, SO THERE’S A VERY MAJOR GAP IF ENERGY EXPENDITURE AND YOU CAN THINK ABOUT THIS AS AN ADAPTIVE MECHANISM. THIS IS THE BODY’S WAY TO TRY TO GET US BACK TO HIGHER BODY WEIGHT. WE REMEMBER THAT WE WILL BIOLOGICALLY ADAPTED TO MANY TAN HIGHER BODY WEIGHTS. OUR GOAL IS NOT TO DIE FROM MALMUSEUM TRICIAN. SO WE LEARNED A LOT ABOUT THE MECHANISMS THAT UNDERLIE THIS METABOLIC ADAPTATION TO WEIGHT LOSS, SO WHY THAT THE EXPENDITURE GOES DIRECTOR OF NATIONAL INSTITUTE AND NICE WORK ON THIS HAS BEEN DONE BY RUDE EXPE COLLEAGUES AND HE TOOK SUBJECTS AT THEIR INITIAL BODY WEIGHT AND HE MADE THEM LOSE 10% OF THEIR INITIAL BODY WEIGHT BY GIVING THEM AN 800-CALORIE PER DAY LIQUID DIET AND YOU START OFF WITH INITIAL BODY WEIGHT AND YOU GO ON THE DIET AND WHAT HE DOES IS HE STABILIZES THOSE ON EXACTLY THE NUMBER OF CALORIES NEED TO MAINTAIN THE 10% REDUCED BODY WEIGHT AND ONE THING HE OBSERVED AS YOU MIGHT EXPECT, LEPTIN LEVELS FALL WHEN YOU LOSE 10% OF YOUR BODY WEIGHT AND THEY FELL BY ABOUT 25%. SO THEN HE TRIED TO UNDERSTAND WHAT’S GOING ON WITH ENERGY EXPENDITURE IN THESE SUBJECTS SOPHISTICATED THEY–THE IS TOTAL ENERGY EXPENDITURE AND HE’S LOOKING AT THE DIFFERENCE BETWEEN THE 10% STATE VERSUS BASE LINE WEIGHT AND YOU CAN SEE TOTALLY ENERGY EXPENDITURE DECREASED BY ABOUT 22% AFTER WEIGHT LOSS. ACTUALLY RESTING ENERGY EXPENDITURE DIDN’T CHANGE MUCH AND IF YOU TAKE THE DIFFERENCE BETWEEN TOTAL ENERGY EXPENDITURE AND RESTING ENERGY EXTRAMURAL PENDITTURE, YOU CAN SEE THAT THE BULK WAS NONRESTING ENERGY EXPENDITURE WHICH IS WHEN WE MOVE AROUND DURING NORMAL DAILY ACTIVITIES OR NORMAL EXERCISE. SO THEN HE LOOKED AT PHYSIOLOGICAL MECHANISMS THAT MIGHT LEAD TO REDUCTION IN ENERGY EXPENDITURE AND CATACOLLA MINES WERE REDUCED IN THE WEIGHT REDUCED ESTATE AND SYMPATHETIC NERVOUS SYSTEM TONE WAS REDUCE AS WELL. HE ALSO FOUND REDUCTIONS IN HIROADWAY HORMONES AND ALL THESE WOULD BE EXPECTED TO LEAD TO A DECREASE IN ENERGY EXPENDITURE. SO THEN HE DID SOMETHING REALLY INTERESTING WHICH IS THAT HE HAD THE HYPOTHESIS THAT THE REDUCTION IN LEPTIN AFTER WEIGHT LOSS MIGHT BE CAUSEALLY RELATED TO REDUCTION AND ENERGY EXPENDITURE IN WEIGHT LOSS SO HE TOOK THESE SUBJECTS THAT WOULD REDUCE THESE BY 10% AND HAD THOSE FALL BY 25%. AND HE GAVE THEM LEPTIN BACK AS AN INJECTION IN ORDER TO ACHIEVE THE LEVELS THAT THEY HAD PRIOR TO WEIGHT LOSS. AND SO NOW WHAT WE SEE ON THESE GRAPHS ARE THE CHANGES IN THYROID HORMONES AND CATACOLA MINES WITH JUST THE WEIGHT LOSS SHOWN IN GRAY AND THE WEIGHT LOSS PLUS LEPTIN REPLACEMENT TO WEIGHT LOSS LEVELS AND YOU CAN SEE THE REDUCTION IN EXPENDITURE WAS ALMOST COMPLETELY REVERSED BY LEPTIN REPLACEMENT, THE SAME WAS TRUE FOR THE REDUCTION IN NONRESTING EXPENDITURE, AND HE LOOKED AT SOMETHING GROSS MECHANICAL EFFICIENCY IS HOWENTIOUS FICIENTLY HOUR MUSCLES USE ENERGY IN THE CONTEXT OF ACTIVITY AND FOUND THAT MOST OF THIS CHANGE WAS ACCOUNTED FOR BY GROSS MECHANNAL EFFICIENCY, THAT IS WHEN YOU LOSE WEIGHT YOUR MUSCLES BECOME MORE EFFICIENT AND IF YOU REPLACE IT BACK TO PREWEIGHT LEVELS THEN YOUR MUSCLES BECOME LESS EFFICIENT AGAIN. SO SORT OF LOOKING AGAIN AT THESE HORMONE LEVELS, THE CHANGES IN THYROID HORMONES FOR TTHREE AND TFOUR, THE CIRCULATING HORR MONITORS WERE COMPLETLY ABNORMALITIES BROIGATED BY WANT LEPTIN PLACEMENT, AND TSA CHANGES DESCRNT ANY EFFECT WITH LEAPT INNER AND AGAIN THE CATADOLLA MINES WERE REVERGSED BY LEPTIN REPLACEMENT TO PREWEIGHT LOSS LEVELS AS WERE THE CHANGES IN THE SYMPATHETIC NERVOUS SYSTEM. SO I MENTION THAD LEPTIN IS A HIGHLY EFFECTIVE THERAPY IN THE CONTEXT OF LEPTIN DEFICIENT RODENT OR LEPTIN DEFICIENT HUMAN, IS IT A HIGHLY EFFECTIVE THERAPY FOR A GARDEN VARIETY OBESITY. SO THAT STUDY WAS DONE IF 1999 BY HANES FIELD AND COLLEAGUES, THEY GIVE LEPTIN REPLACEMENT TO ABOUT 200 OBESE MEN AND WOMEN AND THEY FOUND REALLY NOT MUCH. SO MODEST WEIGHT LOSS AT THE DOSES BUT NOTHING TO WRITE HOME ABOUT. SO WHY IS THIS. AND I WILL CROACH THE LIABLE STUDY AND WHAT HE SAID IN THE DISCUSSION OF THAT STUDY IS, THE PRIMARY FUNCTIONAL ROLE OF LEPTIN IS APPARENTLY TO DEFEND, NOT REDUCE BODY FAT BY INCREASING FOOD SEEKING AND DECREASING ENERGY EXPENDITURE WHEN FAT STORES ARE INSUFFICIENT. SO IF WE GO BACK TO THIS MODEL IF WE START OFF WITH NORMAL FAT STORES AND YOU LOSE FAT STORES, LEPTIN WILL SIGNAL TO US TO REVERSE THAT. LOW LEPTIN LEADS TO INCREASED APPETITE WHEN YOU LOSE YOUR BODY FAT BUT THAT PROPOSAL I MADE TO YOU EARLIER THAT HIGH LEPTIN WILL DECREASE YOUR APPETITE TURNS OUT TO BE UNTRUE. AND IF WE THINK ABOUT THIS AGAIN, A DIFFERENT WAY, LET’S JUST LOOK AT CORRELATION BETWEEN BODY FAT AND LEPTIN LEVELS, THEY ARE VERY HIGHLY CORRELATED SUCH THAT SOMEBODY WHO WAS OBOES AND HAS HIGH BODY FAT AND HAS A HIGH LEPTIN LEVEL, AND YOU CAN THINK ABOUT LEPTIN RESPONSIVENESS OCCURRING AT THE LOW LEVELS OF LEPTIN AS A SIGNAL OF STARVATION, IN SOMEBODY WHO WAS ALREADY OBESE AND ENDOGENOUS LEPTIN LEVELS THAT’S ABOVE THE RESPONSIVE RANGE FOR THESE BIOLOGICAL SYSTEMS AND ADDING ADDITIONAL LEVELS FOR THIS DRUG WILL HAVE A CLINICAL EFFECT. SO NOW WE’RE IN A SITUATION WHERE LEPTIN AS A DRUG IS ONLY A UTILITY IN PEOPLE WHO ARE LEPTIN-DEFICIENT. SO WHAT ARE THE HUMAN CONDITIONS ASSOCIATE WIDE LEPTIN DEFICIENCY, THE MOST OBVIOUS AND STARVATION BUT YOU WOULD NOT WANT TO GIVE IT THISEM IF THEY’RE STARVING AND YOU DON’T WANT TO FURTHER DECREASE THEIR BODY WEIGHT. THE OTHER CONDIGDZ, IS ARE MUTATIONS OF LEPTIN GENE. THESE PATIENTS BECOME SEVERELY OBESE AND LEPTIN IS THERAPEUTIC FOR THEM. THERE IS ANOTHER CONDITION I WILL TALK MORE ABOUT WHICH IS THE FOLK UTION OF MY RESEARCH WHICH IS LIPO DIOF THE ROW FEE, THOSE SIN DROMS ARE REALLY A HETEROGENEOUS ROW GENIUS GROUP OF DISORDERS ABOUT YOU WHAT THEY ARE IN COMMON IS THAT THERE’S SELECTIVE DEFICIENCY IN THE ADIPOSE PHOTOTHIS IS IS A 16 YEAR-OLD GIRL, CAN YOU SEE THE VERY MARKED MUSCULAR APPEARANCE TO THE HIP AND THY, SHE HAS XANTHOMA’S AND THOSE ARE TRI GLYCERIDES AND MORE DRAMATICALLY FILED WHO HAS GENERALIZED LIPO DIOF THEROPHY, THEY’RE GENERAL LE A BIT ON THE BUJY SIDE, NOT LOOKING LIKE BODY BUILDERS, SO THIS IS REALLY A VERY MARKED PHYSICAL ARKTS PEERANCE OF GENERALIZED LIPO DIOF THE ROUGH ATOM SOFY. WHEN WE THINK ABOUT LIPO DYSTROPHY, WE CLASSIFY THEM AS THE DISTRIBUTION OF THE MISSING BODY FAT SO FROM AN ETICSIO LOGIC FACT, THAT I CAN BE GENETIC OR ACQUIRED, THE MOST COMMON IN THE WORLD IS ACQUIRED PAICIAL LIP O DIOF THEROPHY RELATED TO HUMAN IMMUNE O DEFICIENCY VIRUS AND TREATED WITH HAART DRUGS AND I’M NOT REALLY GOING TO FOCUS ON THAT FOR THIS TALK. THERE ARE ALSO AUTOIMMUNE FORMS OF LIPO DIOF THEROPHY IN WHICH THE FAT CELLS THEMSELVES OR THE DROPLETS WITHIN THE FAT CELLS UNDERGO AUTOIMMUNE DESTRUCTION. IN TERMS OF DISTRIBUTION AND BODY FAT. I SHOWED YOU PATIENTS IN
THE–PICTURES WHE
RE ALL THE FAT IN THE BODY IS MISSING. YOU CAN ALSO HAVE PORTIONS OF LIPO DYSTROPHY IS LOST. HOW DO YOU RECOGNIZE THE PATIENT WITH THE LIPO DIOF THEROPHY, THEY WILL HAVE A MUSCULAR APPEARANCE DO YOU TO LACK OF OVERLYING FAT. YOU AM SEE SIGNATURES MATTA OF INSULIN RESISTANCE. THEY TYPICALLY WILL HAVE PROMINENT VAIN WHICH IS IS DUE TO A LACK OF FAT OVERLYING THE VAINS, PATIENT WTION GENERALIZED LIPO DIOF THEROPHY WILL HAVE A PROMINENT BELLY BUTTON FOR REASONS THAT ARE UNCLEAR AND THEY WILL HAVE INCREASED ABDOMINAL GIRTH THAT’S NOT DUE TO FAT. THAT’S ACTUALLY DUE TO INCREASED SAYS OF THE INTERNAL ORGAN SUCH AS LIVER. SO ON THE RIGHT HAND SIDE CSR I’M SHOWING YOU A PATIENT WITH SAME AGE, SHE AS I LAWSKULAR APPEARANCE TO THE LEGS SHE HAS AKAN THOSEIS AS A STIGMATA OF INSULIN RESISTANCE SHE HAS THE PROMINENT VAINS BUT SHE HAS INCREASED FAT IN CERTAIN REGIONS OF HER 3W-D CRITERIA IN THE HEAD, NECK AND TRUNK AREA, THIS IS DEPOST SPECIFIC LOSS OF FAT. THIS IS A LOSS MUCH FAT IN HERICATES IN THE GLUTEAL AND LEG AREAS, LESSER EXTENT TO THE ARMS, PRESERVATION OF FAT IN THE HEAD, NECK AND TRUNK. I’M GOING TO WALK YOU THROUGH THE PATHOPHYSIOLOGY OF LIPO DIOF THE ROUGH ATOMROPHY, THIS BECAUSE THEY HAVE LOW FAT MASS, THEY HAVE LOW LEVELS OF THE DERIVED HORMONES IN PARTICULAR LEPTIN, THE LOW LEPTIN GETS SENSED AND LEADS PATIENTS TO BECOME HYPER PHAGIC. NOW IF THOSE OF US IN THIS ROOM, BACK HYPER PHAGIC WE WILL STORE THOSE EXTRA CALORIES IN OUR FAT CELLS AND THAT’S A FAIRLY HEALTHY PLACE TO STORE EXCESS CALORIES. THAT’S ONE OF THE MAIN JOBS OF OUR ADIPOSE TISSUE. BUT A PATIENT HAS NO FAT CELLS IN WHICH TO STORE EXTRA CALORIES SO INSTEAD THEY WIND UP STORES EXTRA CALORIES IN ECTOPIC LOCATIONS SUCH AS MUSCLE AND LIVER. AND THIS LIQUID IN THE LIVER, LEADS TO INSULIN RESISTANCE AND INSULIN RESISTANCE AS YOU KNOW AS A NUMBER OF CLINICAL CONQUENCES, ENCLOUDING DIABETES, AS WELL AS NONALCOHOLIC FATTY LIVER DISEASE. SO WE CAN THINK OF LIEB O DIOF DYSTROPHY OF THE OBESITY METABOLIC SYNDROME. SO THERE ARE CERTAINLY DIFFERENCES BETWEEN OBESE PATIENTS AND THESE PATIENTS PARTICULARLY THE FAT MASS IS HIGH, IN OBESITY AND LOW IN LIPO DYSTROPHY. LIKEWISE LEPTIN LEVELS ARE HIGH IN OBOESITY AND HIGH IN DYSTROPHY BUT ENERGY IS HIGH IN BOTH ESTATES. ECTOPIC FAT IS PRESENT AND CONTRIBUTES TO INSULIN RESISTANCE IN NOAOF THE CASES BUT THIS IS MORE EXTREME IN PATIENTS WITH LIPO DYSTROPHY. SO I WANT TO GO BACK TO PATIENTS WITH GENERALIZED AND PARTIAL LIPO DYSTROPHY. I PLOTTED THE BODY FATOT X-AXIS AND THE LOG OF THE LEPTIN LEVELOT Y-AXIS AND PATIENTS WITH GENERALIZED LIPO DYSTROPHY, ARE SHOWN IN BLUE AND OTHERS IN RED BUT IN BOTH POPULATIONS THE LEPTIN LEVELS ARE POETIC PROPORTIONAL OF THE GENERAL BODY FAT, TRUE OF THE GBLIZED POPULATION AS WELL, SO THAT THEY HAVE LOW LEPTIN LEVELS AND THOSE ARE PAICIAL LIP O DYSTROPHY, SOME HAVE LOWER AND SOME HAVE HIGHER AND IT’S PROPORTIONAL TO THEIR OVERALL ADIPOSITY. SO I MENTIONED THEY HAVE INCREASED INSULIN AND DIABETES. AND HERE I PLOTTED DIABETES CONTROL. THIS DASHED LINE HERE IS A HEMOGLOBIN A-ONE,-C, WHICH IS A CUT POINT FOR DIAGNOSIS OF DBTS. YOU CAN SEE ALMOST EVERYBODY WITH GENERALIZED LIPO DIOF THEROPHY IN BLUE, MET THE RITERRIA FOR DIABETES AND THIS IS GERONTOLOGYSTS SPITE WHATEVER MEDICATIONS THEY WERE ON TO TREAT THEIR DIABETES. MANY OF THESE PATIENTS HAD WHAT WE TERM EXTREME INSULIN RESISTANCE. AND I’M–DEFINING THIS IN A COUPLE OF WAYS, ONE IS THAT IF WE LOOK AT HOW MUCH INSULIN THEIR BODIES ARE MAKING THE ENDOGENOUS GLUE CO TOLL-LIKE RECEPTOR RANSZ TEST, GREATER THAN A THOUSAND AND TO PUT THAT IN INTO PERSPECTIVE A TYPICAL PERSON WITHOUT DIABETES WHO’S INSULIN SENSITIVE MIGHT HAVE A PEAK OF ABOUT 40 SO THIS IS EXTREMELY ELEVATED. ANOTHER WAY TO SORT OF DISTINGUISH INSULIN RESISTANCE WHO REQUIRES AS A TREATMENT FOR DIABETES, IS TO LOOK AT INSULIN DOSES AND THESE PATIENTS HAD INSULIN DOSES RANGING BETWEEN THREE AND 28 UNITS PER KILOGRAM OF BODY MASS PER DAY AND AGAIN TO PUT THAT INTO PERSPECTIVE A TYPICAL OVERWEIGHT TYPE TWO DIABETIC MIGHT REQUIRE ABOUT ONE UNIT PERKILOPER DAY. SO VERY, VERY HIGH INSULIN REQUIREMENTS IN SOME OF THESE. THESE PATIENTS ALSO HAVE A VERY TYPICAL LIPIT DISORDER, AND GLD CHOLESTEROL. WE SEE THAL IN OBESITY BUT IT’S MORE EXAGGERATE INDEED LIPO DIOF THEORY. AND HERE I BLOTTED THIS ON A LOG SCALE SO CAN YOU SEE MANY OF THESE PATIENTS HAVE EXTREME ELEVATEIVATION. AGAIN I’M SHOWING AGAIN WITH THE DASH LINE AT 150 AND YOU CAN SEE THAT ALMOST EVERYBODY HAS HIGH TRI GLYCERIDES AND SOME OF THEM ARE GETTING UP TO THE 10,000 RANGE. PLACES PATIENTSA THE RISK. THIS CAN BE ALSO CAUSE LIFE-THREATENING PAN KRISTA TITIS. THIS IS THE CUT OFF FOR FORM NORMAL. SO YOU WANT YOUR HDL TO BE ABOVE 40 AND YOU CAN SEE THAT ALMOST EVERYBODY’S HDL IS BELOW 40 AND I VBT SHOWN THE LDL LEVELS BECAUSE THEY’RE PRETTY NORMAL IN THIS POPULATION. AND IT STARTS FROM JUST HAVING FAT DEPOSITION IN YOUR LIVER. THAT CAN SCARRING AND FINAL PATHWAY IS INCLUDING NONALCOHOLIC FATTY LIVER DISEASE IS CIRRHOSIS, SO IF WE LOOK AT THE SEVERITY OF THIS, WHERE PEOPLE ARE IN THIS SPECTRUM AND COMPARE WITH OBOESITY AS THOSE WITH LIPO DYSTROPHY BUT YOU CAN SEE THAT 40% OF THOSE HAVE FATTY LIVER DISEASE. ABOUT 90% OF THESE HAVE FATTY LIVER DISEASE. AMONG PATIENTS WITH OBESITY AND FATTY LIVER DISEASE, ABOUT 10-20% WILL HAVE NONWHOLIC C HEPATITIS. BY CONTRAST 70 TO 90% HAVE HEPATITIS. IF YOU HAVE NONALCOHOLICS, AND YOU ARE OBESE, HAVE YOU A THREE-15% RISK OF PROGRESSION TO CIRRHOSIS OVER A 10-20 YEAR TIME FRAME. WE DON’T HAVE THOSE LONGITUTEDINAL DATA IN THE PATIENTS BUT IF YOU LOOK CROSS SECTIONALLY AT OUR PATIENT POPULATION, 17% OF THEM HAD CIRRHOSIS AT THE TIME WE PERFORM LIVER BIOPSIES ON THEM AND THIS IS QUITE A YOUNG PAICIALT POPULATION, THE MEAN AGE WAS AROUND 18. HAVING CIRRHOSIS PLACES YOU AT RISK AS AS LIVER FAILURE, IN PATIENCES WITH CIRRHOSIS THIS OCCURS AT TWO-FIVE% PER YEAR, I SAID THIS HASN’T BEEN REPORT INDEED PATIENTS WITH LIPO DIOF DYSTROPHY BUT I HAVE HEARD OF ONE OR TWO CASES DM WHICH THE PATIENTS DEVELOPED HEPATITIS EAT O CARC THOMEA. SO I’M AN ENDOCRINOLOGYST SO I’M RESPONSIBLE FOR THIS STUDY BUT THE PEOPLE WHO WERE ARE ENDOCRINOLOGYST. THIS IS OUR PASSION. PATIENTS WITH LIPO DYSTROPHY ARE MISSING LEPTIN AND IT SEEMED LIKE A GREAT PROOF OF PRINCIPLE CONCEPT TO SEE. IF YOU REPLACE LEPTINS IN THE PHENOTYPE JUST AS IN OBESE WITH THE DEFICIENCY. AND THERAPIST IS–THIS IS DESIGNED FOR LEPTIN REPLACEMENT ESCOLLATING DOSES UP TO TWO FOLD. ESTIMATED AS THE PHYSIOLOGIC REPLACEMENT DOSE. RESULTS WERE PRETTY GRAMMATIC. THE HEMOGLOBIN, DIABETES CONTROL IMPROVED BY 1.9% WHICH IS SUBSTANTIAL IMPROVEMENT FROM 9.1 DOWN TO 7.2 AND PUT THAT INTO PERSPECTIVE, THE TARGET FOR A-ONE, C, IS LESS THAN SEVEN. SO THEY WERE CLOSE TO TARGET BY TREATMENT. THEY OBSERVED A DRAMATIC REDUCTION IN TRI GLYCERIDE STARTING FROM ABOUT 1400 DOWN TO 300S. AGAIN NORMAL IS LESS THAN 150. THEY WERE NOT COMLY NORMALIZE SAID ABOUT YOU THEY WERE A LOT CLOSER. LIVER AND SPLEEN WAS REDUCED BY 28%. THIS REDUCED FROM THE FATTY LIVER DISEASE, FATTY REDUCTION IN THE LIVER. AND REMARKABLY, FOOD INCREASE REDUCED DOWN TO ABOUT 1600-CALORIES PER DAY, AND SO, THAT WAS 17 YEARS AGO, WE HAVE EXPANDED THOSE STUDIES ENORM AUSLY SENSE THAT TIME, THERE HAVE BEEN OVER A HUNDRED PATIENTS WITH LIPO DYSTROPHY TREATED WITH LEPTIN AND WHAT OFTEN HAPPENS WHEN YOU DO A SMALL PROOF OF PRINCIPLE STUDY AND YOU GET DRAMATIC RESULT SYSTEM THAT AS YOU EXPAND YOUR POPULATION, THOSE RESUMMITS DISSIPATE AND GET LOST IN THE NOISE. AND FORTUNATELY THAT WAS NOT TRUE WITH LEPTIN IN PATIENT WTION LIPO DYSTROPHY, SO THIS A POPULATION IEMG SHOWING AND YOU THESE ARE TWO KEY OUTCOMES, AND DIABETES AND TRI GLYCERIDES. I’VE DIVIDED THE PATIENTS INTO PAICIAL LIPO DYSTROPHY IN RED AND GENERALIZED LIPO DYSTROPHY IN BLUE. AND I’VE DONE THAT FOR THE BIOLOGY OF THESE CONDITIONS AND YOU MAY RECALL THAT THE LEPTIN LEVELS WITH GENERALIZED WERE LOW AND THIS IS SEVERELY LEPTIN LEVELS IN THE PATIENTS WITH THE PAICIAL LIPO DYSTROPHY ARE MUCH MORE VARIABLE, THEY CAN RERANGE FROM LOW, UP TO NORMAL OR EVEN ELEVATED IF THAT PATIENT HAS OBESITY IN THE DEPOs WHERE FAT IS PRESERVED. BUT YOU WILL SEE THAT IT HAD A MEANINGFUL EFFECT ON BOTH GROUPS ON AVERAGE, SO THESE DECREASES FROM THE EIGHTS DOWN TO THE SIXS AND FROM ABOUT EIGHT DOWN TO ABOUT SEVEN, THERE’S PARTIAL LIPO DYSTROPHY, FROM ABOUT A THOUSAND IN BOTH GROUPS DOWN TO 500 THE PAICIAL LIPO DYSTROPHY PATIENTS AND ABOUT 300 IN THE GENERALIZED LIP O DYSTROPHY PATIENTS AND WE DID FURTHER ANALYSIS. IF YOU’RE PAICIAL LIPO DYSTROPHY LEVEL, YOU ARE LIKE LOW TO RESPOND TO LEPTIN IF YOU ARE A PAICIAL PATIENT AND YOU HAVE A NORMAL OR INCREASED LEPTIN LEVEL. AND I JUST WANT TO ILLUSTRATE BY SHOWING YOU A PATIENT EXAMPLE HOW LIFE CHANGING THIS HORMONE REPLACEMENT CAN BE IN CERTAIN PATIENTS. THIS IS A 21 YEAR-OLD WOMAN WHO CAME TO US FROM ANOTHER COUNTRY WITH GENERALIZED LIPO DYSTROPHY. SHE HAD POORLY CONTROLLED DIABETES AND KETOACIDOSEIS AND NEFF ROTTIC RANGE, AND HERE I’M SHOWING HER LABORATORY VALUES AND PARAMETERS IN BLUE PRIOR TO LEPTIN TREATMENT AND IN PURPLE AFTER A YEAR OF LEPTIN THERAPY. AND HER HEMOGLOBIN A-ONE-C CONTROLLED FROM THE RANGE OF 13.1 DOWN TO NORMAL SO NOT CONSISTENT WITH DIABETES AFTER A YEAR OF LEPTIN. THIS WAS DESPITE HER DISCONTINUING INSULIN. SO SHE STARTED OFF TAKING HIGH DOSES OF INSULIN, ALMOST 300 UNITS I DAY AND THIS NORMAL HEMOGLOBIN WAS OFF INSULIN ENTIRELY. HER TRI GLYCERIDES, FROM 6000 TO ALMOST THE NORMAL RANGE OF 179. –BUT MORE DRAMATICALLY IS HER INCREASE IN ABDOMINAL GIRTH WHICH IS DUE TO THE LIVER, CAN YOU SEE THAT AFTER LEPTIN THERAPY IS DECREASE IN ABDOMINAL GIRTH. SHE LOST ABOUT 20 KILOS OF WEIGHT WHICH IS LEAN BODY MASS AND THIS IS DO YOU TO THE APPETITE SUPPRESSING EFFECT OF LEPTIN. SO THIS IS A LIFE CHANGING TREATMENT FOR THIS YOUNG WOMAN AND SHE’S NOT THE NUMBER ONE POSTER CHILD FOR LEPTIN. THIS IS NOT AN ATYPICAL RESPONSE, ALTHOUGH NOT ALL PATIENTS DO AS WELL AS SHE DID. SO I JUST WANT TO SUMMARIZE WHAT WE KNOW ABOUT THE EFFECTS OF LEPTIN AND LEPTIN DEFICIENT HUMANS, DECREASES HYPER PHASIA BECAUSE APPETITE IS DECREASES AND DEKRESS BODY WEIGHT, IMPROVING INSULIN RESISTANCE, AND BLOOD GLUCOSE AND ALLOWS FOR REDUCTION DMS INSULIN DOSES AND HYPER TRI GLYCERIDEEMIA AND I DIDN’T TALK ABOUT THE REPRODUCTIVE PHENOTYPE IN THESE PATIENTS BUT THEY TEND TO HAVE IMPAIRED INFERTILITY AND ALLOWS FOR PIEWBITTAL PROGRESSION AND MENSTRUAL CYCLES FOR WOMEN AND NORMALIZED OR INCREASES FERTILITY. SO I TOLD I BEFORE THAT THE LOW FAT MASS AND AARON PRESENTED DATA TO YOU FROM THE CDC SHOWING CORRELATION BETWEEN INCREASED FAT MASS AND PROBLEMS SUCH AS DIABETES BUT I HOPE I HAVE PROVEN TO YOU THAT HAVING TOO LITTLE FAT IS JUST AS UNHEALTHY AS HAVING TOO MUCH FAT SO NOW LET’S SEE HOW CAN WE GENERALIZE WHAT WE’VE LEARNED FROM PATIENTS WITH LIPO DIOF THE OFFICER TOW PATIENTS WITH THE MORE COMMON FORMS OF INSULIN RESISTANCE LIKE OBESITY. SO IN A PATIENT WITH OBESITY THE PROBLEM IS NOT LOW FAT MA MASS, IT’S FURGT OR DOWN THIS CHAIN. IT’S EXCESS FOOD INTAKE RELATIVE TO ENERGY EXPENDITURE, AFTER THAT WE SEE A PATHOPHYSIOLOGY AND PATIENTS WITH OBOESITY COMPARED WITH LIPO DYSTROPHY. SO HAVE YOU THIS EXCESS FOOD INTAKE AND YOU ARE SUPPOSED TO BE STORING CALORIES AT ADIPOSE SITES. SO IF FAMINE COMES AROUND, AND THE FOOD STORAGE THAT YOU UTILIZE, WHERE FOOD IS NOT AVAILABLE. BUT WHEN YOU BECOME TOO OBESE YOU EXCEED THE STORAGE CAPACITY AND YOU CAN NO LONGER STORE THOSE COMA–AND IT JUST OCCURS IN A LATEDDER STAGE IN THE OBESE PATIENT AND THAT HAS ALL OF THE SAME BIOLOGICAL CONSEQUENCES IN SOMEONE WHO IS OBESE, CAUSES INVITE–MARILYN SURVEYS LYNN RESISTANCE AND THAT CAN LEAD TO DIABETES, NONALCOHOLIC FATTY LIVER DISEASE, SO WE’RE DEALING WITH THE SAME PATHOPHYSIOLOGY. SO TOO MUCH FAT IS UNHEALTHY. SOPHISTICATED I WANT TO FOCUS ON THE IDEA THAT THE STORAGE CAPACITY IS EXCEEDED BECAUSE I THINK THIS IS WHERE WE UNDERSTAND THE BIOLOGICAL VARIABILITY IN THE PATIENTS WITH OBESITY. SO SOME PATIENTS START TO DEVELOP INSULIN RESISTANCE IN DIABETES, WHEN THEY’RE AT A NORMAL BODY WEIGHT OR SLIGHTLY INCREASED BODY WEIGHT AND OTHER CANS BECOME SEVERELY OBESE WITHOUT SUFFERING CONSEQUENCES AND WE THINK THIS IS RELATED TO THE STORAGE CAPACITY OF DIP O SIGHTS SO WHO HAVE THE FAT SIGHTS OR TISSUE HAVE THE ABILITY TO SHOW A LOT OF EXTRA FOOD THERE IN A SAFE MANNER WILL NOT SUFFER ILL HEALTH EFFECTS FROM OBESITY, WHERE THEY HAVE LIMITED FECESSIBILITY OF THE TISSUE WILL SUFFER CONSEQUENCES IN A MUCH LATER STAGE NOVEMBER GAME THE SO LIMITED STORAGE CAPACITY IS UNHEALTHY. I WILL SHOW YOU DAT THAT SUPPORT THIS. THIS IS A VERY NICE STUDY THAT USED GENOME WIDE ASSOCIATION TO UNDERSTAND THE ROLE OF LIMITED ADIPOSE TISSUE STORAGE IN RESUFFICIENTANCE. SO THE BACKGROUND HERE IS THAT INSULIN RESISTANCE IS SOAPTED AS YOU SAW FROM THE CDC DATA THAT AARON SHOWED AND IT’S A KEY LINK BETWEEN ADVERSITY AND METABOLIC AND CARDIOVASCULAR DISEASE. I SHOWED YOU THAT IN PATIENTS WITH LIPO DYSTROPHY AND PERIPHERAL ADIPOSE TISSUE TO EXPAND WILL LEAD TO ECTOPIC LIPID ACCUMULATION AND THAT LEADS TO INSULIN RESISTANCE AND DIABETES. BUT WE KNOW IN THE GENERAL POPULATION AT GO GIVEN LEVEL OF THE, DIPOSSITY THERE’S HUGE VARIATION AND HOW MUCH METABOLIC DISEASE THEY HAVE AND SO WHAT THESE ARE TRYING TO DO WAS TO IDENTIFY SINGLE NUCLEIE TIDE POLYMORPHISMS THAT THEA A GIVEN LEVEL OF ADIPOSITY WOULD INCREASE OR DECREASE INSULIN RESISTANCE AND METABOLIC DISEASE. SO THEY FOUND THAT THERE WERE 53 INDEPENDENT REGIONS IN THE GENOME THAT WERE ASSOCIATED WITH THE INSURVEYS LIVE RESISTANCE–INVITE–MARILYN SURVEYS LYNN RESISTANCE AND THAT THE GENETIC PREDISPOSITION BY THESE 53 LOSCRRKS I WAS ASSOCIATE WIDE HIGHER METABOLIC RISK BUT AT LOWER LEVELS OF PERIPHERAL ADIPOSITY. AND I WILL SHOW YOU ONE SIMPLE SIMPLE–EXAMPLE OF THE DATA THAT SHOWS THIS. SO QUIENTILE ONE HAS THE LOAOF THEST SCORE, QUENTILE FIVE HAS THE HIGHEST AND HERE ON THE LEFT THEY’RE PLOTTING LEG FAT MASS. CAN YOU SEE PATIENTS WITH THE HIGHEST GENETIC RISK HAVE THE LOWEST LEG FAT MASS, THOSE WITH THE LOWEST LEG HAS THE HIGHEST. SO THOSE WITH THE LOWEST GENETIC RISK HAVE LOWEST RISK OF DIABETES AND THOSE WHO SCR THE HIGHEST GENERATEDET RISK HAVE THE HIGHEST RISK OF DIABETES. AND TO PUT THESE TWO TOGETHER, THAT MEANS THAT THE PEOPLE WITH THE LOWEST LEG FAT MASS HAVE THE HIGHEST RISK OF DIABETES. SO THAT’S A MGHTS NONIN. TUMOR SPECTRUMMATIVE, BUT MAKES SENSE IF YOU THINK ABOUT THIS IDEA OF PERIPHERAL ADIPOSE STORAGE CAPACITY PROTECTING FROM THE LIPID STORAGE. SO THE NEXT THING THEY TRIED TO DO WAS TO SAY, WELL, IF WE HAVE AN EXAMPLE IN THE GENERAL POPULATION, WHERE LOWER LEG FAT MASS IS ASSOCIATE WIDE HIGHER RISK OF INSULIN RESISTANCE, WHAT IF WE LOOK AT A MODEL OF LIPO DYSTROPHY AND TRY TO UNDERSTAND ARE THESE SAME SINGLE NUCLEOTIDE POLYMORPHISMS ASSOCIATE WIDE INSULIN RESISTANCE WITH A DRAATIC PATIENT EXAMPLE AND THE EXAMPLE THEY CHOSE WAS FAMILIAL PAICIAL LIPO DYSTROPHY AND CHARACTERIZED BY AN ABSENCE OF FAT IN THE LEGS AND IN THE TRUNK AND FOLLOWS SORT OF AN AUTOSTUDIES OF MULTIPLE ENDOCRINAL DOMINANCE AND THERE’S NO KNOWN GENES CAUSING IT SO THEY SPECULATE THAD MAYBE THIS WAS POLYGENIC AND THESE SICKLE NUCLEIE TIDE POLYMORPHISMS WERE PLAYING A ROLE HERE. SO THEIR HYPOTHESIS WAS THAT THERE’S A POLYGENIC PREDISPOSITION TO INSULIN RESISTANCE IMPARTED BY THESE LOCI, MIGHT CONTRIBUTE TO THE PATHOGENESIS OF THIS LIPO DYSTROPHY SUBTYPE. SO THE FIRST TIME THEY DEMONSTRATE, HERE THEY SHOW THE DIFFERENCE BETWEEN THE WHOLE BODY FAT MASS AND LEG MASS. THIS IS GIVING AUSA RATIO OF THESE TWO AND THEY PLOTTED THIS IN BLUE IN HEALTHY CONTROLS. AND IN RED IN THE PATIENT WHO IS HAD PARTIALITY FAMILIAL LIPO DYSTROPHY TYPE ONE AND YOU CAN SEE THEY HAD A LOWER LEG FAT MASS COMPARED TO TOTAL FAT MASS RELATIVE TO THOSE IN THE GENERAL POPULATION AND THEN THEY COMPARED THE NUMBER OF RISK ALLELES IN THE 53 LOCI AMONG PATIENTS WITH PARTIAL FAMILIAL DYSTROPHY. AND YOU CAN SEE THERE’S A RIGHT SHIFT IN THE GENETIC RISK BURDEN IN THE PATIENTS WITH LIPO DYSTROPHY. SUGGESTING THAT THE–THEY HAVE A HIGHER BURDEN OF THESE RISK ALLELES AND THAT MIGHT BE CONTRIBUTING TO THE PHENOTYPE.% SO THEY SORT OF SUMMARIZED OVER ALL WHAT HAY STUDIED ON THE GRAPH, THE INVERSION OF THE GENETIC RISK EXPOSURE, SO LOW GENETIC IS ON THE RIGHT AND HERE’S THE SEVERITY OF THE FEIGN TYPE, SO OVEROT FAR LEFT, THIS IS SEVERE PHENOTYPE AND HIGH GENETIC RISK ARE PATIENT WHO IS HAVE SINGLE GENE DEFECTS THAT LEAD TO INSULIN SIGNALING PROBLEMS SO THIS INCOLLIDES PATIENT WHO IS HAVE INNERSURVEYS LYNN RECEPTOR OR MUTATIONS IN GENES LIKE PITHREE KINASE THAT LEAD TO LIPOIVITYROPHY. SORT OF SOMEWHAT TO THE RIGHT HERE ARE PATIENT WHO IS HAVE FAMILIAL PARTIAL LIPO DYSTROPHY TYPE ONE WHERE WE HAVE AN INCREASED BURDEN OF THESE COMMON RISK ALLELES THAT LEAD TO A MORE DRAMATIC PHENOTYPE. OVER HERE WE HAVE THE COMMON POPULATION BUT EXTREMES OF THE DISTRIBUTION FOR ENHANCED SUSCEPTIBILITY TO INSULIN RESISTANCE AND THE GENERAL POPULATION HERE, CERTAIN GENES THAT MAY CONTRIBUTE, SOME POLYMORPHISMS THAT INCREASE INSULIN RESISTANCE. OKAY, SO I WANT TO COME BACK TO LIPO DYSTROPHY AND MEKS–MENTION THAT EVEN THOUGH WE CAN’T CURE IT BY REPLACING THE FAT MASS, WHICH IS THE UNDERLYING PROBLEM, WE CAN INTERVENE AT STEP TWO IN THE PATHOPHYSIOLOGIC PROCESS. AND SO, YOU KNOW THIS IS SOT OF ACTIVITIES AND AN EXAMPLE OF PERSONALIZED MS. WHERE WE REPLACE A MISSING HORR MOPE AND WE WOULD LOVE TO DO THE SAME THING IN OBESITY BUT COMMON IN RESISTANCE ARE MUCH, MUCH MORE COMPLEX IN A PARENT POPULATION LIKE THOSE OF LIPO DYSTROPHY. SO I WANT TO OFFER CONCLUSIONS, FIRST ABOUT FAT AS A STORAGE ORGAN. AND THIS SORT OF TAKES US BACK AGAIN TO THE 1970S OR 1990S BUT WHITE IS A PASSIVE STORAGE ORGAN BUT IT’S IMPORTANT AS A STORAGE ORGAN GOES BEYOND THAT BUT IT’S ALLOWING FLEXIBILITY IN CHANGING AVAILABILITY SO IT’S ALLOWING US TO STORE FATTED TIMES OF PLENTY AND UTILIZE IT IN TIMES OF SHORTAGE AND THE CAPACITY TO EXPAND ADIPOSE TISSUE IS EXTREMELY IMPORTANT. INADEQUATE WHITE ADIRKS IPOSE WILL LEAD TO ECTOPIC FAT STORAGE IN BOTH LIPO DYSTROPHY AND OBESITY AND COMMON INSULIN RESISTANCE. FAT IS ALSO SERVING A KEY FUNCTION AS AN ENDOCRINE O GENIC AN SO WE IT SECRETES LEPTIN AS WELL AS OTHER ADIPOKINES, LEPTIN SERVES AS A SIGNAL TO LONG-TERM ENERGY SUFFICIENCY, LEPTIN ACTS AS A STARVATION SIGNAL LEADING TO HYPER PHAGIA, AND LEPTIN REPLACEMENT CORRECTS HYPER PHAGIA AND METABOLIC DISEASE BUT ONLY IN LEPTIN DEFICIENT STATES AS CONGENITAL LEPTIN DEFICIENCY. THIS IS THE WORK OF MANY PEOPLE AND NONE OF THIS IS POSSIBLE WITHOUT OUR PATIENTS AND FAMILIES. HAPPY TO TAKE QUESTIONS. [ APPLAUSE ]>>[INAUDIBLE QUESTION FROM AUDIENCE ]>>I AVOIDED THE TERM GIRELLINBECAUSE IT’S MADE BY THE TOMAC AND IT’S NOT I ADIPOSE DERIVED HORMONE, BUT THERE ARE MANY, MANY THINGS I DIDN’T DISCUSS IN THIS TALK THAT REGULATE APPETITE. SO WHEN I TALK ABOUT LEPTIN-REGULATING APPETITE THAT WAS A MASSIVE OVERSIMPLIFICATION OF THE REGULATORY SYSTEM.>>PUTTING TOGETHER AARON’S TALK AND YOUR TALK, WHAT HAPPEN FIST YOU CONVERT MOST WHITE POETIC BROWN FAT. IS THAT I RISK?>>THAT IS A VERY INTERESTING QUESTION. ARE YOU GOING TO LACK A STORAGE CAPACITY TO STORE YOUR EXCESS CAPACITY, NO YOU WILL BURN THOSE BUT YOU DON’T NEED TO STORE THEM ANYWHERE.>>[INDISCERNIBLE].>>AS REBEC’S’ BEEN SHOWING, THE AMOUNT THAT’S WHITE, SO EVEN IF YOU BROWN ALL THAT YOU CAN, YOU HAVE FAT MASS TO SERVE TO RELEASE LEPTIN. YOU WILL NEVER GET INTO TROUBLE. IF YOU BROWN THE SUBQ FAT OR ALL OF THAT, THAT WOULD BE A PROBLEM BUT WE VBT SEEN THAT.>>AND BY THE WAY, WE HAVE NO IDEA WHAT BROWN FAT IS LIKE IN PATIENTS WITH LIPO DYSTROPHY.>>A QUICK TEST, ANYONE REMEMBER THE COMPLICATIONS OF HEART THERAPY? OKAY, MAYBE, MY QUESTION CENTERS AROUND THAT, SOME FORMS OF INDUCED LIPO DYSTROPHY, IS PROBABLY DUE TO INHIBITION OF PROTEASES AND HEART THERAPY HAS LEPTIN BEEN ATTEMPTED TO LOCK AT THOSE KINDS OF SYNDROMES.>>IT HAS. THERE HAVE BEEN SMALL STUDIES BUT NICELY DONE. I WANT TO SAY THE TOTAL NUMBERS OF PATIENTS IS 25-30. THOSE PATIENTS HAVE METABOLIC DISEASE ALTHOUGH IT CAN BE VARIABLE AND THEY DON’T HAVE TERRIBLY LOW LEPTIN LEVELS AND THE RESPONSE IS SORT OF PREDICTABLE BASED ON THAT. IT’S A FAIRLY MODEST RESPONSE.>>SO, DIET MANAGEMENT IS CRITICALLY IMPORTANT WITH PATIENTS WITH TYPE TWO DIABETES ASSOCIATE WIDE–ASSOCIATED WITH LIPO DYSTROPHY. THE SAME KIND OF DIET WE’RE ALL SUPPOSED TO FOLLOW THAT’S A HEART HEALTHY DIET THAT’S NOT HIGH IN SUGARS, BALANCE SAID AMOUNT OF PROTEIN, FAT, CARBOHYDRATES BUT IT’S ESSENTIALIALG.>>OKAY, I’M PRETTY SURE. THESE FOLKS WILL HANG AROUND FOR ANY,A DITIONAL QUESTIONS BUT I WANT TO THANK THE SPEAKERS, AARON AND THE REBECCA FOR A REALLY NICE PRESENTATIONS. THANK YOU ALL FOR ATTENDING AND I BELIEVE WIN WILL BE BACK FOR THE NEXT SECTION. SO YOU WILL GET TO HEAR HIS TAKE ON THE NEXT SESSIONS BUT THANK YOU ALL AGAIN AND HAVE A GOOD