Demystifying Medicine 2017: Obesity: Brown and Other Fat

Demystifying Medicine 2017: Obesity: Brown and Other Fat

November 1, 2019 1 By William Morgan


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