>>WELCOME TO THE 13TH SESSION
OF THE 23RD YEAR OF A COURSE
CALLED DEMYSTIFYING MEDICINE,
HELD AT THE NATIONAL INSTITUTES
OF HEALTH IN BETHESDA, MARYLAND.
I'M WIN ARIAS, A SENIOR
SCIENTIST EMERITUS, AND ONE OF
YOUR HOSTS FOR THIS PROGRAM.
THE OTHER IS DAN KASTNER OF THE
HUMAN GENOME RESEARCH INSTITUTE.
AND WE WELCOME YOU ALL TO THIS
AFTERNOON'S SESSION ON A TOPIC
OF ENORMOUS INTEREST,
IMPORTANCE, EXCITEMENT, AND
ACTUALLY IS OF GREAT INTEREST TO
EVERYONE.
THE PURPOSE OF THIS COURSE IS TO
ACT LIKE A BRIDGE TO BRIDGE
EXCITING DEVELOPMENTS IN BIOLOGY
AND ENGINEERING WITH CLINICAL
MEDICINE.
THE LOGO IN THE UPPER RIGHT-HAND
CORNER ON MY SCREEN IS THE
BROOKLYN BRIDGE.
AND TWO FOLKS ON THE CATWALK
REPRESENT TODAY'S SPEAKERS, WHO
ARE DISCUSSING THE IMPORTANT
PROBLEM OF OBESITY FROM TWO VERY
DIFFERENT PERSPECTIVES.
AND THE PURPOSE OF A BRIDGE IS
TO SHARE NEW IDEAS WITH THOSE
WHO ARE NOT IMMEDIATELY AWARE OF
THEM.
MUCH OF OUR SCIENCE TODAY IS IN
THE FORM OF A SILO SHOWN IN THE
LOWER RIGHT-HAND SECTION.
WHERE WE ALL KNOW AS IF IT WERE
SMALL PIECES OF THE PIZZA PIE,
BUT WE DO NOT COMMUNICATE
BROADLY ACROSS EITHER BIOLOGY OR
ENGINEERING OR CLINICAL MEDIC
MEDICINE.
SO IN THIS COURSE, WE TRY TO
CREATE MANY DIFFERENT KINDS OF
BRIDGES, AND FREQUENTLY START
WITH A LIVE PATIENT WHO
DESCRIBES THEIR DISEASE IN THEIR
OWN WORDS, AND THEN A CLINICIAN
AND INVESTIGATOR, AND FINALLY A
BASIC SCIENTIST WHO DESCRIBES
WHAT DO WE KNOW AND WHAT DO WE
REALLY NEED TO KNOW AND WHAT IS
THE CHALLENGE FOR YOUNG PEOPLE
LIKE YOU WHO ARE WATCHING THIS
PROGRAM AROUND THE WORLD.
THIS VIRTUAL SCHEDULE HAS
EXPANDED THE SCOPE OF
DEMYSTIFYING MEDICINE, WHICH IS
NOW WATCHED IN OVER
38 COUNTRIES AROUND
THE WORLD.
IN THE 17TH, 18TH AND EARLY
19TH CENTURY, OBESITY WAS A SIGN
OF, AS ONE OF THE SPEAKERS JUST
INFORMED ME, PROBABLY OF WEALTH,
AND IT CERTAINLY WAS ENVIABLE.
MEN HAD BIG BELLIES, EVEN
NAPOLEON HAD A RATHER HUGE
ABDOMEN, ABDOMINAL BIG BELLY.
AND THEN THINGS CHANGED.
MAYBE BECAUSE THE IMAGES CHAN
CHANGED, FROM HISTORICAL
FIGURES, TELEVISION, MOVIES,
BROUGHT OUT THE IDEA THAT THE
HEROS WERE SLIM MEN, THINK CARY
GRANT, AND THE WOMEN LIKEWISE.
BUT THEN IT CHANGED AGAIN.
AND IT CREATED WHAT IS A TRUE
EPIDEMIC.
OBESITY HAS WORSENED ENORMOUSLY
IN THE PAST 50 YEARS.
THE ECONOMIC BURDEN IS ESTIMATED
TO BE SOMETHING LIKE
$100 BILLION A YEAR.
AND IT'S THE SECOND MOST COMMON
CAUSE OF PREVENTABLE DEATH,
SMOKING BEING THE FIRST.
NOW, IN OUR COUNTRY, EVEN 40, 50
YEARS AGO, THE STATEMENT AT THE
TOP OF THIS SLIDE PRETTY MUCH
TOLD THE STORY.
FAT WAS FAT, AND THAT WAS THAT.
BUT MY, HOW THINGS HAVE CHANGED.
WE NOW RECOGNIZE THAT ADIPOSE
TISSUE IS DIVERSE.
THERE'S WHITE FAT AND BROWN FAT.
THEY'RE METABOLICALLY AND
HORMONALLY DIFFERENT.
AND ALL FAT IS METABOLICALLY AND
HORMONALLY AN ACTIVE TISSUE.
IT RELEASES FREE FATTY ACIDS,
PRODUCES HORMONES OF DIFFERENT
KINDS, WHICH ACT ON BRAIN,
LIVER, MUSCLE AND OTHER TISSUES
TO REGULATE FOOD INTAKE, ENERGY
BALANCE, AND INSULIN
SENSITIVITY.
AS A RESULT OF THESE
MANIFESTATIONS, OTHER EFFECTS
INVOLVED INFLAMMATION, IMMUNITY
AND PREDISPOSITION TO CANCER,
DIABETES, CARDIOVASCULAR, AND
NEURODEGENERATIVE DISEASES.
AND PROBABLY OTHERS.
NOW, TO BALANCE THIS EXPLOSION
OF SCIENTIFIC INFORMATION
REGARDING WHAT FAT IS AND WHAT
IT DOES, THERE IS A HUGE
CLINICAL CHALLENGE TO RELATE THE
DISCOVERIES BEING MADE TO
ADVANCES IN NUTRITION, HEALTH,
AND WHETHER PROPOSED TREATMENTS,
PARTICULARLY THOSE POPULAR WITH
A LARGE NUMBER OF PEOPLE,
WHETHER THOSE TREATMENTS,
DIETARY OR PHARMACOLOGIC WORK,
AND IF SO, HOW DO THEY WORK?
NOW, THIS IS THE BALLPARK OF
TODAY'S DEMYSTIFYING MEDICINE.
AND WE ARE VERY PLEASED TO HAVE
TWO NIH LEADERS IN THIS FIELD.
NOW OUR FIRST SPEAKER IS GOING
TO BE AARON CYPESS.
AARON WAS A GRADUATE OF
PRINCETON, TOOK A PH.D. FROM
ROCKEFELLER UNIVERSITY, AND HIS
MEDICAL DEGREE FROM CORNEL, AND
THEN A MASTER OF MEDICAL
SCIENCES AT HARVARD.
HE DID A RESIDENCY AT BETH
ISRAEL DEACONESS MEDICAL CENTER
IN BOSTON AND BECAME AN
ASSISTANT INVESTIGATOR, STAFF
PHYSICIAN AT THE JOSLIN DIABETES
CENTER AND THEN ASSISTANT
PROFESSOR OF MEDICINE AT HARVARD
MEDICAL SCHOOL UNTIL 2014.
WHEN HE WAS RECRUITED TO THE
NATIONAL INSTITUTES OF DIABETES,
DIGESTIVE DISEASE AND KIDNEY AS
THE ACTING CHIEF OF THE
TRANSLATIONAL PHYSIOLOGY SECTION
IN THE DIABETES, ENDOCRINE AND
OBESITY BRANCH OF NIDDK.
SO AARON RESEARCHES WHITE AND
BROWN FA FAT STRUCTURE, PHYSIOL,
RELATION TO METABOLIC DISEASE,
AND SEEKS TO DEVELOP
PHARMACOLOGIC TREATMENT OF
OBESITY-RELATED METABOLIC
DISEASES, AND IN THIS PROCESS,
HE ALSO USES EXTENSIVELY
CLINICAL TRIALS BASED TO A GREAT
EXTENT IN THE CLINICAL CENTER AT
THE NIH.
HIS APPROACH IS ONE OF
INTEGRATIVE PHYSIOLOGY, USING IN
VITRO AND IN VIVO MODELS AS WELL
AS CLINICAL TRIALS, AND THEY'VE
DEVELOPED NONINVASIVE IMAGING
TECHNIQUES FOR THE
QUANTIFICATION OF BROWN FAT MASS
AND ACTIVITY.
AND HAVE DEVELOPED THERAPEUTIC
ATTEMPTS TO INCREASE BROWN FAT
METABOLIC ACTIVITY AND CLINICAL
USE.
OUR SECOND SPEAKER, NEXT SLIDE,
PLEASE, IS KEVIN HALL.
SO KEVIN IS A PHYSICIST, AND HE
HAS APPLIED A PHYSICIST'S VIEW
TO THE UNDERSTANDING OF ENERGY
EXPENDITURE AND EXPERIMENTAL
MODELS, IN MATHEMATICAL MODELS,
AND IN STUDIES, EXTENSIVE
STUDIES, IN HUMAN PATIENTS.
HE RECEIVED A PH.D. IN PHYSICS
FROM MCGILL UNIVERSITY, AND FROM
2003 TO THE PRESENT TIME, IS A
SENIOR INVESTIGATOR IN THE
INTEGRATIVE PHYSIOLOGY SECTION
IN THE LABORATORY OF BIOLOGICAL
MODELING AT THE NATIONAL
INSTITUTE OF DIABETES, DIGESTIVE
DISEASE AND KIDNEY.
KEVIN HEADS A TEAM OF
MATHEMATICIANS, NEUROSCIENTISTS,
DIETITIANS AND CLINICIANS, WHO
STUDY AND MODEL ENERGY
EXPENDITURE AND BODY COMPOSITION
WHEN DIETS AND PHYSICAL ACTIVITY
ARE ALTERED.
THE RESULTS HAVE SHAKEN SOME
LONG-HELD BELIEFS, AND WE WILL
HEAR MORE ABOUT THIS.
KEVIN HAS ALSO DEVELOPED A MODEL
WHICH HAS BEEN USED BY MILLIONS
OF PEOPLE FOR PREDICTING
LIFESTYLE CHANGES THAT ARE
NEEDED IN ORDER TO REACH AND
MAINTAIN A WEIGHT GOAL.%
SO IN THESE STUDIES, THEY'VE
USED FUNCTIONAL MRI, MEASURED
BRAIN LOCALIZATION AND ACTIVITY
IN RELATION TO SEEING OR
INGESTING VARIOUS FOODS.
THE APPLICATION OF A PHYSICIST'S
APPROACH TO THE STUDY OF ENERGY
EXPENDITURE HAS LED TO RESULTS
THAT WERE COMPLETELY
UNANTICIPATED.
AND WHICH HE WILL SHARE WITH US
TODAY.
SO OUR FIRST SPEAKER NOW IS
AARON CYPESS, AND AARON, WILL
YOU PLEASE TAKE THE BATON.
>>THANK YOU, DR. ARIAS, FOR
THAT DETAILED AND OUTSTANDING
INTRODUCTION TO OUR WORK.
I WANT TO THANK YOU AND
DR. KASTNER AND THE ENTIRE TEAM,
INCLUDING KENNY AND JOY, FOR
INVITING ME HERE AND MAKING IT
POSSIBLE FOR US TO TALK ABOUT
OUR RESEARCH.
FAT BIOLOGY AND STAYING THIN IS
SOMETHING I'VE BEEN THINKING
ABOUT FOR OVER THREE DECADES IN
MY PROFESSIONAL CAREER, AND I'M
GOING TO FOCUS TODAY ON THE
POLYCHROMATIC HUMAN ADIPOSE
TISSUE, STRUCTURE AND
DYSFUNCTION.
AS MY DISCLOSURE, I WILL BE BE
DESCRIBING THE USE OF A
MEDICATION MIRABEGRON, ABOVE TE
FDA'S APPROVED DOSE FOR
OVERACTIVE BL BLADDER.
THE OBJECTIVES TODAY, FIRST I'D
LIKE TO IDENTIFY THE MULTIPLE
TYPES AND SITES OF HUMAN ADIPOSE
TISSUE.
THEN WE'LL SUMMARIZE THE CURRENT
KNOWN PHYSIOLOGICAL ROLES OF
WHITE AND BROWN ADIPOSE TISSUE,
OR WAT AND BAT, OR WHITE FAT AND
BROWN FAT.
THEN WE'LL EXPLAIN THE
CONNECTIONS BETWEEN THE BRAIN
AND FAT IN LEADING TO OBESITY
AND ITS COMPLICATIONS.
AND THEN BY THE END, HOPEFULLY
DEVELOP A HYPOTHESIS AS TO HOW
CHRONIC TREATMENT WITH BETA
3 ADRENERGIC RECEPTOR AGONISTS
WILL IMPACT GLUCOSE AND
LIPOPROTEIN HOMEOSTASIS.
SO I'LL BEGIN WITH A SLIDE THAT
DR. ARIAS REFERRED TO, THAT
THERE IS AN INCREASE IN THE
RATES OF OBESITY AND DIABETES IN
OUR COUNTRY, IT'S A SLIDE MANY
OF YOU HAVE PROBABLY SEEN
BEFORE, AND THE FACT THAT
THEY'RE MOVING IN PARALLEL
INDICATES THAT POSSIBLY TOO MUCH
FAT IS UNHEALTHY.
THABUT IS TOO MUCH FAT UNHEALTH?
IT'S NOT REALLY THAT SIMPLE.
IT'S TIME TO RE-ASSESS.
SO I'M GOING TO START THE TALK
BY GOING THROUGH SOME OF THE
MATERIAL THAT I WROTE ABOUT IN A
REVIEW ARTICLE IN THE NEW
ENGLAND JOURNAL OF MEDICINE
PUBLISHED LAST YEAR, AND IT'S
AVAILABLE FREE ONLINE.
NOW HUMAN WHITE AND BROWN FAT
ARE FOUND THROUGHOUT THE BODY
BUT LOOKS CAN BE DECEIVING SO
WE'LL START WITH THE STRUCTURE.
SO HERE IS THE FRONTAL VIEW OF A
HUMAN.
YOU CAN SEE HERE IN ORANGE IS
THE SUBCUTANEOUS FAT, DIFFERENT
REGIONS ARE INDICATED HERE, AND
THE HEAD, THE DRA CRANIAL REGIO,
THE LIMB, AND THE GLUTEOFEMORAL
RENAL.
THERE ARE BROWN FAT AS WELL,
BROWN AND BEIGE ADIPOCYTES, THE
NECK, THE SHOULDER, ARMPIT, DOWN
THE SPINE AND AROUND THE
KIDNEYS.
WHITE FAT ALSO HAS A VISCERAL
FLAVOR, AS IT WERE, AND THAT IS
THE INTERNAL ORGANS, THEIR FAT,
AND YOU CAN SEE HERE THERE'S
EPICARDIAL, OMENTAL, MESENTERIC,
PARIRENAL, GONADAL, THEY HAVE A
DIFFERENT STRUCTURE.
IN THIS THIRD VIEW, THE AXIAL
VIEW, THIS IS A CUT THROUGH THE
CENTER OF THE BODY, ONE CAN SEE
THAT LOOKS CAN BE DECEIVING.
SHOWN HERE IS A 37-YEAR-OLD MAN
WHO HAS A WAIST CIRCUMFERENCE OF
91 CENTIMETERS, THAT'S ABOUT
36 INCHES.
SHOWN HERE IS A MAN WHO'S
82 YEARS OLD, WHOSE WAIST
CIRCUMFERENCE IS THE SAME.
BUT WHEN YOU LOOK INSIDE, YOU
CAN SEE THERE'S FAR MORE
SUBCUTANEOUS FAT, WHICH IS
EITHER NEUTRAL OR EVEN POSITIVE
FOR HEALTH.
WHEREAS THIS INDIVIDUAL AT
82 HAS MUCH MORE VISCERAL FAT,
WHICH IS MORE LIKELY TO BE
NEGATIVE IN TERMS OF AFFECTING
HIS HEALTH.
AND SO HUMAN WHITE FAT BEGINS TO
DEVELOP IN THE SECOND TRIMESTER
OF PREGNANCY, AND BY BIRTH, BOTH
THE VISCERAL AND THE
SUBCUTANEOUS DEPOTS ARE WELL
ESTABLISHED.
THE BROWN FAT OR BAT FIRST
ARISES DURING THE LATE SECOND
TRIMESTER, AND PROTECTS NEWBORNS
FROM COLD WHILE THEY DEVELOP THE
ABILITY TO SHIVER.
IN LEAN ADULTS, THE ENTIRE WHITE
FAT DEPOT RANGES FROM 20 TO
30 KILOGRAMS IN WOMEN, THAT'S 30
TO 40% OF TOTAL BODY MASS.
AND IN MEN, 10 TO 20 KILOGRAMS
OR 15 TO 25% OF TOTAL BODY MASS.
SO YOU CAN APPRECIATE THAT THE
ADIPOSE TISSUE DEPOT IS ONE OF
THE LARGEST IF NOT THE LARGEST
ORGAN IN THE BODY.
NOW, IN THE ADIPOSE TISSUES, THE
FORM FOLLOWS THE FUNCTION.
WHITE ADIPO CYTES STORE ENERGY.
IT HAS IMPORTANCE FOR THERMAL
INSULATION.
THEY'VE SHOWN THAT WHITE FAT IS
IMPORTANT FOR KEEPING US WARM
JUST BY FORMING A PROTECTIVE
BLANKET.
IN ADDITION, THERE IS MECHANICAL
PROTECTION, AND WHITE FAT HAS
DR. ARIAS MENTION IS INVOLVED AS
AN ENDOCRINE ORGAN AND I'LL SHOW
YOU MORE DETAILS ABOUT THAT.
ON THE OTHER END ARE BRIGHT
ADIPOCYTES, ORGANELLES INVOLVED
IN ATP, CHEMICAL ENERGY AND ALSO
HEAT AND THE BEIGE CELLS ARE IN
BETWEEN.
BOTH CELL TYPES, THE WHITE AND
THE BROWN, CAN GENERATE HEAT AS
I'LL SHOW YOU IN A MOMENT.
SO THERE'S THE WHITE THAT STORE
ENERGY, THE BROWN THAT EXPEND
ENERGY, AND THEN THESE BEIGE OR
BRITE CELLS IN BETWEEN.
THEY RESPOND TO BOTH COLD AND
ADRENERGIC STIMULATION, MEANING
EPINEPHRINE, NOREPINEPHRINE, AND
THEY CAN TRANSITION FROM AN
ENERGY STORING FOR AN ENERGY
EXPENDING TYPE OF CELL.
HOW DOES IT HAPPEN?
LET'S GO BACK TO YOUR HIGH
SCHOOL CHEMISTRY AND
BIOCHEMISTRY CLASSES, AND YOU
CAN SEE HERE THAT TH THIS LEADSO
THE PRODUCTION OF HYDROGEN ATOMS
THAT GET SPLIT AND THE PROTONS
GO TO THE INTERMEMBRANE SPACE,
TAKEN UP BY OXYGEN TO MAKE
WATER, AND THOSE PROTONS GO DOWN
THESE PROTEINS HERE TO GENERATE
ATP.
BUT IN A BROWN ADIPOCYTE,
UPC1 ALLOWS THOSE PROTONS TO
RUSH RIGHT BACK IN TO THE
MITOCHONDRIAL MATRIX.
WHEN THAT HAPPENS, THERE'S NO
LONGER A BACK PRESSURE OF
PROTONS, AND THAT LEADS THE TCA
CYCLE AND ELECTRON TRANSPORT
CHAIN TO START GOING VERY, VERY
QUICKLY, AND THAT GENERATES A
LOT OF HEAT.
BY ANALOGY, IF YOU WERE IN YOUR
CAR AND YOU SHIFTED FROM DRIVE
TO NEUTRAL AND THEN YOU PUT YOUR
FOOT ON THE ACCELERATOR, A LOT
OF FUEL WOULD GO THROUGH THE
SYSTEM, THERE WOULDN'T BE ANY
ENERGY BEING CONVERTED TO
ANYTHING BUT HEAT.
AND THERE ARE NEW PROCESSES OF
GENERATING HEAT SHOWN BY BRUCE
SPIEGELMAN WHERE THEY'VE SHOWN
THERE'S ALSO SUPPER
STOICHIOMETRIC FUTILE CYCLING.
THERE'S ALSO SOMETHING CALLED
TRIGLYCERIDE FATTY ACID CYCLING,
BROKEN DOWN TO FATTY ACIDS BUT
REBUILT, BROKEN DOWN AND REBUILT
IN A CYCLE.
ALL THAT'S HAPPENING HERE IS A
FUTILE PRODUCTION OF HEAT.
IF THAT'S WHAT THE CELL WANTS,
IT'S VERY IMPORTANT, SO AS YOU
CAN SEE HERE, THERE ARE SEVERAL
MECHANISMS IN BOTH BROWN FAT AND
WHITE FAT FOR GENERATING HEAT.
WHICH ONES ARE ACTIVE, WHAT THE
PROPORTIONS ARE, AND HOW DO YOU
TURN THEM ON AND OFF ARE AREAS
OF ACTIVE INVESTIGATION.
NOW YOU HAVE TO REMEMBER THAT
WHITE FAT AND BROWN FAT JUST
LIKE EVERY OTHER TISSUE IN THE
BODY ARE MADE UP OF A DIVERSITY
OF CELL TYPES.
WHITE FAT HAS MANY.
AS YOU CAN SEE HERE, THERE ARE
ADIPOCYTES, BUT WHITE FAT HAS A
LOT OF MACROPHAGES, IMMUNE
CELLS, T-CELLS, B CELLS, THERE'S
ALSO BLOOD CELLS AND BLOOD
VESSELS.
THERE'S ALSO EOSINOPHILS,
DENDRITIC CELLS FOR THE IMMUNE
SYSTEM, AND THEN THERE'S THE ECM
OR EXTRACELLULAR MATRIX AND
THESE ARE PROTEINS AND OTHER
KINDS OF MOLECULES THAT PROVIDE
STRUCTURE AND SUPPORT BUT IT'S
ACTIVE.
THE ECM IS IN COMMUNICATION WITH
THE CELLS WITHIN THISH TISSUE. .
THERE ARE DOZENS OF FACTORS
RELEASED AND THEY PROFOUNDLY
IMPACT ORGANS THROUGHOUT THE
BODY.
SHOWN HERE ARE FACTORS RELEASED
BY THE WHITE FAT, BOTH THE WHITE
ADIPOCYTES AND THE OTHER CELLS.
THERE ARE ADIPOKINES, YOU'VE
HEARD OF LEPTIN PERHAPS, THERE
ARE MANY AS WELL, CYTOKINES,
ENZYMES, COMPOUNDS INVOLVED IN
LID I ID TRANSPORT AND OTHER
FACTORS AS WELL.
SO THERE'S OVER 50 AND THESE ARE
JUST A FEW HERE.
AND THEY AFFECT EVERY ORGAN IN
THE BODY PRACTICALLY.
IN THE BRAIN, THE HORMONES IN
THE WHITE FAT CAN FEEDBACK AND
IMPACT APPETITE, SENSES OF
SATIETY, ENERGY EXPENDITURE, THE
IMMUNE SYSTEM, THE
CARDIOVASCULAR SYSTEM, LIVER,
PANCREAS, THE GASTROINTESTINAL
TRACT IN TERMS OF AB SORNTION, D
MUSCLES AS WELL JUST TO NAME A
FEW OF THE ORGAN SYSTEMS
INVOLVED.
NOW THE ROLES OF HUMAN BROWN
ADIPOSE TISSUE ARE ONLY
BEGINNING TO BE DISCOVERED.
WHAT'S FASCINATING TO ME IS THAT
THE BROWN ADIPOCYTES ARE PACKED
WITH MITOCHONDRIA.
THERE ARE SACKS OF MITOCHONDRIA.
SHOWN HERE IS AN EOSINE STAIN
AND YOU CAN SEE THESE ARE
INDIVIDUAL CELLS I'M DRAWING OUT
AND THESE ARE THE LIPID
DROPLETS.
IF YOU USE A HIGHER
MAGNIFICATION, YOU CAN SEE ONE
BROWN AD ADIPOCYTE, HERE ARE LID
DROPLET'S USED AS FUEL, AND
EVERY OTHER LITTLE BROWN CIRCLE
HERE, EVERY LITTLE GREY SITE IS
A MITOCHONDRIAN.
NOW THE MAXIMUM DETECTABLE BROWN
ADIPOSE TISSUE MASS ON A HUMAN
WE'VE SEEN SO FAR IS ROUGHLY
1-KILOGRAM OR JUST OVER 2 POUNDS
BUT USUALLY BASED ON OUR IMAGING
IT'S FROM 50 TO 500 GRAMS, WHICH
IS LESS THAN A POUND, .1 TO .5%
OF TOTAL BODY MASS AND .2 TO 3%
OF TOTAL ADIPOSE TISSUE.
AND WE'RE JUST BEGINNING TO
IDENTIFY THE ADD POE KINES, THE
HORMONES RELEASED BY BROWN
ADIPOSE TISSUE.
CAN YOU SEE SOME IN THE DIAGRAM
OVER HERE.
I LIKE TO FOCUS IN PARTICULAR ON
12, 13DIHOME AND 12HEPE, AND
THESE HAVE BEEN IDENTIFIED
SAYING A COLLEAGUE AND
COLLABORATOR AT JOSLIN DIABETES
CENTER IN BOSTON, AND THESE GO
TO OTHER TISSUES AND CAUSE
RELEASE OF THE UPTAKE OF FATTY
ACIDS AND GLUCOSE INTO THOSE
TISSUES.
THE FLIP SIDE IS WHEN TR
TRIGLYCERIDES ARE IN EXCESS OR
STORED INCORRECTLY, IT CAN LEAD
TO COMPLICATIONS.
SHOWN HERE IS A DIAGRAM
DISPLAYING THE VARIOUS
COMPLICATIONS IN THE DIFFERENT
ORGAN SYSTEMS FROM OBESITY.
AND HOW THIS HAPPENS IS THAT
WHITE ADIPOCYTES CAN SWELL ON
THE BASELINE OF ROUGHLY 30, 40
40 MICRONS ACROSS TO OVER
100 MICRONS.
THAT'S A 10 TIMES INCREASE IN
VOLUME.
NOW THE ANATOMICAL LOCATION AND
GENETICS LARGELY DETERMINE THE
PROPORTIONAL INCREASE IN THE
ADIPOCYTE SIZE AND NUMBER AS
WELL AS THE PHYSIOLOGICAL
RESPONSES THAT CAN BE SEEN.
SO FOR EXAMPLE, PEOPLE WHOSE
SUBCUTANEOUS DEPOTS MAINTAIN
SMALLER ADIPOCYTES HAVE FEWER
METABOLIC COMPLICATIONS.
OTHERS HAVE A GENETIC INABILITY
TO RECRUIT NEW ADIPOCYTES SO
THEY INSTEAD GO TO THE REST OF
THE BODY AND CAUSE ADDITIONAL
COMPLICATIONS SUCH AS STROKE,
CATARACTS, PROBLEMS IN THE
LUNGS, GASTROINTESTINAL TRACT,
CARDIOVASCULAR WE KNOW ABOUT,
MUSCULOSKELETAL SYSTEM AS WELL.
SO ULTIMATELY, WHAT HAPPENS IS
THAT WHEN THAT WHITE FAT BECOMES
VERY LARGE OR HYPERTROPHIC, AND
EXPANDS, THE PROBLEM IS THAT
THERE'S NOT ENOUGH OXYGEN
GETTING TO THE CELLS.
THERE ARE OTHER PROBLEMS WITH
THE -- INSIDE THE CELLS AS WELL,
FOR EXAMPLE, THERE'S THE
UNFOLDED PROTEIN RESPONSE IN THE
ENDO PLASMIC RETICULUM, BUT IT'S
THE HYPOXIA THAT'S A REAL
PROBLEM, BECAUSE WHAT HAPPENS
IS, THAT HYPOXIA IS A BIOLOGICAL
RED ALERT FOR THE CELLS AND IT
ALTERS THE EXPRESSION OF MORE
THAN A THOUSAND GENES AND
TRIGGERS A SERIES OF
INTERCONNECTED RESPONSES THAT
LEAD TO LOCAL RESISTANCE TO
INSULIN SIGNALING, INCREASED
INFLAMMATION, AND CELLULAR
DAMAGE.
HOWEVER, AS THE TITLE INDICATES,
IT'S REALLY USEFUL TO
CONCEPTUALIZE OBESITY AS A
DISEASE ORIGINATING IN THE BRAIN
THAT IS MANIFESTED MORE AS AN
EXCESS OF WHITE ADIPOSE TISSUE
AND A DYSFUNCTIONAL BROWN
ADIPOSE TISSUE.
AND STUDYS HAVE SHOWN THAT
THERE'S A PERNICIOUS CYCLE THAT
ACCELERATES THE DEVELOPMENT OF
OBESITY ONCE A PERSON HAS BEGUN
TO GAIN WEIGHT.
AND IN THE BRAIN IN PARTICULAR,
IT'S THE HYPOTHALAMIC REGION
THAT'S OF INCREASING INTEREST
BECAUSE IT INTEGRATES MULTIPLE
PHYSIOLOGICAL SIGNALS FROM THE
BODY, AND THEN TRANSMITS THEM TO
DIFFERENT BRAIN REGIONS AND
COORDINATE THE REGULATION OF
DIVERSE PROCESSES, INCLUDING
BODY TEMPERATURE AND FEEDING.
AS YOU CAN IMAGINE, CHILLED WITH
OBESITY ARE AT RISK AS SHOWN BY
THIS DIAGRAM AND EVEN MORE
TROUBLING IS THE RATES OF
OBESITY ARE INCREASING MUCH
FASTER AMONG CHILDREN THAN AMONG
ADULTS.
CERTAINLY IN OUR COUNTRY AND
WORLDWIDE.
AND CHILDREN WITH OBESITY ARE
MORE LIKELY TO BECOME ADULTS WHO
HAVE A HIGH RISK OF SEVERE
HEALTH COMPLICATIONS.
WE NEED TO DO SOMETHING ABOUT
IT.
AND I'M GOING TO GO TO ONE PART
OF THAT AND THAT'S ON THE BROWN
ADIPOSE TISSUE, SOMETHING THAT
I'VE BEEN STUDYING FOR NEARLY
TWO DECADES, AND SO I'M GOING TO
GO INTO SOME RELEVANT RECENT BAT
HISTORY.
AND THE MODERN ERA OF BAT
STUDIES BEGAN IN 2002, AND AN
ENTIRELY DIFFERENT AREA FROM
METABOLISM AND THAT IS IN THE
AREA OF RADIOLOGY AND CANCER
SURVEILLANCE.
AND IT WAS FOUND THAT ADULT
HUMANS HAD SOMETHING -- A
GLUCOSE-AVID ADIPOSE TISSUE,
WHICH SUGGESTED THERE MIGHT BE
FUNCTIONAL BAT.
AND THE REASON THIS WAS POSSIBLE
IS THAT PREVIOUSLY, PEOPLE WERE
USING COMPUTED TOMOGRAPHY,
THAT'S A THREE-DIMENSIONAL X-RAY
THAT GIVES STRUCTURE AS AN
EXAMPLE SHOWN HERE, HERE'S THE
HEART, HERE'S THE LIVER, THE
LUNGS.
THERE'S THE RIBCAGE OF THIS
32-YEAR-OLD MAN.
AND THEN THERE'S SOMETHING
CALLED PET IMAGING, THAT'S
POSITRON EMISSION TOMOGRAPHY,
ONE CAN LABEL GLUCOSE, FOR
EXAMPLE, AS A TRACER, AND IT
SHOWS WHAT'S FUNCTIONALLY
ACTIVE.
FOR EXAMPLE, IN THIS PERSON OVER
HERE, YOU CAN SEE THERE'S A LOT
OF GLUCOSE GOING INTO THE HEART,
TAKING UP A LOT OF GLUCOSE AS IT
PUMPS, IT GOES INTO THE BRAIN
AND THEN CURIOUSLY INTO THESE
CELLS THAT ARE LYING IN THE
UPPER CHEST.
THE ABILITY TO FUSE THE CT AND
PET TOGETHER INTO A PET/C T
OPENED THE DOORS TO AN ENORMOUS
AMOUNT OF EXCITEMENT AND
RESEARCH ACTIVITY BECAUSE IT WAS
DETERMINED THAT THESE CELLS,
THESE TISSUES THAT WERE TAKING
UP A LOT OF THE GLUCOSE AND THE
IMAGE WAS FUSED, IT TURNED OUT
IT WAS FAT.
IT WASN'T MUSCLE, IT WASN'T
TUMOR.
SO THAT SUGGESTS THERE WAS
FUNCTIONAL BROWN FAT WHICH HAD
BEEN DENIED IN HUMANS.
I WAS VERY EXCITED BY THIS SO AT
THE END OF MY ENDOCRINE
FELLOWSHIP, I PRESENTED THE
SLIDES SAYING THERE MIGHT BE
BROWN FAT IN ADULT HUMANS.
HOW EXCITING WOULD THAT BE?
WELL, I WAS CHALLENGED AT THE
END OF THE TALK AND I WROTE BACK
IN EMAIL TO ONE OF THE
CHALLENGERS AND SAID YOU BELIEVE
THERE'S NO SIGNIFICANT BROWN FAT
IN ADULT HUMANS AND THAT WHAT
WE'RE SEEING ON THOSE PET/CT
SCANS IS NOT BROWN FAT?
AND HE WROTE BACK, YES, THAT'S
PRETTY MUCH IT.
I WILL BE VERY SURPRISED IF
THOSE PET IMAGES WERE BROWN FAT
DEPOSITS.
THIS IS A HARVARD MEDICAL SCHOOL
ENDOCRINOLOGIST SO THIS WAS
REALLY IMPORTANT AND SOMEWHAT
DISPERIODISSPIRITTING AT THE TI.
BUT I RECEIVED ENCOURAGEMENT
FROM SOMEBODY ELSE, A HARVARD
MEDICAL SCHOOL RADIOLOGIST.
I WROTE TO HIM AND SAID, IN
THOSE FDG-PET SCANS YOU VERY
OFTEN SEE FALSE POSITIVE SIGNALS
FROM BROWN FAT.
HOW DO WE KNOW THAT IT'S BROWN
FAT?
AND HE SAID, BECAUSE EVERYONE
SAYS SO.
SO THIS WAS THE STATE OF THE
FIELD BACK IN 2006.
AND LED US TO GET WORKING AND
SHOW THAT WHAT WE WERE SEEING ON
THOSE IMAGES TRULY WAS BROWN
FAT.
IT WASN'T JUST OUR GROUP.
FIVE PAPERS CAME OUT IN THE SPAN
OF ONE MONTH IN 20 2009 PUBLISH
DOLLARS IN THE NEW ENGLAND
JOURNAL OF MEDICINE AND OTHER
SOURCES AND IT WAS FOUND THAT
BROWN FAT WAS PREDOMINANTLY IN A
FEW SPECIFIC REGIONS OF THE
BODY, NOT EVERYWHERE, BUT WE CAN
FINALLY MEASURE IT
NON-INVASIVELY VIA PET/CT AND
FINALLY UNDERSTAND THE TISSUE IN
REALTIME.
WHAT WE LEARN FUNCTIONALLY, IT
PROTECTS AGAINST THE COLD
ACUTELY AND CHRONICALLY,
NON-SHIVERING THERM ROW GENESIS.
NOW NOISE THERE'S A TISSUE
KEEPING US WARM WITHOUT MAKING
US FEEL UNCOMFORTABLE.
PEOPLE WITH BROWN FAT BASED ON
RETROSPECTIVE BACKWARD LOOKING
STUDIES, PEOPLE WITH MORE BROWN
FAT WERE FREQUENTLY FEMALE,
YOUNGER, LEANER, AND NOT TAKING
BETA-BLOCKER MEDICATIONS, WHICH
MEANS THAT BROWN FAT COULD BE
AFFECTED BY MEDICATIONS.
AND FINALLY, IT APPEARED THAT
NEARLY EVERY ADULT HUMAN HAS
SOME BROWN FAT.
IT'IT'S REALLY THERE, AND THEY E
A BIG IMPACT ON OUR PHYSIOLOGY.
AND IN THE 10 YEARS SINCE THEN,
A LOT OF EXCITING RESEARCH HAS
BEEN DONE USING RODENT MODELS.
SHOWN HERE IS INFORMATION ABOUT
CHOLESTEROL PROFILE AND
CARDIOVASCULAR RISK, DONE BY
GROUPS LED BY PATRICK RENSEN IN
THE NETHERLANDS, VIRTANEN IN
FINLAND.
BASICALLY WHAT WE SHOWED IN A
PARTICULAR MOUSE MODEL, THAT
BROWN FAT ACTIVATION INCREASES
ENERGY EXPENDITURE BUT IT ALSO
DECREASES PLASMA TRIGLYCERIDES
AND REDUCES CHOLESTEROL LEVELS,
LEADING TO HEALTH BENEFIT.
THEN IN A SERIES OF STUDIES
CONDUCTED IN GERMANY, THEY
SHOWED A FASCINATING NEW AXIS, A
BROWN FAT, LIVER, GUT MICROBIOME
AXIS.
SO WHAT HAPPENS IS, COLD
EXPOSURE ACTIVATES BROWP FAT, B,
AND CAUSES THE FAT IN OUR FOOT
AFTER EATING, POSE PRANDIALLY,
UPTAKE IN BROWN FAT.
THIS ACCELERATES CHOLESTEROL
UPTAKE INTO THE LIVER.
BAT ACTIVATION CAUSES INCREASED
SYNTHESIS OF BILE ACIDS, WHICH
YOU MAY KNOW OF AS SMALL
DETERGENTS MADE BY THE BODY THAT
HELP ABSORB FAT.
THEY DO MORE THAN THAT.
THEY GO INTO THE GUT AND AFFECT
THE MICROBIOME AND THAT'S VERY
IMPORTANT FOR OVERALL HEALTH.
THEN A RETROSPECTIVE STUDY
CONDUCTED BY PAUL COHEN'S GROUP
PUBLISHED TWO YEARS AGO, THEY
LOOKED AT OVER 50,000 PATIENTS
AND FOUND THAT PEOPLE WITH BROWN
FAT HAD LOWER RATES OF TYPE
2 DIABETES, DYSLIPIDEMIA,
CORONARY ARTERY DISEASE,
CARDIOVASCULAR DISEASE,
CONGESTIVE HEART FAILURE, AND
HYPERTENSION.
SO THEY SAID THEIR STUDY
INDICATES AN IMPORTANT
CONTRIBUTION OF BAT IN HUMANS TO
CARDIOMETABOLIC HEALTH AND
SUGGESTS THAT BAT HAS
THERAPEUTIC POTENTIAL IN HUMANS.
WE'RE IN THE RIGHT PLACE.
SO WHEN ONE DISCOVERS A NEW
FUNCTIONAL ORGAN IN HUMANS THAT
HAS THE POTENTIAL OF IMPACTING
HUMAN HEALTH NEED TO BUILD A
RESEARCH PLATFORM THIS IS WHAT
WE'VE DONE.
OURS RESTS ON THREE PILLARS.
NONINVASIVE IMAGING, INTEGRATIVE
PHYSIOLOGY, AND THERAPEUTICS,
AND ALL THREE IMPACT EACH OTHER.
SO ON THE IMAGING SIDE, WE WANT
TO MEASURE BROWN FAT MASS AND
ACTIVITY, WE USE PET/CT AS I
SHOWED YOU AND I'LL SHOW YOU
SOME IMAGES IN OUR STUDIES,
WE'RE DEVELOPING MRI IN
COLLABORATION WITH COLLEAGUES
HERE AT THE NIH, AND USING
ULTRASOUND.
ON THE OTHER SIDE, YOU NEED TO
UNDERSTAND MECHANISM, AND WHILE
ONE CAN USE CLINICAL TRIALS, ONE
CAN GET MUCH MORE DETAILED AND
WELL DESIGNED STUDIES USING
HUMAN AND RODENT MODELS TO LOOK
AT BIOINER JE TICS, THE HEAT
BEING GENERATED, BIOINFORMATICS,
AND INTERVENTIONAL THROUGH GENE
EDITING AND REGULATION.
THEN WE CAN GO FROM THE BED TO
THE BENCH BACK TO BED AND DO
THERAPEUTIC TRIALS WHERE YOU USE
MILD COLD EXPOSURE AND IN
PARTICULAR, BETA THREE
ADRENERGIC RECEPTOR AGONISTS, IN
PARTICULAR, MIRABEGRON, WHICH I
WILL SHOW YOU.
SO HOW DO YOU ACTIVATE BROWN
FAT?
COLD EXPOSURE IS WHAT'S COMMONLY
USED.
THIS IS ME TESTING OUT A SYSTEM
BACK IN 2010.
WHEN WE FIRST WANTED TO USE COLD
EXPOSURE WE WEREN'T SURE BEST
HOW TO DO IT.
THANKS TO NUMEROUS CONVERSATIONS
AND ASSISTANCE FROM MARTIN T
TORRIANI AND GRINSPOON,
COLLEAGUES AND COLLABORATORS, WE
IDENTIFIED THIS VEST SYSTEM AND
WE WERE ABLE TO INFUSE WATER
THROUGH THESE TUBES HERE.
YOU CAN SEE TUBES ON A VEST THAT
I'M WEARING AND WE'RE ABLE TO
INCREASE THE BROWN FAT
ACTIVATION.
WE MOVE TO A PHARMACOLOGICAL
APPROACH, SO WHY DO THAT?
FOR ONE THING, A PHARMACOLOGICAL
APPROACH ALLOWS FOR POTENTIAL
FOR MORE SPECIFIC TARGETING OF
HUMAN BROWN FAT.
AS I'LL GO INTO MORE DETAIL, THE
BETA THREE ADRENERGIC REACCEPT
PORE IS EX-TRESSED IN VERY FEW
ORGANS BUT BROWN FAT IS ONE OF
THEM.
ANIMAL MODELS SHOW THEY ARE VERY
EFFECTIVE IN METABOLIC HEALTH.
THERE'S LIKELY TO BE GREATER
ADHERENCE FROM A PATIENT
POPULATION IF THEY HAVE TO TAKE
A FEW PILLS RATHER THAN HAVING
TO SIT IN THE COLD FOR TWO OR
EVEN SIX HOURS A DAY.
AND IN THE END, ACCOMMODATIONS
OF APPROACHES MAY BE NECESSARY.
THE FACT IS THAT COLD MAY BE
HELPFUL WITH USING DRUGS OR
MULTIPLE MEDICATIONS TOGETHER.
SO I'M GOING TO TALK ABOUT THE
BETA 3 ADRENERGIC RECEPTOR
AGONISTS.
THEY CAN BE USED WIDELY IN
HUMANS AND THAT WASN'T TRUE
UNTIL 2012.
AND IT CAME FROM, AGAIN, A VERY
DIFFERENT AREA OF MEDICINE.
THIS TIME UROLOGY.
TURNS OUT OVER 45 MILLION PEOPLE
IN THE UNITED STATES ARE
AFFECTED BY OVERACTIVE BLADDER,
AND THAT'S COMPARED FOR EXAMPLE
TO 26 MILLION WITH TYPE 1 AND
TYPE 2 DIABETES COMBINED.
NOW THERE ARE BETA 3 ADRENERGIC
RECEPTORS IN THE URINARY
BLADDER.
ACTIVATION OF THESE RECEPTORS
RELAXES THE BLADDER AND THEN
ALLOWS TO HOLD MORE URINE AND SO
SOMEONE DOESN'T HAVE TO RUN TO
THE BATHROOM THAT FREQUENTLY.
NOW THIS IS MEDICATION
MIRABEGRON, A BETA THREE
ADRENERGIC RECEPTOR AGONIST AND
WAS APPROVED IN 2012 BY THE FDA
FOR TREATMENT OF OVERACTIVE BLAH
TER AT MAXIMUM DOSAGE OF
50 MILLIGRAMS DAILY.
AS I MENTIONED THERE ARE ALSO
BETA THREE ADRENERGIC RECEPTORS
IN BOTH HUMAN WHITE AND BROWN
FAT.
SO WE WANTED TO DO A PROOF OF
CONCEPT STUDY DESIGN AND THIS
WAS LED BY LAUREN WEINER,
DR. WEINER NOW, AND IN THIS
STUDY, WE WANTED TO SEE THE
EFFECTS OF MIRABEGRON ON 12
YOUNG, LEAN, HEALTHY MEN.
WE WANTED TO SEE IF IT COULD
ACTIVATE THE BROWN FAT AND
INCREASE THERMOGENESIS.
SO WE CONDUCTED THE STUDY WITH
PLACEBO AS THE NEGATIVE CONTROL,
MILD COLD AS THE POSITIVE
CONTROL, AND BY TESTING OUT THIS
VEST SYSTEM THAT I SHOWED YOU
PREVIOUSLY.
AND THEN WE GAVE MIRABEGRON AT
200 MILLIGRAMS, A ONE-TIME DOES.
WE CHOSE THAT DOSE BECAUSE WE
DIDN'T WANT A FALSE NEGATIVE
SIGNAL SO WE CHOSE THE HIGHEST
DOSE HIGHEST IN CLINICAL TRIALS,
SAFE IN MEN BUT NOT IN WOMEN SO
WE HAD TO STUDY MEN FIRST.
WE EVENTUALLY STUDIED WOMEN AS
I'LL SHOW YOU LATER.
IN THIS STUDY WE MONITOR VITAL
SIGNS, ENERGY EXPENDITURE AND
MEASURED BROWN FAT METABOLIC
ACTIVITY.
THE FIRST THING WE IDENTIFIED
WAS THAT THERE WAS AN INCREASE
IN ENERGY EXPENDITURE, 200 KILL
CALORIES PER DAY, THE HIGHEST
WITH THE MIRABEGRON IN BLACK,
BOTH VERY EFFECTIVE AS WE
EXPECTED.
ALSO AN INCREASE IN SYSTOLIC
BLOOD PRESSURE IN BOTH THE
MIRABEGRON IN BLACK AND COLD
EXPOSURE IN GREY THAT WE KNEW
WOULD HAPPEN AND THAT'S WHY WE
CANNOT USE 100 OR 200 FOR ANY
KIND OF CHRONIC TREATMENT BUT
FOR THIS KIND OF EXPERIMENT IT'S
USEFUL.
DIASTOLIC BLOOD PRESSURE DIDN'T
CHANGE MUCH BUT HEART RATE WENT
UP 13 BEATS PER MINUTE WITH MIR
ABEGRON.
WHEN COLD EXPOSURE IS USED IT
CAUSES INCREASE IN BLOOD
PRESSURE AND THE HEART RATE
RESPONDS BY GOING DOWN TO REDUCE
THE OVERALL BLOOD PRESSURE IN
THE BODY.
MIRABEGRON OVERRIDES THE SYSTEM
AND CAUSES INCREASE IN BLOOD
PRESSURE AND HEART RATE.
SO WHAT HAPPENED TO THE BROWN
FAT?
WELL, THIS IS A PET IMAGE
SHOWING WHERE THE GLUCOSE IS
GOING INTO A 21-YEAR-OLD MAN,
IT'S GOING INTO THE HEART HERE.
IT'S GOING INTO HIS BRAIN HERE.
IT'S BEING FILTERED BY THE
KIDNEYS OVER HERE, BUT NOTHING
ELSE IN THE REGION WHERE WE
TYPICALLY SEE BROWN FAT.
WITH COLD EXPOSURE, THERE WAS A
MASSIVE INCREASE IN GLUCOSE
UPTAKE IN THE BROWN FAT AS YOU
CAN SEE IN THE SHOULDERS, DOWN
THE SPINE, AND INTO THE KIDNEY
REGION.
IN ADDITION, MIR ABEG RON WAS
VERY EFFECTIVE.
ENERGY EXPENDITURE INCREASES IN
THERMOGENESIS BY THE BROWN FAT
IN THE SHOULDERS, SPINE, AND THE
KIDNEYS.
WE FOUND BROWN FAT NOT SEEN ON
AUTOPSY OR OTHER KIND OF STUDY,
SO DONE IN REALTIME IN HEALTHY
PATIENTS IS VERY HELPFUL.
SO WHAT WILL HAPPEN AFTER LONG
TERM THERAPY WITH MIRABEGRON?
WELL, I GOT AS FAR AS WE COULD
IN THE STUDIES WE WERE ABLE TO
CONDUCT IN BOSTON SO I MOVED TO
THE NIH CLINICAL CENTER AND WAS
ABLE TO TAKE ADVANTAGE OF THE
TEAM AND THE NIH METABOLIC
CLINICAL RESEARCH UNIT OF THE
MCRU, AND IN PARTICULAR,
COLLABORATIONS WITH CONGRESS KO,
WHO RUNS THE HUMAN ENERGY AND
BODY WEIGHT REGULATION CORE IN
THE BUILDING 10 CLINICAL CENTER.
THE METABOLIC RESEARCH UNIT ON Y
SPECIAL PLACE, UNLIKE ALMOST ANY
OTHER PLACE IN THE COUNTRY.
THERE ARE EIGHT PRIVATE
INPATIENT RESEARCH BEDS, AND
THESE ROOMS ARE DESIGNED FOR
METABOLIC STUDY.
SO YOU CAN SEE HERE OUR TYPICAL
ROOM.
HERE'S A BED AND HERE ARE THE
CHAIRS, AND YOU'LL NOTICE THAT
THEY'RE LARGER THAN A TYPICAL
BED OR CHAIR AND THAT WAY WE CAN
ACCOMMODATE PEOPLE OF A VARIETY
OF SIZES AND WEIGHTS.
WE COULD ALSO MEASURE ENERGY
EXPENDITURE USING A PROCESS
CALLED INDIRECT CALORIMETRY,
TESTING OUT A SYSTEM HERE, AND
IT'S DONE SHORT TERM, YOU CAN DO
BREATH TO BREATH OR MINUTE TO
MINUTE IN THE METABOLIC UNIT.
THERE'S ALSO A WHOLE ROOM
CALORIMETER, I'LL SHOW YOU HOW
THAT WORKS IN A MINUTE.
THAT'S ALSO MEDIUM TERM MINUTES
TO HOURS AND THEN THERE'S A
PROCESS USING DOUBLY LABELED
WATER THAT PEOPLE DRINK, AND
THAT'S HOW ONE CAN MEASURE LONG
TERM ENERGY EXPENDITURE IN FREE
LIVING PEOPLE.
I'M NOT GOING TO TALK ABOUT THIS
TODAY.
IF YOU'RE GOING TO BE ABLE TO
STUDY METABOLIC CHANGES, YOU
NEED TO HAVE A GREAT KITCHEN AND
NUTRITIONAL UNIT.
SHOWN HERE IS ONE IMAGE OF THE
NUTRITIONAL UNIT AT THE CLINICAL
CENTER, AND DR. HALL WILL TALK
MORE ABOUT THAT HOW THAT HAS
SUPPORTED HIS STUDIES.
AND SHOWN HERE, ONE CAN MEASURE
ENERGY EXPENDITURE USING AN
EXERCISE BIKE, OR RESTING ENERGY
EXPENDITURE HERE.
AND AGAIN AS I MENTIONED, THIS
IS DONE FOR 30 MINUTES ROUGHLY,
AND IT'S DONE IN AWAKE, FASTED
VOLUNTEERS, EITHER LYING DOWN
AND RESTING OR THEN EXERCISING,
AND THE ADVANTAGES OF THIS
SYSTEM IS THAT THEY'RE ACCURATE
MEASUREMENTS WHEN BEST PRACTICES
ARE FOLLOWED AND IT'S A
RELATIVELY INEXPENSIVE AND
SOMEWHAT PORTABLE SYSTEM.
HOWEVER, IF YOU WANT TO
UNDERSTAND THE ROLES OF THE
DIFFERENT PARTS OF THE BODY, YOU
NEED TO MEASURE BODY
COMPOSITION.
AND THE BEST WAY WE FIND TO DO
IT IS IN OUR BODY COMPOSITION
LABORATORY ON 7 SOUTHWEST SOUTH,
AND THAT'S USING SOMETHING
CALLED DUAL ENERGY X-RAY
ABSORPTIOMETRY OR DXA, IT TAITS
ABOUT 10 TO 12 MINUTES AND
MEASURED THREE DIFFERENT
COMPARTMENTS OF THE BODY.
FAT MASS, LEAN MASS, AND THE
BONE MINERAL CONTENT.
THIS IS HIGHLY REPRODUCIBLE,
PLUS OR MINUS 1%.
IT PROVIDES GOOD REGIONAL BODY
COMPOSITION INFORMATION, AROUND
AND FORTUNATELY IT HAS A VERY
SMALL AMOUNT OF RADIATION
EXPOSURE.
ROUGHLY THE SAME AMOUNT OF ONE
DAY'S SUNLIGHT EXPOSURE OR ABOUT
1% OF WHAT YOU'D HAVE IN A CHESS
EXRAI.
CHEST
X-RAY.
THE ROOM CALORIMETER IS WHERE
YOU CAN DO THE MOST STUDY, AND
I'LL SHOW YOU THE DESIGN AND
ADVANTAGES OF IT.
A VOLUNTEER PATIENT CAN BE
SITTING IN THIS ROOM, THEY'LL BE
TAKING IN OXYGEN, GIVING OFF
CARBON DIOXIDE, THE AIR MIXING
FAN SENDS AIR TO THE TUBES AND
EFFICIENTLY THE AIR IS THEN
GOING THROUGH A PUMP AND THEN
CARBON DIOXIDE AND OXYGEN
ANALYZERS TELL YOU HOW MUCH OF
EACH OF THESE GASES ARE BEING
CONSUMED AND PRODUCED BY THE
BODY.
IN ADDITION TO THE CART, WHEN
RUN WELL BY OUR TEAM HERE IS
HIGHLY REPRODUCIBLE AND CAN GIVE
AN ACCURATE MEASUREMENT OF
ENERGY EXPENDITURE SITTING,
EXERCISING OR SLEEPING EVEN.
IT ALLOWS MORE FLEXIBILITY IN
TERMS OF WHAT PEOPLE DO THAN THE
METABOLIC CARTS.
AND IT'S APPROPRIATE TO MEASURE
ADAPTIVE THERMOGENESIS, IN OTHER
WORDS, HOW THE BODY RESPONDS IN
TERMS OF HEAT GENERATION WHEN
THERE ARE CHANGES IN DIET,
AMBIENT TEMPERATURE.
THESE ROOMS CAN BE TAKEN DOWN TO
20 DEGREES CELSIUS OR 60 DEGREES
FAHRENHEIT, AND HOW PEOPLE
RESPOND TO MEDICINES AND OTHER
STRUCTURED ACTIVITIES.
WHAT DOES THIS ROOM LOOK LIKE?
THIS IS HOW YOU WALK IN.
THIS IS THE WELCOME VIEW.
HERE'S A BED, HERE'S A WINDOW TO
THE OUTSIDE, A TAPESTRY, AND
THEN A WORK STATION ONE CAN WORK
AT.
HONESTLY THIS IS A LOT NICER
THAN MY DORM ROOM WHEN I WAS IN
COLLEGE.
WHAT IT LOOKS LIKE IN TERMS OF
THE INTERFACE WITH THE CARE
TEAM, CAN YOU CAN SEE COMPUTERM
BEFORE, THIS IS WHERE ONE CAN
GET FOOD BEING BROUGHT IN
THROUGH THESE WINDOWS HERE, THIS
IS THE DOOR TO THE OUTSIDE, AND
THEN IF ONE WANTS TO HAVE
SOMETHING INFUSED, FOR EXAMPLE
THE TRACER FOR THE PET/CT
STUDIES, ONE CAN STICK ONE'S ARM
THROUGH HERE AND MAINTAIN THE
ABILITY TO MEASURE THE OXYGEN
CARBON DIOXIDE.
ON THE OW SIDE OUTSIDE OF THESS
IS WHERE THE PRECISION EQUIPMENT
IS KEPT, JUST SHOWING WHAT IT
LOOKS LIKE IN THE OVERALL SENSE,
AND THEN WE HAVE HERE THE
MEASUREMENT, THE TEMPERATURE,
THE CONSUMPTION OF OXYGEN,
RELATIVE HUMIDITY AND ALL THESE
THINGS BEING TESTED AT THE SAME
TIME.
AND SO WE HAVE THE TOOLS, WE
HAVE THE TALENT.
LET'S CONDUCT SOME CLINICAL
TRIALS.
SO ONE OF THE KEY ONES IS
CHRONIC MIRABEGRON TREATMENT.
WE SHOWED YOU WHAT HAPPENS
ACUTELY, A LOT OF EXCITING
THINGS.
A STUDY LED BY EELY NA OMARA,
STARTING RESIDENCY IN TWO
MONTHS.
IN THIS COHORT OUR PRIMARY END
POINT IS THE CHANGE IN
DETECTABLE BROWN FAT METABOLIC
ACTIVITY ASSOCIATED WITH THE
DAILY DOSE OF MIRABEGRON OVER A
FOUR-WEEK PERIOD.
WE STUDIED 14 WOMEN THIS TIME
FOR FOUR WEEKS AS I MENTIONED,
100 MILLIGRAMS OF MIRABEGRON,
AND THEN WE USED THE
SOPHISTICATED TESTING EQUIPMENT
IN THE MCRU TO FIND OUT HOW THEY
RESPONDED ON BOTH THE INITIATION
AND AT COMPLETION.
DAY ZERO-1 AND DAY 27-28.
YOU CAN SEE HERE WE DID A
FREQUENTLY SAMPLED INTRAVENOUS
GLUCOSE TOLERANCE TEST, DID A
LIVER SCAN, EXERCISE TOLERANCE
TEST, BODY COMPOSITION WITH DXA,
THEY SPENT THE NIGHT IN THE
METABOLIC SUITE SO WE COULD
STUDY SLEEPING ENERGY
EXPENDITURE, WE DREW BLOOD, THEN
GAVE THE VOLUNTEERS MIRABEGRON,
DREW BLOOD AGAIN FIVE HOURS
LATER, GAVE FDG FOR THE PET/CT
STUDY WHICH WE DID AFTERWARD,
AND THEN THE VOLUNTEERS GOT
LUNCH.
WHAT DID WE FIND?
SO THIS IS DAY ONE, THIS IS DAY
28, THESE ARE 14 WOMEN, AND YOU
CAN SEE HERE BASED ON ALL THESE
OTHER ANTHROMETRIC MEASURES OF
THE BODY, THE ONLY THING THAT
MATTERED, JUST THE RESTING HEART
RATE.
AND THAT'S EXPECTED.
IT WENT UP BY 10 BEATS PER
MINUTE.
HOWEVER, AT MAXIMUM EXERCISE
THERE'S NO DIFFERENCE IN PULSE,
MEANING THAT MIRABEGRON LOWERED
THE FLOOR BUT DIDN'T HAVE ANY
OTHER EFFECTS.
I'M SORRY, RAISE THE THE FLOOR.
NOW, WHAT DID MIRABEGRON DO TO
BROWN FAT METABOLIC ACTIVITY AND
VOLUME?
SHOWN HERE IS A PET IMAGE OF ONE
OF THE VOLUNTEERS ON DAY ONE,
THE BLACK HERE, THE SPECKLED
AREA THAT'S PRETTY SPARSE IS HER
BROWN FAT, AND THEN AFTER 28
DAYS OF TREATMENT, YOU CAN SEE
ON THIS GREEN ARROW HERE, A
PROFOUND INCREASE IN GLUCOSE
UPTAKE, A VERY LARGE INCREASE IN
BROWN FAT MASS AND VOLUME.
NOT JUST IN THIS VOLUNTEER BUT
AMONG THE 14 PEOPLE STUDIED,
THERE WAS A VERY LARGE INCREASE
IN BROWN FAT METABOLIC ACTIVITY,
AND THERE WAS AN INCREASE IN THE
MAXIMUM BROWN FAT ACTIVITY TOO.
OUR PRIMARY END POINT WAS
REACHED, CHRONIC MIRABEGRON
100 MILLIMETERS WAS VERY
EFFECTIVE.
THAT'S NOT ALL WHAT MIRABEGRON
DID.
THIS IS WHERE WE DEPART FROM
BROWN FAT SPECIFICALLY TO OTHER
ORGANS IN THE BODY.
CHRONIC MIRABEGRON TREATMENT
RAISED THE HDL CHOLESTEROL.
THAT'S THE GOOD CHOLESTEROL, BY
8%.
IT ALSO INCREASED GIP.
THIS IS A HORMONE THAT INCREASES
INSULIN SENSITIVITY.
THAT INCREASED BY 30%.
ADIPONECTIN WENT UP BY 35%.
AND THE CIRCULATING LEVEL OF
BILE ACIDS IN THE BLOOD WENT UP
BY NEARLY 50%.
AND THAT'S IMPORTANT BECAUSE
BILE ACIDS, THEY'RE NOT JUST
SURFACTANTS THAT HELP ABSORB
DIETARY LIPIDS AND CHOLESTEROL,
THEY BIND TO HORMONE RECEPTORS
IN THE LIVER AND OTHER PLACES
AND CAUSE CHANGES IN GLUCOSE
HOMEOSTASIS, LIPOPROTEIN SUCH AS
THE GOOD CHOLESTEROL, BILE ACID
METABOLISM ITSELF, BILE ACIDS
MAY BE CARDIOPROTECTIVE, HAVE
IMPACTS ON THE GI, THE BRAIN,
SKM, BAT AND IMMUNE SYSTEM.
THESE CHANGES ALONE ARE ENOUGH
TO KEEP SOMEONE BUSY STUDYING
THE EFFECTS OF MIRABEGRON ON
HEALTH.
WE FREQUENTLY SAMPLED GLUCOSE
TOLERANCE TEST, THERE WE
MEASURED THE CAPACITY FOR
GLUCOSE TO MEDIATE ITS OWN
DISPOSAL, GLUCOSE INCREASED ITS
OWN DISPOSAL AFTER THE END OF 28
DAYS.
IT ALSO INCREASED INSULIN
SENSITIVITY IN THE VOLUNTEERS BY
37%, AND ON THE BETA CELL
INCREASE, INSULIN PRODUCTION BY
THE PANCREAS WENT UP BY 37% AND
DISPOSITION INDEX, BETA CELERY
SPON SIEVENESS, WENT UP BY 82%.
SO FOUR WEEKS OF MIRABEGRON
TREATMENT HAD A LOT OF IMPACT ON
THE BODY.
SOME FROM BROWN FAT, SOME FROM
WHITE FAT, SOME TO BE
DETERMINED.
JUST TO COMPARE ON MIRABEGRON
FOUR WEEKS IS IN RELATION TO
OTHER TYPES OF HORMONES, THIS IS
GLP-1 GIVEN INTRAVENOUSLY,
METFORMIN, BARIATRIC SURGERY,
AND MILD EXERCISE.
THESE ARE THE PARAMETERS I
SHOWED YOU, SG AND SI RELATE TO
INSULIN SENSITIVITY AND
MIRABEGRON IS COMPARABLE.
ON THE BETA CELL SIDE IN TERMS
OF INSULIN SECRETION, MIRABEGRON
IS ONCE AGAIN COMPARABLE TO MANY
OF THESE INTERVENTIONS.
THIS MAKES MIRABEGRON A
PROMISING PATHWAY TOWARDS
TREATING METABOLIC HEALTH AS
SOON AS WE CAN GET TO A SAFE
LEVEL.
SO IN SUMMARY, THE CHRONIC
MIRABEGRON TREATMENT STUDIES,
TREATMENTS FOR FOUR WEEKS LED TO
THE FOLLOWING, AN INCREASE IN
BROWN FAT METABOLIC ACTIVITY,
INCREASE IN RESTING ENERGY
EXPENDITURE I DIDN'T SHOW YOU 6%
ABOVE BASELINE, INCREASES IN THE
HDL, THE GOOD CHOLESTEROL, APOE
AND REDUCTION OF A RATIO THAT IS
ASSOCIATED WITH CARDIOMETABOLIC
RISK SO IT'S A GOOD THING THE
RATIO WENT DOWN.
THERE WERE IMPROVEMENTS IN
GLUCOSE UP TAKE AND BETA CELL
FUNCTION.
IT WAS NOT YET KNOWN ALL THE
UNDERLYING MECHANISMS BUT AS WE
MENTIONED, WE THINK BROWN FAT
AND WHITE FAT LIKELY HAVE
IMPORTANT ROLES AND THEREFORE WE
BELIEVE BETA THREE ADRENERGIC
REACCEPT INVENTORIES MAY BE A
NEW APPROACH TO TREATING OBESITY
RELATED COMPLICATIONS SUCH AS
TYPE TWO DIABETES AS WELL AS
COMPONENTS OF THE METABOLIC
SYNDROME INCLUDING POSSIBLE
INFERTILITY AS I'LL DESCRIBE AT
SOME POINT IN THE FUTURE.
SO NEXT STEPS AND FUTURE
STUDIES, WHERE DO YOU GO FROM
HERE?
ONE OF THE THINGS WE NEED TO DO
IS TRY TO UNDERSTAND THE
MECHANISM OF THE DISCOVERIES I
JUST DESCRIBED.
SO WORK DONE BY CHERYL CERO, A
POSTDOCTORAL FELLOW WHO
COMPLETED HER TIME AND MOVED ON
TO THE NCI, IN COLLABORATION
WITH ATCC, A BIOLOGICAL RESOURCE
CENTER, WE HAVE GENERATED TWO
DIFFERENT CELL TYPES THAT WILL
BE AVAILABLE IN THE FUTURE, NEAR
FUTURE, OF WHITE CELLS AND BROWN
CELLS THAT CAN BE THEN GROWN IN
CULTURE TO STUDY HUMAN WHITE AND
BROWN ADIPOCYTE FUNCTION.
ONE OF THE THINGS WE'VE BEEN
ABLE TO DO SO FOR IS THROUGH THE
BIOINER JE TICS I DESCRIBED.
HUMAN BROWN ADIPOCYTES HAVE A
MUCH HIGHER BASAL RESPIRATION
COMPARED TO WHITE, THERE'S
HIGHER MAXIMAL RESPIRATION IN
BROWN COMPARED TO WHITE CELLS,
THERE'S A HIGHER FLEXIBILITY IN
FUEL UTILIZATION IN THE BROWN
COMPARED TO THE WHITE, AND THE
THERMOGENESIS THAT I MENTIONED
FROM UCP1 IN BROWN ADIPOCYTES IS
HAPPENING FROM UCP16789 AND ALSO
NON-UCP1 SOURCES AND WE'RE GOING
TO FIND OUT WHAT THEY ARE IN THE
NEXT MONTHS AND YEARS.
IN ADDITION, CAN YOU DO
TRANSCRIPTOMICS, WORKING WITH
THE ATCC GROUP, WE HAVE GENETIC
SIGNATURES OF WHITE AND BROWN
ADIPOCYTES BEFORE
DIFFERENTIATION AND AFTERWARD.
AND WE'RE GOING TO STUDY THE
IMPACT OF ALL THESE GENES IN
ADDITION TO THE GENETIC
SIGNATURES.
SO OUR FUTURE RESEARCH LOOKING
AT OUR PLATFORM OF INTERRELATED
PILLARS, WE'RE GOING TO DEVELOP
MRI IMAGING, WE'RE GOING TO
LEVERAGE THE CELL LINES TO STUDY
HUMAN WHITE AND BROWN ADIPOCYTES
SIGNALING AND SYNTHESIS AND
WE'RE GOING TO ASSESS
MIRABEGRON'S ABILITY TO AK VAIT
WHITE FAT AND BROWN FAT IN
PATIENTS AND POPULATIONS AT RISK
FOR METABOLIC DISEASE.
SO THE FINAL SUMMARY IS THAT
ADIPOSE TISSUE IS POLYCHROMATIC.
IT CAN BE WHITE, BEIGE, BROWN
AND EVEN MORE.
EACH TISSUE CONTAINS MULTIPLE
CELL TYPES.
WHITE ADIPOSE TISSUE STORES FAT
AS A RESERVOIR FOR BOT DE'S
TISSUE NEEDS.
BROWN ADIPOSE TISSUE STORES FAT
TEMPORARILY AS A FUEL TO SUPPORT
THE GENERATION OF HEAT.
THE ENDOCRINE ROLES, MANY STILL
TO BE DETERMINED, RELATE TO
THEIR OVERALL GOALS, AND
SOMETHING I LIKE TO CALL A
TELEOLOGICAL ENDOCRINOLOGY.
WHAT IS THE IMOAL O GOAL OF THE
TISSUE AND WHAT KIND OF MESSAGES
IS IT SENDING?
BASED ON THE MESSAGES, WE CAN
LEARN MORE ABOUT WHAT IT'S
SUPPOSED TO BE DOING.
OBESITY IS A DISEASE DRIVEN BY
THE BRAIN THAT IS MANIFESTED AS
AN EXCESS OF WHITE ADIPOSE
TISSUE AND A DYSFUNCTION OF THE
BROWN ADIPOSE TISSUE.
AND FINALLY, CHRONIC TREATMENT
WITH BETA THREE ADRENERGIC
RECEPTOR AGONISTS, AK VAIT BAT
AND WAA LEADS TO CHANGES IN
GLUCOMETABOLISM IN THE BODY,
CHOLESTEROL PROFILE AND OTHER
RESPONSES WAITING TO BE
DISCOVERED.
STAY TUNED FOR MORE!
SO WITH NA, I WAN THAT, I WANT Y
GROUP WHO WORKS WITH ME ON A
REGULAR BASIS, FORMER MEMBERS OF
THE GROUP HERE, COLLABORATIVE
WITH THE NIH, HARVARD,
CEDARS-SINAI AND MCGILL.
>>THANK YOU VERY MUCH FOR AN
EXTRAORDINARILY EXCITING
BRILLIANT PRESENTATION.
YOU'VE GIVEN EVERYBODY A LOT TO
THINK ABOUT, AND WE WILL HAVE
PLENTY OF QUESTIONS, I'M SURE.
SO NOW WE'RE GOING TO PROCEED TO
KEVIN HALL, WHO'S GOING TO
EXPLAIN TO US HOW DO YOU GET
THIN AND STAY THAT WAY?
OR CAN YOU?
A PHYSICIST'S VIEW.
KEVIN?
>>THANKS VERY MUCH, WIN, AND
THANKS, AARON, FOR AN EXCELLENT
INTRODUCTORY TALK HERE.
IT'S GREAT TO SEE SUCH EXCITING
RESEARCH FROM MY FRIENDS AND
COLLABORATORS HERE AT THE NIH.
SO I DON'T HAVE ANYTHING TO
DISCLOSE IN TERMS OF FINANCIAL
DISCLOSURES.
I WAS PROVIDED THREE LEARNING
OBJECTIVES WHICH YOU CAN READ IN
YOUR OWN TIME.
I WANT TO START OFF BY KIND OF
FLASHING BACK TO HOW MANY
PHYSICIANS HAVE THOUGHT ABOUT
WEIGHT CONTROL AND TREATING
PEOPLE WITH OBESITY OVER THE
YEARS.
THIS HAS REALLY SORT OF
CULMINATED IN A PIECE PUBLISHED
IN THE JOURNAL OF THE AMERICAN
MEDICAL ASSOCIATION BACK IN
2018, ENTITLED COUNTING CALORIES
AS AN APPROACH TO ACHIEVE WEIGHT
CONTROL.
AND THE IDEA WAS THAT IF A
PATIENT REDUCES THEIR CALORIC
INGESTION BY 500-CALORIES PER
DAY FOR SEVEN DAYS, SHE OR HE
WOULD LOSE ABOUT 1-POUND OF BODY
WEIGHT PER WEEK.
THIS IS AN OLD RULE OF THUMB
THAT GOES BACK MANY, MANY
DECADES.
DIETITIANS ARE TESTED ON THIS
RULE, PEOPLE HAVE BEEN USING
THIS RULE OF THUMB TO PREDICT
HOW PEOPLE MIGHT CHANGE THEIR
WEIGHT OVER TIME BY MAKING
CHANGES IN THEIR DIET, POLG SEE
MAKERS HAVE USED THIS RULE OF
THUMB TO PREDICT WHAT WOULD
HAPPEN WITH A SODA TAX IN THE
OBESITY COMMUNITY.
THE PROBLEM WITH THIS RULE OF
THUMB IS IT'S JUST PLAIN WRONG.
AND IT DOESN'T TAKE A LOT OF
THINKING TO REALIZE THAT
SOMETHING MUST BE WRONG WITH
THIS RULE OF THUMB.
BECAUSE IF YOU IMAGINE THAT YOU
ARE A MAN, SAY, THAT WEIGHS
100-KILOGRAMS AND IS EATING
ABOUT 3,000KILLICALORIES PER DAY
AND YOU PUT THAT MAN ON A DIET
BY CUTTING THEIR CALORIES BY 500
KILLICALORIES PER DAY SUCH THAT
NOW THEY'RE EATING 25, THIS
PREDICTS THAT PERSON WOULD
DISAPPEAR AFTER FOUR YEARS SO
SOMETHING IS CLEARLY WRONG WITH
THIS MODEL OF HOW THE
RELATIONSHIP BETWEEN CALORIE
INTAKE AND BODY WEIGHT IS
RELATED.
AND ONE OF THE REASONS IT'S
WRONG, THE MAIN REASON IT'S
WRONG IS IT TREATS CALORIE
INTAKE AND CALORIE EXPENDITURE
AS INDEPENDENT QUANTITIES.
WHEREAS IF YOU CHANGE ONE,
NOTHING HAPPENS TO THE OTHER,
AND BECAUSE WE HAVE A LAW OF
CONSERVATION OF ENERGY, I'M A
PHYSICIST BY TRAINING SO THAT'S
ALSO CALLED THE FIRST LAW OF
THERMODYNAMICS, THE IDEA IS IF
YOU OFFSET THE CALORIE INTAKE
FROM CALORIE EXPENDITURE BY
CUTTING THE CALORIES IN THE
DIET, THEN THIS RULE OF THUMB
PREDIBTS THAT NPRETICKETS THAT S
TO THE CALORIE EXPENDITURE OF
THE BODY SO THEREFORE THE BODY
HAS TO MAKE UP THE DEFICIT OF
CALORIES COMING IN THE DIET BY
MOBILIZING PRIMARILY BODY FAT TO
MAKE UP THAT DIFFERENCE AND THAT
GIVES RISE TO THIS LINEAR RATE
OF WEIGHT LOSS.
THE PROBLEM, OF COURSE, IS THAT
CALORIE INTAKE AND CALORIE
EXPENDITURE ARE NOT INDEPENDENT,
THAT THEY ARE ACTUALLY
INTERRELATED IN A VERY
INTERESTING WAY.
AND A VERY COMPLEX WAY THAT WE
DON'T FULLY UNDERSTAND, TO BE
HONEST.
ONE OF THE THINGS WE DO
UNDERSTAND IS THAT TISSUES LIKE
ADIPOSE TISSUE THAT WE JUST
HEARD A WONDERFUL LECTURE ABOUT,
SECRETE ADIP KINES, ONE OF WHICH
IS LEPTINS DISCOVERED A COUPLE
DECADES AGO OR SO, AND THOSE
HORMONES FROM ADIPOCYTES AS WELL
AS OTHER AREAS OF THE BODY LIKE
THE GUT, IMPINGE ON REGIONS OF
THE BRAIN TO MODULATE CALORIE
EXPENDITURE AND ALSO APPETITE
CALORIE INTAKE IN SUCH A WAY
THAT YOU HAVE ESSENTIALLY A PAIR
OF NEGATIVE FEEDBACK CONTROL
LOOPS THAT ARE GOVERNING BOTH
THE CALORIE INTAKE SIDE OF THE
EQUATION AND THE CALORIE
EXPENDITURE SIDE OF THE EQUATION
TO OFFSET ANY CHANGES THAT ONE
MIGHT TRY TO MAKE IN EITHER THE
EXPENDITURE SIDE OR THE INTAKE
SIDE, THE BODY FIGHTS BACK IN
SOME WAY AGAINST THOSE
PERTURBATIONS.
SO ONE OF THE THINGS THAT I'VE
BEEN DOING IN MY LAB AT THE NIH
FOR MANY, MANY YEARS HAS BEEN
TRYING TO BUILD MATHEMATICAL
MODELS OF THE PHYSIOLOGY OF
THESE FEEDBACK LOOPS AND TO TRY
TO QUANTIFY THEIR STRENGTH.
AS WELL AS ANALYZE DATA
COLLECTED IN PEOPLE WHO ARE
TRYING TO CHANGE THEIR WEIGHT
AND QUANTIFY HOW THESE DIFFERENT
FEEDBACK LOOPS RESPOND TO THEIR
EFFORTS TO CHANGE WEIGHT.
SO ONE OF THE MORE POPULAR
EXAMPLES OF THAT, THAT WE'VE
STUDIED, WAS CONTESTANTS ON A
TELEVISION PROGRAM CALLED THE
BIGGEST LOSER, WHICH WAS A
NATIONAL TELEVISED WEIGHT LOSS
COMPETITION FOR MANY, MANY
YEARS, AND WE STUDIED SEASON
8 CONTESTANTS OF THE BIGGEST
LOSER.
AND HERE'S THE WINNER OF THAT
SEASON OF THE BIGGEST LOSER.
THIS IS DANNY CAHILL.
HE LOST 239 POUNDS OVER THE
COURSE OF SEVEN SMON MONTHS ON S
CRAZY FAT SHAMING TELEVISION
PROGRAM, WHICH I DON'T ENDORSE
THE METHODS THAT WERE USED BUT I
THOUGHT IT WAS A REALLY
WONDERFUL WAY TO KIND OF STUDY
THESE FEEDBACK CIRCUITS THAT I
WAS TALKING ABOUT A MOMENT AGO.
AND TRY TO QUANTIFY THEM IN AN
ACTUAL STUDY WHERE WE SENT
POSTDOCS OUT TO THIS RANCH IN
MALIBU, WHERE THIS PROGRAM WAS
BEING FILMED, WE MEASURED USING
A VARIETY OF THE METHODS THAT
AARON NICE LEGAL SUMMARIZED,
ENERGY EXPENDITURE, BODY
COMPOSITION CHANGES, BOTH IN
THESE FOLKS AS THEY UNDERWENT
THIS CRAZY WEIGHT LOSS
COMPETITION, AND THEN MANY YEARS
LATER.
AND I'LL SHARE WITH YOU SOME OF
THE DATA THAT WE MEASURED AND
SOME OF OUR MATH MACKALL MODEL
SIMULATIONS OF WHAT WE THINK
HAPPENED IN TERMS OF THEIR
PHYSIOLOGY.
BUT THESE ARE THE MEAN DATA IN
THE BOXES FOR BODY WEIGHT AND
FAT MASS ALONG WITH OUR
COMPUTATIONAL MODEL SIMULATIONS
OF WHAT HAPPENED IN THESE FOLKS.
SO FOR THE FIRST 13 WEEKS,
THEY'RE ISOLATED ON THIS RANCH
IN MALIBU, AND THEY'RE
UNDERGOING BASICALLY A WEIGHT
LOSS COMPETITION AND THEY'RE
LOSING WEIGHT AT AN ASTONISHING
RATE OF ABOUT A POUND A DAY OVER
THE COURSE OF THIS 13-WEEK
PERIOD.
AND YOU CAN SEE IT'S A PRETTY
LINEAR RATE OF WEIGHT LOSS OVER
13 WEEKS AND THAT THE VAST
MAJORITY OF THE WEIGHT LOSS IS
COMING FROM LOSS OF BODY FAT.
WHICH IS THE GREEN CURVE IN OPEN
BOXES HERE.
THESE FOLKS ARE BASICALLY THEN
SENT HOME FOR ANOTHER PERIOD OF
TIME BEFORE THEY'RE CALLED BACK
TO THE FINALE THE PROGRAM AND
THEY'RE STILL IN THIS
COMPETITION AND THEY'RE TOLD
JUST KEEP IT UP AT HOME, KEEP
DOING YOUR EXERCISE, KEEP DOING
YOUR DIET, AND YOU CAN SEE THAT
THE RATE OF WEIGHT LOSS AND FAT
MASS LOSS SLOWS DOWN SLIGHTLY SO
IT'S ONLY ABOUT HALF A POUND A
DAY EVERY DAY, WHICH IS PRETTY
CRAZY, WHEN YOU THINK ABOUT THE
SHEER MAGNITUDE OF THAT.
AND THEN THEY CAME BACK AT THE
FINALE AFTER 30 WEEKS OR ABOUT .
NOW, UNDERLYING THESE WEIGHT AND
FAT MASS TRAJECTORIES, WHAT WE
MEASURED WAS HOW MANY TOTAL
CALORIES PER DAY THAT THEY WERE
EXPENDING.
AND WE USE THE DOUBLY LABELED
WATER METHOD THAT AARON
MENTIONED VERY BRIEFLY AND I'M
NOT GOING TO GO INTO DETAILS
ABOUT HOW IT WORKS, BUT BEFORE
THE COMPETITION, BEFORE THEY
WERE ENGAGING IN THIS PROGRAM,
THESE FOLKS HAD A BODY MASS OF
ABOUT 140 KILOS.
THEY WERE BURNING ABOUT
3700-CALORIES PER DAY AT THE
START.
SIX WEEKS IN TO THIS
COMPETITION, WHILE THEY'RE STILL
AT THIS RANCH IN MALIBU, ENERGY
EXPENDITURE, TOTAL NUMBER OF
CALORIES THAT THEY WERE BURNING
GOES UP BY ALMOST A THOUSAND
CALORIES PER DAY, AND THEN BY
THE END OF THIS 30-WEEK
COMPETITION, THE TOTAL NUMBER OF
CALORIES PER DAY HAS DROPPED TO
ABOUT 3,000-CALORIES PER DAY.
AND UNDERLYING THAT, WE CAN USE
OUR MATHEMATICAL MODEL
SIMULATIONS TO ESTIMATE WHAT
CONTRIBUTION WAS DUE TO
EXERCISE.
SO THESE FOLKS WEREN'T
EXERCISING AT ALL BEFORE THE
COMPETITION, AND THEY QUICKLY
RAMPED UP THEIR EXERCISE SO THAT
BY 6 TO 8 WEEKS, THEY'RE JUST IN
THE EXERCISE BURNING ABOUT 2,000
KILL CALORIES PER DAY.
NOW, ANY OF YOU EXERCISERS OUT
THERE WHO MIGHT HOP ON A
TREADMILL KNOW THAT THAT'S AN
ASTONISHING AMOUNT OF EXERCISE.
IT WORKS OUT TO ABOUT THREE
HOURS PER DAY EVERY DAY SEVEN
DAYS A WEEK.
OF EXERCISE.
THAT'S NOT ACCOUNTING FOR JUST
WALKING AROUND FROM PLACE TO
PLACE.
THAT'S JUST THE EXERCISE
COMPONENT.
YOU CAN SEE AFTER THEY GO HOME,
THE AMOUNT OF EXERCISE QOAS DOWN
SLIGHTLY BUT STILL ACCOUNTS FOR
ABOUT AN HOUR OF VIGOROUS
EXERCISE EVERY DAY SEVEN DAYS A
WEEK.
THE REASON WHY IT GOES DOWN MUCH
MORCH YOU MIGHT EXPECT BASED ON
THE ORIGINAL AMOUNT AT 6 TO
8 WEEKS IS BECAUSE THE ENERGY
COST OF PHYSICAL ACTIVITY AND
EXERCISE IS PROPORTIONAL TO THE
AMOUNT OF BODY WEIGHT THAT
PEOPLE HAVE.
SO IT'S A LITTLE BIT UNFAIR, BUT
FOR THE SAME INTENSITY AND
DURATION OF EXERCISE, A PESH
LOSING WEIGHT WILL BURN FEWER
AND FEWER CALORIES IN EXERCISE.
I SHOWED YOU IN THE PREVIOUS
GRAPH THESE FOLKS NE END ON
AVERAGE HAD LOST 60-KILOS OF
BODY WEIGHT, SO 122 POUNDS ON
AVERAGE, AND THAT GIVES RISE TO
A DECREASE IN THE ENERGY
EXPENDITURE OF PHYSICAL
ACTIVITY.
WE ALSO MEASURED THEIR RESTING
METABOLIC RATE THROUGH INDIRECT
CALORIMETRY.
WHAT WE FOUND IS THEY HAD A
SUPPRESSION OF RESTING METABOLIC
RATE THAT I'LL TALK A LITTLE BIT
MORE ABOUT IN THE NEXT SLIDE.
BUT THEN WE COULD ALSO CALCULATE
HOW MANY TOTAL CALORIES THAT
THEY WERE EATING.
AGAIN, APPLYING THAT LAW OF
ENERGY CONSERVATION, AND DURING
THE PERIOD OF TIME THAT THEY'RE
ON THE RANCH, WHEN THEY'RE DOING
THIS INCREDIBLE AMOUNT OF
EXERCISE, THEY'RE ONLY EATING
ABOUT 1100-CALORIES PER DAY.
SO A VERY, VERY SMALL AMOUNT OF
FOOD.
AND THEN WHEN THEY GO HOME, THAT
INCREASES SLIGHTLY, BUT IT'S
STILL WELL BELOW 2,000-CALORIES
PER DAY.
IT'S ABOUT 1900-CALORIES PER
DAY.
SO THIS IS A CLEARLY
UNSUSTAINABLE DIET AND EXERCISE
INTERVENTION.
IT JUST KIND OF SHOWS THE FACT
THAT THESE FOLKS ON -- THESE ARE
THE AVERAGE DATA, CAN ENGAGE IN
SUCH INCREDIBLE INTERVENTIONS IN
BOTH THEIR DIET AND THEIR
PHYSICAL ACTIVITY SHOWS THAT
REALLY THESE FOLKS WHO CLEARLY
HAD OBESITY AT THE BEGINNING OF
THIS PROGRAM, THEY DID NOT LACK
WIWILLPOWER.
THESE ARE FOLKS WHO HAVE
ENORMOUS AMOUNTS OF WILL POWER.
BUT WE WERE INTERESTED IN
INVESTIGATING SOME OF THE
PHYSIOLOGY UNDERLYING THE
CHANGES IN RESTING ENERGY
EXPENDITURE.
SO WHAT I'M PLOTTING HERE IS THE
RESTING METABOLIC RATE AT
BASELINE BEFORE THESE FOLKS
ENGAGED IN ANY OF THIS CRAZY
DIET AND EXERCISE PROGRAM, AND
I'M PLOTTING IT AGAINST THE
GREATEST DETERMINANT OF RESTING
ENERGY EXPENDITURE, WHICH IS
THEIR FAT FREE MASS.
SO THIS IS THEIR TOTAL BODY
WEIGHT MINUS THE AMOUNT OF FAT
THAT THEY HAVE ON THEIR BODY.
COUNTLESS NUMBER OF STUDIES HAVE
SHOWN THAT THE BEST PREDICTOR OF
RESTING METABOLIC RATE IS NOT
YOUR WEIGHT, IT'S NOT YOUR
HEIGHT, IT'S NOT YOUR SEX, IT'S
BASICALLY YOUR FAT FREE MASS.
AND SO WHAT WE'RE SHOWING HERE
IS THAT THERE'S A LINEAR
RELATIONSHIP BETWEEN FAT FREE
MASS AND RESTING METABOLIC RATE,
AND THESE ARE ALL THE BASELINE
DATA FOR THE BIGGEST LOSER
SUBJECTS.
THE SLOPE OF THE LINE IS VERY
CONSISTENT FROM STUDY TO STUDY.
AND WHAT WE WOULD THEN PREDICT
IS THAT IF PEOPLE WERE TO LOSE
WEIGHT, THEY WOULD LOSE BOTH FAT
MASS AND FAT FREE MASS, AND
THERE IS A PREDICTION ABOUT WHAT
SHOULD HAPPEN TO THEIR RESTING
METABOLIC RATE.
AND SO FOR EXAMPLE, THIS PERSON
WHO STARTS AT THE TOP OF THIS
LINE THAT'S VERY CLOSE TO THE
LINE, IF THEY LOSE A CERTAIN
AMOUNT OF FAT FREE MASS THEY
WOULD BE PREDICTED TO JUST SLIDE
ALONG THE LINE AND LOSE A
CERTAIN AMOUNT OF THEIR RESTING
ENERGY EXPENDITURE CORRESPONDING
TO THE LOSS OF FAT FREE MASS.
SO ONE OF THE THINGS WE WANTED
TO TEST WAS, DID THESE FOLKS WHO
ENGAGED IN THIS CRAZY DIET AND
EXERCISE INTERVENTION JUST SLIDE
ALONG THE LINE AND LOSE THE
EXPECTED AMOUNT OF RESTING
METABOLIC RATE.
AND THE ANSWER WAS NO, THE OPEN
CIRCLES ARE AT THE END OF THIS
30-WEEK WEIGHT LOSS COMPETITION
YOU CAN SEE THAT EVERYBODY IS
FALLING WELL BELOW THE BEST FIT
LINE OF REGRESSION AT A MUCH
STEEPER SLOPE.
SO FOR EXAMPLE, THE PERSON THAT
I ILLUSTRATED BEFORE INSTEAD OF
FALLING ALONG THE LINE, HE FELL
TO THIS OPEN CIRCLE AT THE END
OF THE RED ARROW.
CLEARLY THERE'S A BIG
DISCREPANCY BETWEEN THE
PREDICTED AMOUNT OF DECREASE IN
RESTING ENERGY EXPENDITURE AND
THE AMOUNT THAT THEY ACTUALLY
EXPERIENCED.
A MUCH GREATER SLOWING OF
METABOLISM THAN WOULD BE
PREDICTED BASED ON THE BODY
COMPOSITION CHANGES ALONE.
SO WHAT WE CALL THAT PROCESS AND
MANY OTHER PEOPLE HAVE CALLED
THIS IS THE METABOLIC ADAPTATION
THAT'S HAPPENING AS A RESULT OF
THEIR WEIGHT LOSS.
IT'S THE GREATER THAN EXPECTED
SLOWING OF METABOLISM AS PEOPLE
LOSE THEIR WEIGHT.
LOSE WEIGHT AS A RESULT OF THIS
DIET INTERVENTION.
NOW, ONE OF THE PREDICTIONS
WOULD BE, IS THAT BECAUSE THESE
PEOPLE ARE NOW BURNING SO MANY
FEWER CALORIES THAN WOULD BE
EXPECTED FOR THEIR LOSS OF BODY
WEIGHT, THAT PERHAPS PEOPLE WHO
HAD THE GREATEST SLOWING OF
METABOLISM WOULD BE EXPECTED TO
REGAIN THE MOST AMOUNT OF
WEIGHT.
AFTER ALL, THEY'RE BURNING SO
MANY FEWER CALORIES THAT THEY
WOULD BE EXPECTED TO INCREASE
THEIR WEIGHT MORE THAN THOSE WHO
MIGHT HAVE HAD A MUCH LETTER
METABOLIC ADAPTATION.
YOU CAN SEE IN THE DATA OF THE
INDIVIDUAL DATA POINTS HERE,
THERE IS A RANGE, SO WE COULD
TEST THAT HYPOTHESIS AND IT WAS,
IN FACT, AN ASSUMPTION FOR A
VERY LONG TIME.
AND SO WE BROUGHT BACK THE
CONTESTANTS OF THAT SEASON OF
THE BIGGEST LOSER TO THE NIH
CLINICAL CENTER TO MEASURE THEIR
METABOLIC RATE AND BODY
COMPOSITION AGAIN.
THIS IS DANNY CAHILL SIX YEARS
AFTER THE BIGGEST LOSER
COMPETITION.
AND IT WAS A FEATURE OF A "NEW
YORK TIMES" ARTICLE.
YOU CAN SEE JUST VISUALLY HE'S
CLEARLY REGAINED SOME OF HIS
LOST WEIGHT.
I'LL SHOW YOU SOME OTHER PHOTOS
OF SOME OF THE OTHER CONTESTANTS
BEFORE AND AFTER THE BIGGEST
LOSER COMPETITION.
THIS IS DENA ON THE LEFT, BEFORE
THE COMPETITION BEGAN, ON THE
RIGHT, AFTER 30 WEEKS, AND THEN
SIX YEARS LATER.
THIS IS SHAWN, BEFORE ON THE
LEFT, AFTER ON THE RIGHT, AND
THEN SIX YEARS LATER.
THIS IS ABBY BEFORE ON THE LEFT,
AFTER ON THE RIGHT.
AND THEN SIX YEARS LATER.
AND TRACY, BEFORE ON THE LEFT,
AFTER ON THE RIGHT, AND THEN SIX
YEARS LATER.
I THINK WHAT YOU CAN SEE IS JUST
VISUALLY, THERE IS QUITE A BIT
OF VARIABILITY IN THE AMOUNT OF
WEIGHT THAT WAS REGAINED.
HERE ARE ALL THE DATA POINTS.
AT 30 WEEKS, AT THE END OF THE
COMPETITION, LIKE I MENTIONED
BEFORE, THE GREY LINE IS SAYING
THAT ON AVERAGE, PEOPLE HAD LOST
60-KILOS.
AND SIX YEARS LATER, THEY HAD,
ON AVERAGE, REGAINED ABOUT TWO
THIRDS OF THEIR LOST WEIGHT, BUT
THERE WAS QUITE A BIT OF
VARIABILITY.
ONE PERSON EVEN CONTINUED TO
LOSE EVEN MORE WEIGHT AFTER SIX
YEARS.
AND THIS WAS PORTRAYED IN THE
"NEW YORK TIMES" ARTICLE AND A
LOT OF THE SUBSEQUENT COVERAGE
AS A BIG FAILURE, RIGHT, THAT
THESE FOLKS HAD REGAINED SO MUCH
WEIGHT AFTER SIX YEARS.
BUT ONE OF THE THINGS I'D LIKE
TO POINT OUT IS THAT AFTER SIX
YEARS, THEY WERE STILL
MAINTAINING AN AVERAGE OF ABOUT
13% WEIGHT LOSS.
WHICH IS PRETTY DARN GOOD.
THAT'S ACTUALLY PRETTY GOOD
LONG-TERM EFFECT OF THIS KIND OF
CRAZY AND UNSUSTAINABLE
INTERVENTION THAT OCCURRED OVER
THE COURSE OF THE ACTUAL
COMPETITION.
BUT THERE WAS SOME VARIABILITY
AND ONE OF THE QUESTIONS THAT WE
WANTED TO ANSWER WAS, DID THE
PEOPLE WHO HAD REGAINED THE MOST
WEIGHT, WERE THEY THE ONES WHO
HAD EXPERIENCED THE GREATEST
SLOWING AT THE END OF THE
30-WEEK COMPETITION, THAT WAS
THE ASSUMPTION AND HAD BEEN THE
ASSUMPTION FOR QUITE SOME TIME.
AND IN FACT, THERE WAS NO
SIGNIFICANT RELATIONSHIP
WHATSOEVER.
SO THE PEOPLE HAD THE GREATEST
METABOLIC SLOWING AT THE END OF
THE COMPETITION WERE -- THERE
WAS NO RELATIONSHIP TO THE
AMOUNT OF WEIGHT THAT THEY
REGAINED AFTER SIX YEARS.
SO WHAT DID PREDICT THE WEIGHT
REGAIN?
WHAT WAS THE GREATEST
CONTRIBUTOR?
ONE OF THE THINGS THAT WE DID
WAS WE SPLIT THE GROUPS UP INTO
THE MEDIAN OF THOSE WHO HAD LOST
MORE THAN 13% OF WEIGHT LOSS AT
THE END OF THE SIX-YEAR PERIOD
AND THOSE THAT WHO LOST LESS
THAN 13%.
THE MEAN VALUES IN THOSE TWO
GROUPS WAS -- ONE GROUP HAD
MAINTAINED 25% WEIGHT LOSS AND
THE OTHER HAD REGAINED BASICALLY
ALL OF THEIR BODY WEIGHT.
AND WE HAD THESE OBJECTIVE
MEASUREMENTS OF ENERGY INTAKE
AND PHYSICAL ACTIVITY ENERGY
EXPENDITURE.
AND IN THESE TWO GROUPS, THERE
WAS NO SIGNIFICANT DIFFERENCE IN
THE ENERGY INTAKE BETWEEN THE
GROUPS, THE CHANGES FROM THE
BASELINE COMPARED TO SIX YEARS,
BUT THERE WAS HUGE DIFFERENCES
IN THE ENERGY EXPENDITURE WITH
ONE GROUP INCREASING THEIR
ENERGY EXPENDITURE BY MORE THAN
150% COMPARED TO BASELINE, IN
TERMS OF THEIR PHYSICAL
ACTIVITY, AND THE OTHER GROUP
BASICALLY HAVING A VERY MODEST
INCREASE IN PHYSICAL ACTIVITY.
CONTINUOUSLY, THE DATA LOOK LIKE
THIS.
CLEARLY THE FOLKS WHO HAD
INCREASED THEIR PHYSICAL
ACTIVITY, ENERGY EXPENDITURE THE
MOST MAINTAINED THE MOST WEIGHT
LOSS.
AND THIS IS SOMETHING THAT HAS
BEEN OBSERVED IN OTHER
REGISTRIES OF PEOPLE WHO HAD
MAINTAINED SUBSTANTIAL AMOUNTS
OF WEIGHT LOSS.
ONE OF THE COMMON FACTORS IS
THAT THEY BECOME RELATIVELY
PHYSICALLY ACTIVE IN ORDER TO
MAINTAIN THAT WEIGHT LOSS.
SO THAT'S DEPICTED HERE IN THESE
LONGITUDINAL STUDIES OF THE
BIGGEST LOSER PARTICIPANTS.
SO SOMETHING ELSE THAT WAS
REALLY INTERESTING WAS THAT
DESPITE REGAINING THE BODY
WEIGHT, TWO THIRDS OF THE BODY
WEIGHT ON AVERAGE RESTING ENERGY
EXPENDITURE OR RESTING METABOLIC
RATE AS PLOTTED HERE IS
BASICALLY UNCHANGED.
SUGGESTING THAT THIS METABOLIC
SLOWING THAT HAD TAKEN PLACE
OVER THE COURSE OF THE BIGGEST
LOSER COMPETITION WAS MAINTAINED
SIX YEARS LATER.
AND IN FACT, ONE OF THE THINGS
THAT WAS VERY INTERESTING WAS
THAT DESPITE WHAT WE MIGHT HAVE
EXPECTED, THE AMOUNT OF
METABOLIC SLOWING AT SIX YEARS
WAS POSITIVELY RELATED TO THE
AMOUNT OF WEIGHT REGAIN SUCH
THAT THOSE WHO EXPERIENCED AT
SIX YEARS THE GREATEST AMOUNT OF
METABOLIC SLOWING WERE THE ONES
WHO HAD BEEN MOST SUCCESSFUL,
NOT LEAST SUCCESSFUL, MOST
SUCCESSFUL AT MAINTAINING THEIR
WEIGHT LOSS AT THE SAME TIME
POINT.
SO HOW DO WE MAKE SENSE OF THIS?
AFTER ALL, THEY'RE THE ONES WHO
HAVE THE GREATEST SLOWING OF
METABOLISM.
HOW CAN THEY BE THE ONES WHO
HAVE BEEN MOST SUCCESSFUL AND
KEEPING THE WEIGHT OFFER?
ONE WAY TO KIND OF THINK ABOUT
IT IS THIS RESISTANCE TO WEIGHT
LOSS AND INTERVENTIONS IS KIND
OF LIKE THE TENSION ON A SPRING.
AND IF THE INTERVENTION IS THE
AMOUNT THAT YOU'RE PULLING ON
THE SPRING, AND IF YOU'RE NOT
PULLING ON THE SPRING, YOU'RE
NOT GOING TO LOSE ANY WEIGHT.
SO THE TENSION ON THE SPRING IS
ZERO.
WHEREAS IF YOU THEN PULL ON THE
SPRING BY CUTTING CALORIES IN
YOUR DIET OR INCREASING YOUR
PHYSICAL ACTIVITY, YOU WILL LOSE
WEIGHT, BUT THERE WILL BE A
TENSION ON THE SPRING, IN
PROPORTION TO THE AMOUNT THAT
YOU'RE PULLING ON IT.
GREATER THAT YOU PULL ON IT, THE
GREATER THE RESISTANCE OR THE
TENSION ON THE SPRING.
SO THAT WOULD BE WHY YOU MIGHT
HAVE THIS RELATIONSHIP I SHOWED
YOU ON THE PREVIOUS CURVE.
THOSE WHO HAD THE GREATEST
METABOLIC ADAPTATION HAD THE
GREATEST TENSION ON THE SPRING
BECAUSE THEY WERE RESISTING A
GREATER INTENSITY OF
INTERVENTION.
AND IN PARTICULAR, PHYSICAL
ACTIVITY IN THE CASE OF THE
BIGGEST LOSERS.
LET'S MOVE ON AND TALK ABOUT
MAYBE NOT SUCH AN EXTREME WEIGHT
LOSS, I DON'T HAVE TIME TO GO
INTO THE DETAILS BUT IN THIS
PAPER IN 2016, WE QUANTIFIED ON
AVERAGE WHAT THE RELATIVE
FEEDBACK CONTROL STRENGTH THAT
RESISTS WEIGHT LOSS IS ON BOTH
THE APPETITE SIDE AND THE ENERGY
EXPENDITURE SIDE OF THE ENERGY
BALANCE EQUATION, AND WHAT WE
COMPUTED WAS THAT ON THE CALORIE
OUTPUT SIDE, FOR EVERY KILO OF
BODY WEIGHT THAT'S LOST, ENERGY
EXPENDITURE GOES DOWN BY ABOUT
25 KILOCALORIES PER DAY.
SO IF YOU LOSE ABOUT 22 POUNDS
OR 10-KILOS, YOU WILL BE BURNING
ROUGHLY 250-CALORIES PER DAY
LESS THAN YOU WERE TO BEGIN
WITH.
ON THE APPETITE SIDE, THE
FEEDBACK CONTROL STRENGTH IS
ACTUALLY MUCH STRONGER.
ACCORDING TO OUR INITIAL
ESTIMATES.
SUCH THAT WILL FOR EVERY KILO OF
WEIGHT THAT'S LOST, YOUR
APPETITE INCREASES ABOVE
BASELINE BY ABOUT 95 KILL
CALORIES PER DAY, AND I'D LIKE
TO TRACE OUT WHAT THAT MEANS
PRACTICALLY FOR PEOPLE WHO ARE
ENGAGING IN CALORIE RESTRICTION
FOR WEIGHT LOSS.
JUST TO KIND OF PLOT WHAT THOSE
TWO SORT OF CURVES LOOK LIKE AS
A FUNCTION OF BODY WEIGHT, WE'RE
ASSUMING THEY'RE LINEAR HERE,
BUT YOU CAN SEE THAT THE
APPETITE CURVE HAS A SLOPE OF
MINUS 95 KILL CALORIES PER DAY
PER KILO OF BODY WEIGHT CHANGE
AND THE EXPENDITURE IS ABOUT
25 KILOCALORIES PER DAY.
WHEN INTAKE AND EXPENDITURE ARE
EQUAL, YOUR BODY IS IN BALANCE
AND YOU WILL MAINTAIN A STABLE
BODY WEIGHT, IN THIS CASE, ABOUT
85 KILOGRAMS EATING ABOUT
3100 KILOCALORIES PER DAY ON
THIS CURVE.
SO WHAT HAPPENS WHEN YOU TRY TO
CUT CALORIES IN YOUR DIET?
ONE WAY TO THINK ABOUT IT IS IF
YOU HAVEN'T CHANGED THE
UNDERLYING BIOLOGY OF THE
SYSTEM, YOU'RE ESSENTIALLY
SEPARATING INTAKE FROM YOUR
APPETITE.
SO YOUR APPETITE STAYS WHERE IT
WAS IN THE PREVIOUS CURVE,
INDICATED BY A DASHED LINE,
INTAKE HAS BEEN SHIFTED
DOWNWARDS, IN THIS CASE, TO A
NEW VALUE OF ABOUT 2500-CALORIES
PER DAY IN THIS PERSON WHO IS
STARTING OFF AT 85-KILOS.
AND THAT SEPARATION OF INTAKE
FROM APPETITE WOULD THEN PREDICT
AS THIS PERSON GOES INTO WHAT'S
CALLED A NEGATIVE ENERGY
BALANCE, THEY'RE BURNING MORE
THAN THEY'RE EATING, AND,
THEREFORE, THEY WOULD HAVE A
CERTAIN AMOUNT OF HUNGER AND
EFFORT ASSOCIATED WITH
MAINTAINING THIS CUT IN CALORIES
BUT THEY WOULD SLIDE UPWARDS THE
INTAKE LINE UNTIL THEY REACH A
NEW EQUILIBRIUM WHERE ENERGY
INTAKE AND EXPEND TEURL ARE IN
BALANCE AND REACH THIS NEW
STEADY STATE OF BODY WEIGHT --
THAT IT TAKES TO SEPARATE THAT
INTAKE CURVE FROM THE APPETITE
CURVE.
SO THE PREDICTION IS THAT WHEN
PEOPLE GO ON A
CALORIE-RESTRICTED DIET THAT
THEY WOULD INITIALLY CUT THEIR
CALORIES QUITE A LOT, THAT'S
THAT INITIAL REDUCTION, AND THAT
THEIR ENERGY EXPENDITURE WOULD
GO DOWN AND SLIDE UP THE INTAKE
CURVE.
SO DOES THAT REALLY HAPPEN?
SO WE HAVE SOME REALLY
REMARKABLE DATA, TWO-YEAR DATA
FROM A 25% CALORIE RESTRICTION
INTERVENTION, SOMETHING CALLED A
CALORIE STUDY THAT WAS SUPPORTED
BY THE NATIONAL INSTITUTES ON
AGING, AND HERE'S THE DATA FOR
THE BODY WEIGHT AND BODY FAT
CHANGES IN THE PARTICIPANTS OF
THE CALORIE DATA.
AND THE GOAL HERE OF THE CALORIE
STUDY WAS TO CUT ENERGY INTAKE
BY A CONSTANT 25% AND KEEP IT AT
THAT LOWER LEVEL FOR THE ENTIRE
DURATION OF THE STUDY.
AND SO FIRST THING TO NOTE IS
THAT THESE PEOPLE DIDN'T
DISAPPEAR AFTER TWO YEARS, THEY
PLATEAUED THEIR BODY WEIGHT
AFTER ABOUT 12 MONTHS.
AND LOST MOST OF THEIR WEIGHT
LOSS COMING FROM BODY FAT
CHANGE, AGAIN, THE SIMULATIONS
ARE THE CURVES AND THE DATA
POINTS ARE THE CIRCLES AND
TRIANGLES RESPECTIVELY FOR
EVALUATING BODY FAT.
BUT UNDERLYING THIS, THESE
INVESTIGATORS WENT TO GREAT
EXPENSE TO USE REPEATED MEASURES
OF DOUBLY LABELED WATER AND BODY
COMPOSITION CHANGES TO INFER
WHAT THE ENERGY INTAKE CHANGES
MUST HAVE BEEN, AND INDEED, WHAT
THEY FOUND WAS THAT ENERGY
INTAKE WAS INITIALLY REDUCED AND
DESPITE THIS CONSTANT INTENSITY
INTERVENTION, SEEING
NUTRITIONISTS ON A REGULAR BASIS
TO TRY TO KEEP A 25% CALORIE
CUT, YOU CAN SEE THAT THE ENERGY
INTAKE CURVE CREEPS UPWARDS
AFTER THAT INITIAL 25% CALORIE
REDUCTION.
JUST EXACTLY ACCORDING TO WHAT
WAS PREDICTED BASED ON THAT
APPETITE MODEL I SHOWED YOU A
MOMENT AGO.
ENERGY EXPENDITURE IN THE ORANGE
CURVE GOES DOWN AND SORT OF
STAYS DOWN, AND OF COURSE WHEN
THOSE TWO CURVES CROSS EACH
OTHER AT 12 MONTHS, THAT'S WHERE
THE PLATEAU IS.
AND SO YOU CAN KIND OF
REINTERPRET THIS AND PLOT THE
APPETITE.
I TOLD YOU THAT APPETITE
INCREASES BY ABOUT
95 KILOCALORIES PER DAY ABOVE
BASELINE, FOR EVERY KILOGRAM OF
WEIGHT THAT IS LOST, SO THAT'S
BASICALLY JUST THIS DASHED LINE
THAT I'M PLOTTING HERE BASED ON
THE OBSERVED BODY WEIGHT
CHANGES.
SO THE THING THAT I THINK IS
INTERESTING IS, AGAIN, ACCORDING
TO THE MODEL THAT WE PREDICTED
THAT THERE IS A PERSISTENT
DIFFERENCE BETWEEN THE SOLID
BLUE LINE WHICH IS WHAT THESE
FOLKS ARE DOING TO ACTUALLY CUT
THEIR CALORIES AND WHAT THEIR
BODY IS TELLING THEM THEY'D LIKE
TO BE EATING, WHICH IS THE
DASHED BLUE LINE, THAT FOR
PERSISTENT AND CONSTANT
INTENSITY INTERVENTION, THE
PREDICTION IS THAT PEOPLE HAVE A
RELATIVELY EASY TIME EARLY ON
CUTTING CALORIES IN THEIR DIET
BECAUSE THEY HAVEN'T LOST MUCH
BODY WEIGHT, BUT AS THEY LOSE
WEIGHT, THE FEEDBACK CONTROL OF
APPETITE INCREASES TO THE TUNE
OF 95 KILOCALORIES PER DAY PER
KILO OF WEIGHT LOSS, AND SO FOR
THE SAME DEGREE OF EFFORT AND
THE SAME EXPERIENCE OF HUNGER,
ENERGY INTAKE WILL GO UP BECAUSE
IT'S FIGHTING A GREATER AND
GREATER BATTLE, THE GREATER THE
INCREASE IN APPETITE BECOMES.
SO THIS, I HOPE, GIVES PEOPLE A
PICTURE FOR WHAT FOLKS WITH
OBESITY EXPERIENCE WHEN YOU JUST
PRESCRIBE A CALORIE RESTRICTION.
JUST CUT CALORIES IN YOUR DIET,
YOU'LL LOSE WEIGHT.
THE OLD RULE OF THUMB OF THAT
3500-CALORIES PER POUND DOESN'T
INCLUDE ANY OF THIS FUNDAMENTAL
BIOLOGY AND GAVE, I THINK,
PHYSICIANS THE WRONG IMPRESSION
FOR MANY, MANY YEARS THAT IT WAS
A SIMPLE MATTER OF WILLPOWER.
JUST CUT A LITTLE BIT OF
CALORIES FROM YOUR DIET AND
YOU'LL LOSE WEIGHT AND THEN YOU
CAN GO BACK TO EATING WHAT YOU
WERE BEFORE AND YOU'LL MAINTAIN
THE WEIGHT LOSS.
THAT'S NOT WHAT HAPPENS.
BUT OF COURSE NOW THAT WE KNOW
SOMETHING ABOUT THE BIOLOGY THAT
RESISTS WEIGHT LOSS, THERE'S THE
HOPE THAT YOU COULD SOMEHOW
SUBVERT IT.
AND THERE'S A VARIETY OF PEOPLE
WHO ARE POPULARIZING VARIOUS
DIETS THAT COULD POTENTIALLY
SUBVERT IT, AND ONE OF THE
POPULAR VERSIONS OF THAT IS
SOMETHING THAT'S BASED ON A
MODEL OF OBESITY CALLED THE
CARBOHYDRATE INSULIN MODEL,
WHICH IS PROMOTED BY DR. DAVID
LUDWIG'S GROUP AT HARVARD, WHO
WROTE A BOOK CALLED "ALWAYS
HUNGRY" BASED ON THIS IDEA.
AND HE CORRECTLY POINTS OUT THAT
WHEN YOU EAT FEWER CALORIES, THE
BODY BECOMES MORE EFFICIENT AND
BYRNES FEWER CALORIES, AND AS
YOUR DESIRE FOR EXTRA CALORIES
ACTUALLY HEIGHTENS.
AND THIS COMBINATION OF RISING
HUNGER AND SLOWING METABOLISM IS
A RECIPE FOR FAILURE.
I SHOWED YOU IN THE PREVIOUS
GRAPH THAT YOU NEED THAT
LONG-TERM PERSIST AT THE PRESENT
TIMEPERSISTENT EFFORTDESPITE THR
WEIGHT LOSS HAS STOPPED IN ORDER
TO MAINTAIN THAT WEIGHT LOSS.
HIS IDEA IS THAT MAYBE YOU CAN
SUBVERT THAT IN SOME WAY.
SO HE SAYS THAT A MORE EFFECTIVE
APPROACH IS TO REPROGRAM YOUR
FAT CELLS TO LOSE WEIGHT BY
EATING IN A WAY THAT LOWERS
INSULIN LEVELS AND REDUCES
INFLAMMATION.
AND WHEN THIS HAPPENS, FAT CELLS
CALM DOWN AND RELEASE THEIR
EXCESS CALORIE STORES AS THE
BODY BEGINS TO ENJOY BETTER
ACCESS TO FUEL, METABOLISM RUNS
BETTER, HUNGER AND CRAVINGS
SUBSIDE AND WEIGHT LOSS OCCURS
NATURALLY.
IT'S A DIET WITHOUT DEPRIVATION.
SO WHAT IS THE BASIS OF THESE
PRETTY EXTRAORDINARY CLAIMS?
WELL, THE IDEA HERE IS THAT AT
THE LEVEL OF THE FAT CELL, THE
MAIN THING THAT IS CONTRIBUTING
TO TRIGLYCERIDE STORAGE IS THE
AMOUNT OF INSULIN THAT'S
SURROUNDING THE BODY.
INDEED INSULIN PLAYS A VERY
IMPORTANT ROLE AS AARON HAD
MENTIONED IN RE REGULATING HOW H
TRIGLYCERIDE IS TAKEN UP FROM
THE BLOOD AND STORED AS
TRIGLYCERIDE INSIDE FAT CELLS BY
THE ENZYME LIPOPROTEIN LIPASE,
AS WELL AS INHIBITING THE
HORMONE SENSITIVE LIPASE INSIDE
FAT CELLS WHICH LIMITS THE
AMOUNT OF FAT THAT IS RELEASED
FROM FAT CELLS.
AND SO THE IDEA OF THIS
CARBOHYDRATE INSULIN MODEL OF
OBESITY IS THAT IF YOUR INSULIN
LEVELS ARE HIGH BECAUSE YOU'RE
EATING TOO MANY CARBOHYDRATES,
THEN THAT ESSENTIALLY IS
TRAPPING YOUR FAT INSIDE YOUR
FAT CELLS CAUSING THEM TO GO
INTO THIS ANABOLIC OVERDRIVE
RESPONSE.
ACCUMULATING BODY FAT, WHICH
THEN DEPRIVES THE REST OF THE
BODY OF CIRCULATING METABOLIC
FUELS, AND SENSING A PROBLEM OR
A SORT OF INTERNAL STARVATION
STATE, YOUR BODY OR YOUR BRAIN
RECEIVES THE SIGNAL THAT YOU'RE
STARVING AND THAT INCREASES
HUNGER, INCREASING ENERGY INTAKE
AND DECREASING ENERGY
EXPENDITURE.
THE WAY THAT DR. LUDWIG
DESCRIBES IT IN THIS JAMA
INTERNAL MEDICINE PAPER, HE SAYS
THAT A HIGH CARBOHYDRATE DIET
PRODUCES POSTPRANDIAL
HYPERINULINEMIA PROMOTES
DEPOSITION OF CALORIES IN FAT
CELLS INSTEAD OF OXIDATION
THEREFORE PREDISPOSES TO WEIGHT
GAIN THROUGH INCREASES IN
HUNGER, SLOWING METABOLIC RATE
OR BOTH.
THIS IS A REALLY INTRIGUING
MODEL BECAUSE IT MAKES
PREDICTIONS ABOUT HOW THE BODY
WEIGHT IS REGULATED AND IT'S
HAPPENING AT THE LEVEL OF THE
FAT TISSUE AND NOT AT THE BRAIN,
AS AARON HAD MENTIONED
PREVIOUSLY, WHICH IS CURRENTLY
WHAT MOST OBESITY RESEARCHERS
THINK IS THE NEXUS OF BODY
WEIGHT REGULATION.
SO ONE WAY TO TEST THIS
HYPOTHESIS WOULD BE TO CHANGE
THE CARBOHYDRATE AND FAT CONTENT
OF THE FOOD ENVIRONMENT THAT
PEOPLE ARE EXPOSED TO, THAT
SHOULD ALTER INSULIN SECRETION,
PEOPLE ON A VERY HIGH
CARBOHYDRATE DIET SHOULD HAVE
HIGHER INSULIN SECRETION AFTER
MEALS, THAT SHOULD KEEP THE FAT
IN THE FAT CELLS AND SHOULD
CAUSE PEOPLE TO EAT MORE
CALORIES.
AND SO ONE OF THE THINGS THAT WE
DID A COUPLE YEARS AGO, JUST
BEFORE COVID, WAS THAT WE
RECRUITED 20 MEN AND WOMEN TO
THE METABOLIC CLINICAL RESEARCH
UNIT AT THE NIH CLINICAL CENTER
THAT AARON DESCRIBED SO NICELY
AND THEY STAYED WITH US FOR 28
CONTINUOUS DAYS, 24 HOURS A DAY,
SEVEN DAYS PER WEEK, AND WE
RANDOMIZED THEM TO EITHER
RECEIVE 14 DAYS OF A VERY LOW
CARB, HIGH FAT DIET, ONE THAT
WAS DESIGNED TO MINIMIZE INSULIN
EXCURSIONS, OR A VERY HIGH CASH
CARBDIET, AND MEASURED THESE FO,
HOW MANY CALORIES THAT THEY ATE.
SO WE GAVE THEM MORE THAN ENOUGH
CALORIES TO EAT TO MAINTAIN
THEIR WEIGHT, AND GAVE THEM VERY
SIMPLE INSTRUCTIONS, EAT AS MUCH
OR AS LITTLE OF THE FOOD YOU'D
LIKE.
WE DIDN'T TELL THEM WHAT THE
PRIMARY OUTCOME OF THE STUDY
WAS, WE TOLD THEM IT WASN'T A
WEIGHT LOSS OR WEIGHT GAIN
STUDY, WE TOLD THEM WE'RE JUST
INTERESTED HOW THESE DIETS
AFFECT THEIR BODY AND WE DID A
NUMBER OF DIFFERENT TESTS AS YOU
CAN SEE ON THIS GRAPH.
AFTER 14 DAYS, WE BASICALLY
SWAPPED THEM TO THE ALTERNATE
DIET, AGAIN TELLING THEM, EAT
HOWEVER MUCH OR AS LITTLE AS
YOU'D LIKE.
SO HERE'S AN EXAMPLE OF WHAT ONE
OF THE SEVEN-DAY ROTATING MENUS
LOOKED LIKE THAT WAS DESIGNED BY
THE REALLY TALENTED CHEFS AND
DIETITIANS AT THE NIH CLINICAL
CENTER NUTRITION DEPARTMENT.
THIS IS A BREAKFAST ON THE LEFT,
A LUNCH ON THE -- IN THE MIDDLE
AND DINNER ON THE RIGHT.
IT'S A VERY HIGH CARBOHYDRATE
LOW FAT DIET, AMOUNTED TO ABO
ABOUT 75% OF TOTAL CALORIES FROM
CARBS, AND ON THE LOW CARB HIGH
FAT MEALS, 10% CARB, 75% FAT,
15% PROTEIN.
SIM PEAT AS MUCH OR AS LITTLE AS
THEY'D LIKE ON THESE TWO DIETS.
POSTPRANDIAL RESPONSES FOR
INSULIN ON THE HIGH CARB LOW FAT
DIET WERE MUCH, MUCH HIGHER IN
THIS MIXED MEAL TEST OF
ISOCALORIC MEAL TESTS IN THESE
TWO GROUPS.
SO WE'RE SETTING UP THE
SITUATION WHERE THE HIGH CARB
DIET LEADS TO MUCH HIGHER
INSULIN LEVELS, KEEP THE FAT
TRAPPED IN THE FAT CELLS, CAUSE
THEM TO BE MORE HUNGRY AND EAT
MORE CALORIES IF THE MODEL IS
CORRECT.
UNFORTUNATELY, WE SAW EXACTLY
THE ON SIT EFFECT.
OPPOSITE EFFECT.
IT WAS THE ONES THAT HAD THE
MUCH HIGHER INSULIN EXCURSIONS
THAT LED TO SUBSTANTIALLY LESS
CALORIE INTAKE IN THESE FOLKS.
THE SAME FOLKS AS COMPARED TO
WHEN THEY WERE ON THE LO LOW CAB
HIGH FAT DIET.
IN FACT EVERY SINGLE INDIVIDUAL
OF THESE 20 FOLKS ATE FEWER
CALORIES ON THE HIGH CARB LOW
FAT DIET, DESPITE THE MUCH, MUCH
HIGHER LEVELS OF INSULIN IN THE
BLOOD.
THEY DID THIS WITHOUT ANY
DIFFERENCES IN THEIR APPETITE,
SO THEY RATED -- THEY BASICALLY
HAD THE SAME HUNGER SATISFACTION
FULLNESS AND EATING CAPACITY ON
BOTH OF THESE DIFFERENT MEALS.
AND NOT TOO SURPRISING, I GUESS,
THAT THEY WERE EATING
700-CALORIES PER DAY LESS ON THE
HIGH CARB LOW FAT DIET INSTEAD
OF KEEPING THE FAT TRAPPED IN
THE FAT CELLS THEIR OVERALL BODY
FAT MASS LOSS WAS GREATER DURING
THE HIGH CARB LOW FAT DIET AGAIN
DESPITE THE HIGHER INSULIN
LEVELS AS OPPOSED TO THE OTHER
GROUP.
I'M GOING TO DIVERT AWAY FROM
THE DIET WARS IN TERMS OF LOW
CARB AND LOW FAT DIET.
THESE WARS HAVE BEEN GOING ON
FOR DECADES AND DECADES.
THEY'RE PROBABLY NOT GOING TO
SUBSIDE ANY TIME SOON, CERTAINLY
NOT FROM ONE STUDY LIKE I JUST
SHOWED YOU.
BUT SOMETHING OCCURRED TO ME
THAT I THOUGHT WAS KIND OF
INTERESTING.
IS THAT BOTH OF THESE DIETS
TYPICALLY RECOMMEND THAT PEOPLE
EAT AN ABUNDANCE OF NON-STARCHY
VEGETABLES, AND THEY TYPICALLY
ALSO PROVIDE -- THE WRITERS OF
DIET BOOKS PROVIDE A BUNCH OF
RECIPES ON HOW TO PREPARE MEALS
THAT MATCH THE QUALITIES OF
THEIR PROPOSED DIETS.
AND AS A RESULT, THEY STEER
PEOPLE AWAY FROM PREPACKAGED
FOODS, THE SORT OF READY TO EAT,
READY TO HEAT MEALS THAT ARE
OFTEN IN THE FREEZER AISLES OF
THE SUPERMARKET.
AND SO IT OCCURRED TO ME THAT,
YOU KNOW, MAYBE ONE OF THE
THINGS THAT THEY HAVE IN COMMON
THAT CAN IMPROVE PEOPLE'S HEALTH
IS THAT THEY STEER PEOPLE AWAY
FROM VERY HIGHLY PROCESSED FOODS
AND TOWARDS PREPARING THEIR OWN
MEALS FROM WHOLE FOODS AND
CULINARY INGREDIENTS.
AND THIS SORT OF ALIGNED WITH
WHAT'S A RELATIVELY RECENT WAY
OF LOOKING AT FOODS THAT IS NOT
FOCUSED ON THE NUTRIENTS, PER
SE, BUT INSTEAD THE EXTENT AND
PURPOSE OF PROCESSING.
AND SO A GROUP IN BRAZIL HAS
PROPOSED THAT WE START
CLASSIFYING FOODS NOT BASED ON
THEIR NUTRIENTS BUT THE EXTENT
AND PURPOSE OF PROCESSING AND
DEVELOPING SOMETHING CALLED THE
NOVA CATEGORIZATION SYSTEM,
WHERE HE CLASSIFIES FOODS INTO
THESE FOUR DIFFERENT CATEGORIES.
UNPROCESSED OR MINIMALLY
PROCESSED FOODS, PROCESSED
CULINARY INGREDIENTS, AND
PROCESSED FOODS WHICH ARE
ESSENTIALLY COMBINATIONINGS OF
GROUP 1 AND GROUP 2 FOODS AND
THEN FINALLY, THIS FOURTH
CATEGORY, WHICH IS THE BAD GUY,
THE ULTRAPROCESSED FOODS WHICH
ARE DEFINED AS FORMULATIONS OF
SEVERAL INGREDIENTS THAT INCLUDE
ORIGINAL OR CHEMICALLY MODIFIED
FOOD SUBSTANCES OBTAINED WITH
THE FRACTIONING OF WHOLE FOODS
AND ADDITIVES USED TO MAKE THE
FINAL PRODUCT PALATABLE OR
HYPERPALATABLE, AND THE AIM IS
TO MAKE CONVENIENT TASTE FULL
AND LOW COST PRODUCTS LIABLE TO
REPLACE ALL OTHER NOVA FOOD
GROUPS.
WHEN I FIRST HEARD ABOUT THIS
CATEGORIZATION THAT IGNORES
NUTRIENTS AND DOESN'T TALK MUCH
ABOUT CALORIES, I WAS VERY
SKEPTICAL.
THE FOLKS WHO INTRODUCED ME TO
THIS IDEA SHOWED ME DOZENS OF
EPIDEMIOLOGICAL STUDIES LINKING
ULTRAPROCESSED FOOD INTAKE TO
OBESITY, AND ONE OF THE THINGS I
ASKED THEM IS WELL WHAT ARE THE
POTENTIAL MECHANISMS?
WHAT THEY CAME BACK TO ME WITH
WAS BASICALLY A LIST OF
NUTRIENTS.
THEY SAID, WELL, ULTRAPROCESSED
FOODS TEND TO BE HIGH IN SALT,
SUGAR AND FAT AND LOW IN FIBER
AND THAT PROMOTES OVEREATING.
AND I SAID WELL, YOU KNOW,
THAT'S INTERESTING, BUT YOU JUST
LISTED A BUNCH OF NUTRIENTS AND
YOU JUST -- AND YET, YOU KNOW,
THIS NOVA CATEGORIZATION SYSTEM
IS NOT REALLY ABOUT THE
NUTRIENTS.
SO COULD WE DESIGN A STUDY THAT
ACTUALLY MATCHED FOR THESE KNEW
TREENDZ OF CONCERN BUT VARIED IN
THE DEGREE OF INDUSTRIAL
PROCESSING?
AND SO WE DESIGNED ANOTHER STUDY
VERY SIMILAR TO THE DESIGN OF
THE LAST STUDY I SHOWED YOU
WHERE AGAIN PEOPLE SPENT FOUR
WEEKS CONTINUOUSLY ON OUR
METABOLIC WARD, 24 HOURS A DAY,
7 DAYS A WEEK, AND AGAIN, WE
TOOK OVER THEIR FOOD ENVIRONMENT
AND GAVE THEM VERY SIMPLE
INSTRUCTIONS TO EAT AS MUCH OR
AS LITTLE OF THE FOOD AS WAS
DESIRED, AND IN THIS CASE, WE
RANDOMIZED THEM TO EITHER A
ULTRAPROCESSED DIET OR AN
UNPROCESSED DIET FOR TWO WEEKS
AND THEN THEY SWAPPED TO THE
ALTERNATE DIET.
AND AGAIN, WE BA BASICALLY TOLD
THEM WE'RE INTERESTED IN HOW
THESE DIETS AFFECT YOUR HEALTH,
EAT AS MUCH OR AS LITTLE AS
YOU'D LIKE, IT'S NOT A WEIGHT
LOSS OR WEIGHT GAIN STUDY.
HERE'S WHAT THE MEALS LOOKED
LIKE.
SO HERE'S ONE OF THE SEVEN DAYS
OF THE ULTRAPROCESSED MEALS, AND
CRITICALLY OUR TALENTED
DIETITIANS MATCHED THE OVERALL
MENUS FOR THE PRESENTED CALORIE,
THE FAT, THE CARBS, SODIUM,
FIBER, GLYCEMIC LOAD AND IN THIS
CASE OF THE ULTRATRA PROCESSED
MEALS, 80% OF THE CALORIES CAME
FROM THE CATEGORY FOR
ULTRAPROCESSED FOOD GROUP.
IN THE UNPROCESSED GROUP, AGAIN,
MATCHED FOR THOSE NUTRIENTS AND
PROPERTIES, 80% OF CALORIES CAME
FROM THE KA CATEGORY 1 GROUP AN%
CAME FROM ULTRAPROCESSED FOODS.
BECAUSE THEY WERE MATCHED FOR
NUTRIENTS OF CONCERN, MY
HYPOTHESIS WAS THAT WE WOULDN'T
SEE MUCH DIFFERENCE IN CALORIE
INTAKE.
AND SO THESE FOLKS DID WHAT THEY
WERE ASKED, THEY AGAIN ATE THE
SAME DEGREE OF HUNGER, FULLNESS,
SATISFACTION OR EATING CAPACITY
ON THESE TWO DIFFERENT DIETS.
BUT IN THE CASE OF THE
ULTRAPROCESSED FOOD, CONTRARY TO
MY EXPECTATIONS, THEY ENDED UP
EATING ABOUT 500-CALORIES PER
DAY MORE THAN THE SAME FOLKS
DURING THE UNPROCESSED DIET.
AND THAT LED TO BODY FAT GAIN
SPONTANEOUSLY IN THE
ULTRAPROCESSED DIET VERSUS BODY
FAT LOSS IN THE UNPROCESSED DIET
IN THESE VERY SAME PEOPLE THAT
SPENT, AGAIN, 28 CONTINUOUS DAYS
ON OUR METABOLIC UNIT.
SO WHAT DOES THIS MEAN IN TERMS
OF THE FEEDBACK AND WHERE WE
SETTLE IN TERMS OF OUR ENERGY
EXPENDITURE?
ONE POSSIBILITY IS THAT OUR FOOD
ENVIRONMENT SEEMS TO AFFECT THE
LOCATION OF THIS CURVE.
IN OTHER WORDS, AN
ULTRAPROCESSED FOOD ENVIRONMENT
SHIFTS THE CURVE UPWARDS, PEOPLE
NOT TRYING TO CHANGE THEIR
WEIGHT SPONTANEOUSLY EAT MANY,
MANY MORE CALORIES AND THAT WILL
GIVE RISE OVER TIME TO WEIGHT
GAIN AND REEQUILIBRATION AT A
MUCH HIGHER ENERGY INTAKE AND A
MUCH HIGHER ENERGY EXPENDITURE
AND A MUCH HIGHER BODY WEIGHT.
AND SO MAYBE THIS IS WHAT'S
UNDERLYING THIS INCREASE IN
ADULT BODY WEIGHT THAT IS
CHARACTERISTIC OF OBESITY
EPIDEMIC THAT THE U.S. IS
EXPERIENCED OVER THE PAST 50
YEARS.
INDEED THE KIND OF QUALITY OF
THE DIET IN AMERICA HAS CHANGED
QUITE SUBSTANTIALLY SUCH THAT
NOW THE DIET IS COMPRISED OF
MORE THAN 50% OF CALORIES COMING
FROM ULTRAPROCESSED FOOD AND A
DECLINE IN THE NUMBER OF
CALORIES THAT ARE CONSUMED FROM
ULTRAPROCESSED FOODS OR CULINARY
INGREDIENTS INDICATING THAT MORE
PEOPLE ARE EATING PREPREPARED
MEALS EITHER AT HOME OR AWAY
FROM HOME.
IN FACT, ONE OF THE THINGS
THAT'S VERY INTERESTING ALSO IS
THAT THE AMOUNT OF CALORIE
INTAKE REQUIRED TO EXPLAIN THE
INCREASE IN BODY WEIGHT THAT'S
OBSERVED IN AMERICA OVER THE
PAST 50 YEARS IS MUCH, MUCH LESS
THAN THE INCREASE IN CALORIES IN
THE FOOD SUPPLY, EITHER MEASURED
BY THE USDA OR THE UNITED
NATIONS FOOD AND AGRICULTURE
ORGANIZATION.
SO I'M PLOTTING HERE THE BLACK
LINE IS WHAT WOULD BE EXPECTED
TO MAINTAIN THAT HIGHER ADULT
BODY WEIGHT THAT AMOUNTS TO
ABOUT 250-CALORIES PER DAY
INCREASE SINCE THE 1970s,
WHEREAS THE ACTUAL NUMBER OF
CALORIES IN THE FOOD SUPPLY IS
ESTIMATED BY THESE FOOD BALANCE
SHEETS HAS INCREASED PER CAPITA
BY A MUCH, MUCH GREATER EXTENT.
IN FACT, THAT PREDIBTS THAT
THERE'S AN INCREASE IN FOOD
WASTE ON A PER CAPITA BASIS, SO
THE DIFFERENCE BETWEEN THOSE
CURVES IS BASICALLY THE BLUE
LINE HERE, CALCULATED FROM OUR
MODEL, AND IF WE GO TO THE
ENVIRONMENTAL PROTECTION AGENCY,
THEY ACTUALLY KEEP TRACK OF WHAT
IS DUMPED IN LANDFILLS AND ONE
OF THE PIECES OF DATA THEY
PUBLISH IS THE AMOUNT OF SOLID
FOOD WASTE.
THEY DON'T PUBLISH THE DATA PER
CAPITA, BUT WE CALCULATED THEIR
DATA PER CAPITA AND THERE'S BEEN
AN EXACTLY PARALLEL 50%
PROGRESSIVE INCREASE IN FOOD
WASTE SINCE THE 1970s.
SO THIS REALLY SUGGESTS
SOMETHING KIND OF STRIKING WHICH
IS THAT WE'VE GOTTEN SO GOOD AT
GROWING THESE STAPLE CROPS OF
SOY AND WEIGHT AND CORN WITH
VERY HIGH YIELDS AND HAVE TURNED
THESE VERY CHEAP COMMODITY
INGREDIENTS INTO THIS MYRIAD OF
ULTRAPROCESSED FOOD PRODUCTS
THAT ARE ENGINEERED TO BE
PALATABLE AND CONVENIENT AND
HAVE ALL SORTS OF WONDERFUL
PROPERTIES, LONG SHELF LIFE AND
RELATIVELY INEXPENSIVE.
AND WE HAVE NOW A FOOD SYSTEM
THAT IS DOMINATED BY THESE
PRODUCTS IN THE U.S.
AND SO ONE HYPOTHESIS IS THAT
THIS INCREASED RELIANCE AND
INCREASED SHARE OF
ULTRAPROCESSED FOODS IN THE U.S.
FOOD SUPPLY AND INDEED AROUND
THE WORLD IN INCREASING AMOUNTS
HAS POTENTIALLY INCREASED
OBESITY.
AND THAT'S THE RESULT OF YEARS
OF AGRICULTURAL RESEARCH,
CHANGES IN FARM TECHNOLOGY AND
POLICY THAT HAVE ESSENTIALLY U
USED CHEAP FOSSIL FUEL AND
HYBRID SEEDS TO GENERATE A
MASSIVE INCREASE IN YIELD AND
PRODUCTION OF THESE GRAIN
PRODUCTS LIKE CORN AND SOY AND
WHEAT, FOUND WAYS TO FEED THESE
GRAINS TO CATTLE AND OTHER
LIVESTOCK THAT WOULD NOT
NORMALLY EAT THOSE FOODS AS WELL
AS CONVERT THOSE GRAINS DIRECTLY
INTO THESE ULTRAPROCESSED FOODS
THAT HAVE THESE CHEAP INPUTS
LEADING TO THE CONVENIENT AND
INEXPENSIVE ULTRAPROCESSED FOOD
IN THE FOOD SUPPLY, AND THE
AMAZING THING TO ME IS THAT TWO
THIRDS OF THAT INCREASE IN FOODS
AVAILABLE IN THE FOOD SUPPLY
WENT IN THE TRASH AND ONLY
ONE-THIRD WAS ASSOCIATED WITH
THE INCREASE IN CALORIE INTAKE
REQUIRED TO EXPLAIN INCREASED
OBESITY IN THE UNITED STATES.
SO WITH THAT, I'LL END MY TALK
AND I LOOK FORWARD TO THE
QUESTION AND ANSWER SESSION.
THANK YOU.
>>THANK YOU VERY MUCH SH KEVIN.
THAT IS CERTAINLY AN EXCITING
AND SOMEWHAT FRIGHTENING
PROSPECT THAT YOU -- WELL, AS
ANTICIPATED, WE HAVE LOTS OF
QUESTIONS.
SO OUR TIME GOES UNTIL 6:00,
WHEN THEY SHUT EVERYTHING DOWN.
SO I'M GOING TO ASK YOU SOME OF
THESE QUESTIONS AND PERHAPS
DON'T TRY AND GO TOO FAR I A WAY
SO WE CAN GET TO MOST OF THEM.
SO ONE OF THE QUESTIONS THAT IS
ASKED IS, HOW DOES HIGH BLOOD
PRESSURE RELATE TO THE FAT BRAIN
CARDIOENDOCRINE SYSTEM?
DOES BLOOD PRESSURE ITSELF
INFLUENCE THE FAT CELL BRAIN
ENDOCRINE SYSTEM?
YOUR RESULTS SEEM TO BE
INDEPENDENT OF BLOOD PRESSURE,
BUT ONE MIGHT EXPECT THAT BLOOD
PRESSURE COULD BE A GREAT
MITIGATING FACTOR, BECAUSE IT
COULD INFLUENCE THE
BETA-ADRENERGIC SYSTEM.
SO WOULD EITHER OF YOU WISH TO
COMMENT ABOUT THIS?
PERHAPS, AARON, YOU'D LIKE TO GO
FIRST.
>>SURE.
I THINK IT'S VERY IMPORTANT TO
CONSIDER HOW BLOOD PRESSURE
INTERACTS WITH OTHER ASPECTS OF
THE CARDIOMETABOLIC SYSTEM.
AND SO THE FIRST QUESTION IS DO
PEOPLE WHO HAVE HIGHER BLOOD
PRESSURES, DO THEY HAVE HIGHER
LEVELS OF BROWN FAT -- ENERGY
PRESSURE, IT DOESN'T SEEM TO BE
THE CASE FOR ANY NUMBER OF
DIFFERENT REASONS.
AND CERTAINLY WHERE YOU
INTERVENE IS GOING TO IMPACT
WHETHER OR NOT THE BLOOD
PRESSURE IS AFFECTED.
SO FOR EXAMPLE, IF YOU WANT TO
DRIVE FAT -- WHITE FAT BREAKD
BREAKDOWN, TO BURN EXCESS FAT
AND YOU WANT TO INCREASE FAT
METABOLIC ACTIVITY TO REDUCE THE
AMOUNT THAT'S IN THE BODY, THE
ADRENERGIC SYSTEM IS THE
SIMPLEST CONCEPTUAL WAY BECAUSE
IT'S HARD WIRED INTO OUR SYSTEM,
SO YOU CAN HAVE AN INCREASE IN
BLOOD PRESSURE ON THE BACK END,
AS WE SAW WITH MIRABEGRON AND HE
IF HE DRIN BEFORE THAT IN YOU A
OF OUR PUBLICATIONS AND OTHER
GROUPS AS WELL.
CAREY, FOR EXAMPLE, IN
AUSTRALIA.
SO I THINK IT'S A GREAT POINT
THAT BLOOD PRESSURE HAS TO BE
ACCOUNTED FOR AND THERE ARE
INTERVENTIONS LIKELY TO BE MORE
SAFE AND NOT INVOLVE INCREASES
IN BLOOD PRESSURE BUT YOU NEVER
KNOW WHAT KIND OF COMMON
REGULATORY RESPONSE WILL COME UP
AND THEREFORE YOU HAVE TO
MONITOR IT CAREFULLY.
>>SO RELATED TO THAT IS THE
QUESTION OF WHETHER DISREGULATED
BROWN FAT ACTIVATION, IS THAT
ASSOCIATED WITH CHANGES IN HARD
COLD SENSITIVITY, OR IS IT THE
HARD COLD SENSITIVITY THAT DRIVE
THE PROCESS?
>>THAT'S A BILLION DOLLAR
QUESTION RIGHT THERE.
I WOULD SAY THAT THERE WAS A
VERY NICE WORK, SOME FROM OUR
COLLEAGUES IN CANADA, SOME WORK
THAT I KNOW MORE DIRECTLY FROM
OUR GROUP AT NIH LED BY KONG
CHEN AND -- AS THE FIRST AUTHOR
WHERE THEY LOOKED AT BROWN FAT
ACTIVITY AND COLD TOLERANCE IN A
GROUP OF MEN WITH OBESITY AND
THEN A GROUP OF MEN WHO ARE LE
LEAN.
AND THE MEAN RESULT OF THAT
STUDY WAS TO FIND THAT MEN WITH
OBESITY HAD LESS COLD TOLERANCE
AND LESS ABILITY TO GENERATE
HEAT THAN MEN WHO WERE LEAN, AND
PART OF THAT DIFFERENCE BETWEEN
THE MEN WITH LEANNESS AND THE
MEN WITH OBESITY IS THAT THE MEN
WITH OBESITY HAD LESS FUNCTIONAL
BROWN FAT.
IT WASN'T SO SIMPLE TO FORM A
DIRECT CORRELATION BETWEEN THE
TWO, BUT IT CERTAINLY DOES
APPEAR THAT PEOPLE WHO HAVE
DISREGULATED THAT ARE ASSOCIATED
WITH DEFICIENCIES IN COLD
RESPONSES.
HEAT, WE DIDN'T STUDY.
THAT IS A CLINICAL TRIAL THAT
SHOULD BE GOING ON SOON, BUT WE
DON'T KNOW THAT OTHER SIDE OF
IT, JUST COLD.
>>SO KEVIN, AS A QUESTION OF
WHETHER YOU THINK THE DRASTIC
DROP IN THE RESTING METABOLIC
RATE IN YOUR STUDY WHICH WAS
BROUGHT ON BY RAPID WEIGHT LOSS,
IS THAT SORT OF ANALOGOUS TO THE
BODY GOING INTO A KIND OF PANIC
MODE, SORT OF MAXIMIZING
CONSERVATION AND IF SO, IS THAT
LINKED TO THE ADRENERGIC NERVOUS
SYSTEM?
>>YEAH, GREAT QUESTION.
SO I THINK THERE'S KIND OF TWO
PHASES OF THIS, WHICH ARE
IMPORTANT TO KIND OF
DISTINGUISH.
ONE IS THE SORT OF ACTIVE WEIGHT
LOSS PHASE WHERE PEOPLE HAVE
DRASTICALLY CUT CALORIES AND ARE
CONTINUING TO LOSE WEIGHT, AND
IT SEEMS LIKE THAT RESPONSE THAT
DROP IN RESTING METABOLIC RATE
IS PROPORTIONAL TO HOW MUCH
PEOPLE HAVE CUT THEIR CALORIES
IN THEIR DIET.
AND IT SEEMS TO BE RELATED TO
SYMPATHETIC NERVOUS SYSTEM TONE,
IT SEEMS TO BE RELATED TO THE
DROP IN LEPTIN, IT MIGHT BE
RELATED TO THE THYROID ACCESS,
BUT THEN THERE'S THIS LONGER
TERM EFFECT WHICH WE OBSERVE
WHERE PEOPLE ARE NO LONGER
ACTIVELY LOSING WEIGHT, SO AT
SIX YEARS, THERE SEEMS TO BE
THIS CONTINUED SUPPRESSION OF
RESTING METABOLIC RATE.
DESPITE THE FACT THAT THEY'RE NO
NO LONGER IN THIS NEGATIVE
ENERGY BALANCE STATE.
AND THE QUESTION IS, IS THERE
SOMETHING DIFFERENT GOING ON
THERE.
AND I THINK THAT THERE'S SOME
INTRIGUING DATA FROM OTHER
PEOPLE'S STUDIES THAT SUGGEST
THAT IT'S POSSIBLE THAT ONE OF
THE THINGS THAT'S INTERESTING IS
THAT OUR PARTICIPANTS HAD BECOME
VERY PHYSICALLY ACTIVE ON
AVERAGE.
THERE WAS QUITE A BIT OF
VARIABILITY, BUT THE FOLKS WHO
HAD BECOME THE MOST PHYSICALLY
ACTIVE INDEED WERE THE ONES WHO
HAD THE GLAI THE GREATEST SUSTAD
REDUCTION IN THE RESTING
METABOLIC RATE OVER THE SIX YEAR
TIME PERIOD.
SO THERE'S AN INTRIGUING IDEA
THAT AS CHRONIC PHYSICAL
ACTIVITY INCREASES, PERHAPS THE
BODY IS LEARNING TO EXPEND LESS
ON OTHER ASPECTS OF MAYBE IMMUNE
SYSTEM FUNCTION IS GOING DOWN
BECAUSE INFLAMMATION IS
DECREASED BECAUSE OF THE
INCREASED PHYSICAL ACTIVITY,
MAYBE LESS ENERGY IS SPENT ON
OTHER PHYSIOLOGICAL FUNCTIONS.
UNFORTUNATELY WE JUST DON'T KNOW
HOW TO TIE EVERY CALORIE THAT WE
CAN MEASURE IN OUR INSTRUMENTS
TO EXACT BIOLOGICAL FUNCTIONS OF
DIFFERENT ORGANS AND DIFFERENT
CELL TYPES OF THE BODY.
THAT WOULD BE THE DREAM, RIGHT,
TO BE ABLE TO JUST COUNT UP ALL
THE FUNCTIONS OF ALL THE
DIFFERENT CELLS AND BE ABLE TO
ASSIGN AN ATP COST AND JUST SAY
OH, YES, WE CAN EXPLAIN EVERY
CALORIE THAT'S EXPENDED, BUT IT
IS AN INTERESTING OBSERVATION
THAT, FOR EXAMPLE, PEOPLE IN
HUNTER GATHERER TRIBES WHO ARE
VERY, VERY ACTIVE, THIS IS WORK
PRIMARILY FROM HER MAN PONZER'S
GROUP, BURN VERY, VERY SIMILAR
NUMBERS OF TOTAL CALORIES AS
SEDENTARY FOLKS WHO ARE MUCH
HEAVIER BUT THEN IF YOU ADJUST
FOR YOUR BODY COMPOSITION CHA
CHANGE, THEY END UP BURNING A
MYSTERIOUSLY SIMILAR AMOUNT OF
CALORIES DESPITE BEING MUCH,
MUCH MORE PHYSICALLY ACTIVE,
SUGGESTING THAT THEY'RE BURNING
FEWER CALORIES ON OTHER THINGS.
PERHAPS THE BIGGEST LOSERS ARE
ANOTHER EXAMPLE OF THAT, WHO
HAVE CHRONICALLY RELAXED
PHYSICAL ACTIVITY OVER A NUMBER
OF YEAST AND -- UNRELATED TO THE
NEGATIVE ENERGY BALANCE AND
WEIGHT LOSS WHICH WE OBSERVED
EARLY ON.
>>APROPOS OF THAT, AARON, I
GUESS THIS IS REALLY FOR YOU,
HAVE THERE BEEN STUDIES OF BROWN
FAT IN NORDIC PEOPLE, PEOPLE WHO
ARE LIVING UNDER LOWER
TEMPERATURE CONSISTENTLY AND
ADAPTING AND, FOR THE MOST PART,
ON A PRETTY HIGH FAT DIET?
>>YES, VERY LITTLE HAS BEEN
DONE SO FAR BECAUSE IT'S REALLY
HARD TO MEASURE BROWN FAT
ACTIVITY IN PEOPLE WHO ARE NOT
NEAR MRIs OR PET/KRCH T PET/CT .
SO THE ONLY THING THAT'S BEEN
DONE IS A STUDY BY STEPHANIE
LEVY'S GROUP, PEOPLE IN
NORTHEASTERN RUSSIAN FEDERATION
OUT IN THE SAHA REGION, AND THEY
USE INFRARED IMAGING WHICH HAS
ITS CHALLENGES TO USE, BULL IT
DID ABUT ITDID APPEAR BASED ON Y
SHOW IS THERE'S A DIFFERENCE IN
THE COLD TOLERANCE AND ENERGY
EXPENDITURE COMPARED TO PEOPLE
LIVING IN CHICAGO.
BUT THESE KINDS OF STUDIES NEED
TO BE REPEATED AND IDEALLY WITH
THE STATE OF THE ART MEASUREMENT
SO WE CAN GET BOTH AN ACCURATE
AND PRECISE ASSESSMENT OF THE
BROWN ADIPOSE TISSUE AND ENERGY
EXPENDITURE AND COLD TOLERANCE
IN COMMUNITIES THAT WOULD HAVE
SPENT HUNDREDS IF NOT THOUSANDS
OF YEARS IN COLDER ENVIRONMENTS.
I WILL SAY THIS, THAT WE HAVE
STUDIED PEOPLE WHO CAME DIRECTLY
FROM CENTRAL AFRICA AND
PARTICIPATED IN THE CLINICAL
TRIALS WE'VE CONDUCTED AT THE
NIH AND THOSE AFRICAN MEN HAD A
LARGE AMOUNT OF BROWN FAT.
SO I DON'T THINK IT'S AS SIMPLE
AS SAYING THAT COMMUNITIES THAT
ARE IN HIGHER LATITUDES WILL
HAVE MORE BROWN FAT AND MORE
COLD TOLERANCE, IT'S ACTUALLY
MORE COMPLICATED AND IT MAY BE
BECAUSE THEY'RE ALSO -- YOU
DRESS TO WHAT YOUR ENVIRONMENT
REQUIRES OF YOU, OR THAT BROWN
FAT IS INVOLVED IN MORE THAN
JUST COLD RESPONSE AND HAS OTHER
RESPONSE EXHIBITS AS WELL.
SO WE NEED TO SEPARATE THOSE TWO
AND GET MORE INFORMATION ABOUT
IT.
>> I VISITED THE MEDICAL CENTER
IN FAIRBANKS ALASKA, WHERE THEY
HAVE A PET SCAN AND ALL THE
MODERN EQUIPMENT AND DEAL WITH
THIS POPULATION, PARTICULARLY
THE ANOMITE.
AT ANY RATE.
KEVIN, WHAT IS ULTRA PROCESSING
ACTUALLY -- WHAT DOES IT
INVOLVE?
IT'S A BIG WORD, IT'S A FANCY
WORD, BUT WHAT DOES IT MEAN?
WHAT DO THEY ACTUALLY DO?
>>YEAH, SO, I MEAN, THERE ARE A
WHOLE BUNCH OF REALLY SMART FOOD
SCIENTISTS AND TECHNOLOGISTS WHO
HAVE FOUND INGENIUS WAYS TO KIND
OF EXTRACT INGREDIENTS FROM
VARIOUS FOOD STUFFS, REPACKAGE
THEM AND REFORMULATE THEM IN
DIFFERENT WAYS TO MAKE THEM
SHELF-STABLE AND LIMIT, YOU
KNOW, MICROBIAL ASPECTS TO KIND
OF MAKE VERY SAFE FOODS, MAKE
THEM CONVENIENT AND INEXPENSIVE,
AND ESSENTIALLY REFORMULATE FROM
KIND OF INGREDIENTS THAT ARE NO
LONGER SORT OF PHYSICALLY
IDENTIFIABLE WITH THE PLANTS AND
ANIMALS THAT THEY CAME FROM.
AND ONE OF THE QUESTIONS IS, WHY
IS IT THAT THESE FOODS, WHICH
ARE NOW RELATED IN HUNDREDS OF
EPIDEMIOLOGICAL STUDIES WITH
INCREASED RISK FOR OBESITY, TYPE
2 DIABETES, CARDIOVASCULAR
DISEASE, MANY FORMS OF CANCER
AND ALL OF THESE OTHER THINGS,
WHAT IS IT ABOUT THESE FOODS
THAT ARE CAUSING THESE PROBLEMS?
AND MY PARTICULAR INTEREST IS
WHAT IS IT ABOUT THESE FOODS
THAT CAUSE PEOPLE TO CLEARLY
OVEREAT AND GAIN WEIGHT AND GAIN
BODY FAT DESPITE THEM NOT TRYING
TO DO SO, EVEN WHEN YOU MATCH
THE OVERALL DIETS FOR THE
PRESENTED CALORIES, SALT, SHEUL
GAR, FAT, AND FIBER, AND
GLYCEMIC LOAD?
AND WE DON'T KNOW THE ANSWER.
THAT'S, I THINK, A GREAT
MYSTERY, AND I THINK WE NEED --
GIVEN THAT THESE FOODS NOW MAKE
UP MORE THAN HALF OF THE U.S.
FOOD SUPPLY, I THINK WE NEED TO
KNOW THE ANSWER TO THAT
QUESTION.
SO WE HAVE A STUDY ONGOING NOW
AT THE CLINICAL CENTER WHERE
WE'VE REFORMULATED THE
ULTRAPROCESSED DIET IN WAYS THAT
WE THINK MIGHT MITIGATE THE
INCREASE IN ENERGY INTAKE, AND I
THINK THAT WE'LL WAIT AND SEE
FOR THE RESULTS OF THAT IF WE'RE
SUCCESSFUL OR NOT.
BUT WE HAVE DESIGNED THESE NEW
ULTRAPROCESSED DIETS THAT STILL
MAINTAIN 80% OF CAL R CALORIES M
ULTRAPROCESSED FOODS BUT ARE NOW
BURIED IN OTHER NUTRITIONAL
PARAMETERS THAT WE THINK WILL
MITIGATE THOSE PROPERTIES.
BUT I THINK THAT THIS IS ONE OF
THE GREAT MYSTERIES, IS THAT
THERE'S THIS CLEAR SIGNAL THAT
CONSUMPTION OF THESE FOODS IS
PROBLEMATIC IN THE EPIDEMIOLOGY.
THERE'S OUR TRIAL WHICH SHOWS
THAT THEY SEEM TO CAUSE PEOPLE
TO CONSUME EXCESS CALORIES.
WHAT'S THE MECHANISM?
AND WHAT IS IT ABOUT THESE FOODS
THAT CAUSES THAT?
WE JUST DON'T KNOW.
>>IS THERE A CULTURAL ELEMENT
TO IT?
I MEAN, THE PUBLIC, WE'RE ALL
SUBJECTED THROUGH ADVERTISING
AND EVERYTHING ELSE OF THESE
THINGS THAT NOT ONLY LOOK GOOD,
THEY TASTE GOOD, AND ALWAYS, THE
ACTORS AND ACTRESSES ARE USUALLY
SLIM AND TRIM AND VERY ACTIVE
AND SO FORTH.
IS THERE A CULTURAL THING?
IF YOU INTRODUCED A PROCESSED
FOOD THING AMONGST THE
POPULATION THAT'S NOT EXPOSED TO
THOSE CULTURAL THINGS, I DON'T
KNOW, MAYBE THAT'S IMPOSSIBLE,
BUT --
>>THIS IS ACTUALLY ONE OF THE
THINGS THAT FOLKS LIKE CARLOS
MONTERO IN BRAZIL WERE CONCERNED
ABOUT, BECAUSE IN THEIR COUNTRY,
WHEN HE INTRODUCED THE NOVA
CLASSIFICATION SYSTEM, MUCH,
MUCH LOWER PROPORTION OF THE
FOOD SUPPLY WAS COMING FROM
ULTRAPROCESSED FOODS, AND YET
ONE OF THE THINGS THAT HAS BEEN
CLEAR IS SOMETHING THAT BARRY
POPKIN IN NORTH CAROLINA HAS
MENTIONED AS DIFFERENT CULTURES
UNDERGO WHAT'S CALLED THE
NUTRITION TRANSITION, AS THEY
BECOME RICH ENOUGH TO START TO
KIND OF MOVE OUT OF POVERTY AND
AFFORD THE KINDS OF LIFESTYLE
THAT WE IN THE WEST ARE
FORTUNATE ENOUGH TO HAVE, ONE OF
THE THINGS THAT THEY DO IS THEY
CHANGE THEIR DIETS QUITE
DRAMATICALLY.
THE LOWER AMOUNTS OF THEIR
INCOME IS SPENT ON FOODS AND
THOSE FOODS BECOME RELATIVELY
ACCESSIBLE AND EASIER TO EAT.
AND SO EVEN IN THOSE COUNTRIES,
WE SEE THAT THE INCREASE -- AS
ULTRAPROCESSED FOODS INCREASE,
THERE IS A CORRELATION WITH
INCREASING RATES OF OBESITY AND
EVEN WITHIN THE POPULATIONS, YOU
CAN LOOK AT A CORRELATION
BETWEEN -- IN PROSPECTIVE
LONGITUDINAL STUDIES AS WELL AS
CROSS-SECTIONAL STUDIES, THOSE
WHO EAT MORE ULTRAPROCESSED
FOODS TEND TO HAVE GREATER RATES
OF EE BEES IT.
AGAIN, WHY, WE DON'T KNOW.
THE GOAL WOULD BE TO FIGURE OUT
WHAT THE MECHANISM IS SO WE CAN
INFORM PRODUCT REFORMULATIONS
AND FOREIGN POLICY MAKERS TO
WHAT THE REAL PROBLEMS ARE.
WHEN YOU HAVE A SYSTEM RIGHT NOW
LIKE THE NOVA SYSTEM THAT
BASICALLY DEMONIZES MORE THAN
HALF OF THE FOOD SUPPLY, IT'S
NOT A VIABLE RECOMMENDATION TO
JUST CUT HALF OF THE FOOD SUPPLY
OUT OF THE FOOD SUPPLY.
YOU HAVE TO BETTER UNDERSTAND
WHAT THE PROBLEMS ARE IN ORDER
TO ADDRESS THEM, EITHER WITH
POLICY OR WITH REFORMULATIONS.
>>STUDIES OF THE TYPE THAT
EITHER OF YOU DESCRIBE BEEN
PERFORMED IN NATIVE AMERICAN
POPULATIONS, PARTICULARLY THOSE
LIVING ON A RESERVATION WHERE
THE AVAILABILITY OF FRESH
FOODS IS PROFOUNDLY LIMITED AND
IN SOME INSTANCES, THERE IS
ACTUALLY GOVERNMENT SUPPORT FOR
FAST FOODS.
HAVE THOSE POPULATIONS BEEN
STUDIED FROM THE STANDPOINT OF
THE ISSUES THAT BOTH OF YOU DEAL
WITH?
>>I CERTAINLY KNOW OUR
COLLEAGUES IN PHOENIX AT THE
NIDDK BRANCH OUT THERE STUDIED
THEM EXTENSIVELY.
I DON'T KNOW THAT THEY'VE LOOKED
AT ULTRAPROCESSED FOODS BUT
THEY'VE CERTAINLY MEASURED
VARIOUS ASPECTS OF ENERGY
METABOLISM AND FOOD INTAKE, AND
AARON MIGHT BE FAMILIAR WITH ANY
BROWN ADIPOSE TISSUE STUDIES,
BUT I'M NOT AWARE OF -- IF
THEY'VE FOCUSED ON THAT.
>>BOTH OF YOU -- GO AHEAD,
AARON.
>>I WAS GOING TO SUPPORT WHAT
KEVIN JUST SAID, THAT OUR
COLLEAGUES HAVE DONE SOME VERY
EXTENSIVE STUDIES LOOKING AT THE
PIMA INDIANS.
THERE WAS A PAPER PUBLISHED LIKE
30 YEARS AGO SHOWING THAT THEIR
DIETS HAVE CHANGED AND THAT
MIGHT BE ASSOCIATED WITH THE
HIGH RATES OF OBESITY AND
DIABETES THAT ARE SEEN IN THOSE
POPULATIONS, BUT NOT
SPECIFICALLY ULTRAPROCESSED
FOODS PER SE AS OPPOSED TO THE
KINDS OF DETAILED STUDIES THAT
KEVIN IS CONDUCTING.
>> HMMM.
THAT'S INTERESTING.
SO IS A KETOGENIC DIET -- DOES
IT HAVE ANY ADVANTAGES AS A
DIET, PER SE?
WHAT ARE YOUR COMMENTS?
THAT SEEMS TO BE ALMOST THE
LATEST RAGE.
>>SO THE STUDY THAT I SHOWED
WITH THE VERY LOW CARBOHYDRATE,
HIGH FAT DIET, THAT WAS A
KETOGENIC DIET.
THERE ARE VERY HEALTHY VERSIONS
OF KETOGENIC DIETS AND WE TRIED
TO EMULATE A VERY HEALTHY
VERSION IN OUR STUDY.
IN TERMS OF WEIGHT LOSS, A LOT
OF PEOPLE EXPERIENCE, YOU KNOW,
GREAT SUCCESS WITH THOSE DIETS.
BUT A LOT OF PEOPLE ALSO
EXPERIENCE GREAT SUCCESS WITH
THE KIND OF DIET THAT WE TESTED
IT AGAINST, WHICH WAS A VERY LOW
FAT PLANT-BASED DIET.
AND SO THE QUESTION IS WHY, WHY
ARE SOME PEOPLE MORE SUCCESSFUL
ON ONE DIET VERSUS ANOTHER, IS
IT SOMETHING ABOUT THE DIETS,
PER SE, INTERACTION BETWEEN
THEIR PARTICULAR BIOLOGY AND THE
DIETS OR SOCIAL SUPPORT SYSTEMS,
THEY WERE AT THE RIGHT PLACE AT
THE RIGHT TIME IN THEIR LIFE TO
MAKE THAT CHANGE MORE ADHERENT
AS OPPOSED TO THE LAST TIME THEY
TRIED A DIFFERENT DIET, WHERE
THEY WERE UNDERGOING SOME SOCIAL
UPHEAVAL LIKE LOSING A JOB,
GOING THROUGH DIVORCE, SOMETHING
LIKE THAT.
SOME PEOPLE SEEM TO HAVE GREAT
SUCCESS ON SOME DIETS WHILE
OTHERS DON'T.
WHAT WE DO KNOW IS THIS
FUNDAMENTAL BIOLOGY THAT RESISTS
WEIGHT CHANGE SEEMS TO BE
RELEVANT ON ALL OF THESE
DIFFERENT KINDS OF DIETS.
ONE OF THE ADVANTAGES OF THE
KINDS OF STUDIES THAT WE DO IS
THAT WE DON'T ALLOW PEOPLE TO
CHEAT, RIGHT?
WE ESSENTIALLY COMPLETELY TAKE
OVER THEIR FOOD ENVIRONMENT.
THEY HAVE NO ACCESS TO FOODS
THAT ARE NOT PART OF THE
KETOGENIC DIET.
THEY HAVE NO ACCESS TO FOODS
THAT ARE NOT PART OF THE PLANT
BASED LOW FAT DIET OR THEY DON'T
HAVE ACCESS TO FOODS THAT ARE
NOT PART OF THE UNPROCESSED
DIET.
AND SO WHEN YOU TAKE AWAY THOSE
FACTORS, THOSE OTHER INFLUENCES
IN THE FOOD ENVIRONMENT AND THE
ABILITY TO KIND OF CHEAT ON YOUR
DIETS, WHAT WE SEE ARE THESE
KIND OF VERY PROFOUND EFFECTS ON
ENERGY INTAKE AND BODY WEIGHT
CHANGE WHEN PEOPLE AREN'T EVEN
TRYING TO CHANGE THEIR BODY
WEIGHT, WHICH I THINK IS PRETTY
INTERESTING.
AND IF WE COULD BETTER
UNDERSTAND WHAT ARE THE FACTORS
IN OUR FOOD ENVIRONMENT THAT ARE
RESULTING IN JUST THESE SHIFTS
IN THE BIOLOGY OF WHERE OUR
APPETITE CURVE IS SITTING, THEN
WE WOULD GO A LONG WAY TO BETTER
UNDERSTANDING, NUMBER ONE, WHY
WE HAVE AN OBESITY EPIDEMIC IN
THE FIRST PLACE, AND NUMBER TWO,
WHAT WE COULD DO TO ACTUALLY DO
SOMETHING ABOUT IT, AND WHY SOME
PEOPLE MIGHT BE MORE SUCCESSFUL
ON ONE DIET VERSUS ANOTHER.
>>IS OVEREATING AN ADDICTION?
>>I THINK THE WORD ADDICTION IS
USED OUTSIDE MY FIELD OF
EXPERTISE.
I AM NOT AN ADDICTION SCIENTIST,
AND SO I WOULD NOT CHARACTERIZE
IT THAT WAY WITHOUT MUCH BETTER
UNDERSTANDING.
IT'S CERTAINLY TRUE THAT THE
REGIONS OF THE BRAIN THAT HAVE
BEEN IMPLICATED IN BOTH
ADDICTION TO DRUGS OF ABUSE WERE
PROBABLY NATURALLY FORMED TO
KIND OF MOTIVATE BEHAVIORS THAT
ARE IMPORTANT FOR PROPAGATION OF
THE SPECIES.
THINGS LIKE SEX AND THINGS LIKE,
YOU KNOW, EATING AND SO I DON'T
THINK THAT THERE'S MUCH EVIDENCE
THAT FOOD INTA INIS ADDICTIVE IE
SAME WAY A DRUG OF ABUSE IS, BUT
IT CERTAINLY SEEMS LIKE SOME OF
THE NEUROBIOLOGY MIGHT BE IN
COMMON BETWEEN THE TWO THINGS.
>>SO SPEAKING OF NEUROBIOLOGY
AND ADDICTION, I READ -- TO
PREPARE A LITTLE BIT, I READ
ABOUT CANNABINOIDS AND THE FACT
THAT APPARENTLY THERE ARE
RECEPTORS IN BOTH WHITE FAT AND
BROWN FAT.
AND NOW THAT IT SEEMS AS IF
CANNABINOIDS ARE BEING
INTRODUCED INTO GENERAL LIFE FOR
AN AWFUL LOT OF PEOPLE, I GUESS
IT'S APPROPRIATE TO ASK WHAT
THEIR EFFECT IS, DO WE KNOW, ON
THE BROWN FAT POPULATION, IT'S
SIZE OR ITS ACTIVITY, IS THERE
SOMETHING THAT SHUL HAVE SOME
CONCERN OR INTEREST IN?
AARON?
>>YES.
THERE ARE RECEPTORS AND THERE IS
RESEARCH IN THIS AREA, SOME OF
WHICH I'M ACTUALLY REVIEWING SO
I CAN'T COMMENT TOO MUCH ABOUT
IT, BUT I WILL SAY THAT AT THE
GLOBAL LEVEL, CLEARLY THERE'S AN
IMPACT OF CANNABINOIDS ON
APPETITE, AND THAT BLOCKING
THOSE SIGNALS CAN LEAD TO SOME
WEIGHT LOSS BUT CAUSES A LOT OF
OTHER EFFECTS THAT, THEREFORE,
MAKE IT DIFFICULT TO DEVELOP A
PHARMACEUTICAL AGENT BASED ON
THOSE SIGNALING PATHWAYS TO BE
AVAILABLE IN THE MARKET
CURRENTLY.
CAN SPECIFIC CANNABINOID
RECEPTORS, CAN THEY CAUSE BROWN
ADIPOCYTE PROLIFERATION THAT IS
STILL BEING INVESTIGATED AND
IT'S A DISTINCT POSSIBILITY AND
HOPEFULLY WE'LL GET MORE CLARITY
ON THAT OVER THE NEXT FEW MONTHS
AND YEARS.
>>GOOD.
SO WOULD EITHER OF YOU LIKE TO
COMMENT ABOUT THE -- WHAT SEEMS
TO BE THE CURRENT FOCUS PUBLIC
ATTENTION, AND THAT'S THE NEW
TYPES OF DRUGS THAT ARE BEING
PROMOTED FOR CONTROL OF DIABETES
AND PEOPLE SEEM TO LOSE A
TREMENDOUS AMOUNT OF WEIGHT
WHILE THEY'RE TAKING THESE DRU
DRUGS.
DO WE REALLY UNDERSTAND HOW
THAT'S HAPPENING OR WHAT ARE
YOUR THOUGHTS ABOUT IT?
KEVIN, DO YOU WANT TO COMMENT ON
THAT?
>>SURE.
I MEAN, I THINK THAT, YES, IT'S
A VERY EXCITING TIME TO BE IN
OBESITY SCIENCE, AND THE FACT
THAT THERE ARE THESE DRUGS THAT
ARE MIM MIBGING VERY HIGH LEVELS
OF GLP1, WHICH IS AN ENDOCRINE
HORMONE, THESE DRUGS BASICALLY
ARE LONG-ACTING VERSIONS OF GLPR
MUCH LONGER THAN IS
PHYSIOLOGICALLY NORMAL AFTER
MEALS AND CAN REACH VERY HIGH
LEVELS AND AS A RESULT, DECREASE
PEOPLE'S APPETITE BY WAYS THAT
ARE NOT COMPLETELY UNDERSTOOD,
ALTHOUGH A LOT OF THE
NEUROBIOLOGY IS BEGINNING TO BE
UNCOVERED, BUT THAT SEEMS TO BE
THE PRIMARY WAY THAT THEY WORK
IN HUMANS AS OPPOSED TO CHANG CE
IN CALORIE EXPENDITURE, FOR
EXAMPLE, ALTHOUGH I THINK THAT
THERE IS SOME OPEN QUESTIONS IN
THAT REGARD, WHETHER OR NOT THEY
CAN HELP PREVENT SOME OF THE
SLOWING OF METABOLISM THAT
OCCURS I THINK WITH WEIGHT LOSS
IS STILL A LITTLE BIT OF AN OPEN
QUESTION, BUT IT'S CLEAR THAT
THE PRIMARY REASON THAT THEY
WORK IS THEY DECREASE PEOPLE'S
APPETITE.
HOW THAT EXACTLY WORKS AND WHAT
PARTICULAR AREAS OF THE BRAIN,
HINDBRAIN IS IMPORTANT,
HYPOTHALAMUS IS IMPORTANT, BUT I
DON'T THINK WE KNOW IN HUMANS
EXACTLY THE RELATIVE ROLE OF
BOTH OF THOSE BRAIN REGIONS.
>>SO YOUR STUDIES FOCUSED ON
PEOPLE WHOM AS YOU SAY YOU'RE
CONTROLLING EVERYTHING THAT'S
GOING IN AND COMING OUT AND SO
FORTH.
BUT YOU'RE FOCUSING ON DIET AND
CALORIES.
SO SUPPOSE IF EXERCISE IS ADDED
ON TOP OF THAT, IS THERE SOME
SYNERGISTIC RELATIONSHIP, AND IF
SO, HOW DOES THAT WORK?
AND YOU MIGHT WONDER HOW IT
WORKS WITH THE BROWN FAT AS
WELL.
>>EXERCISE IS REALLY
INTERESTING.
YOU KNOW, WE DO HAVE OUR FOLKS
DO A MANDATORY AMOUNT OF
EXERCISE EVERY DAY, JUST SO THAT
THEY DON'T BECOME COMPLETELY
SEDENTARY AND WE CAN MIMIC THE
SORT OF PHYSICAL OVERALL
PHYSICAL ACTIVITY LEVEL OF FREE
LIVING FOLKS.
AND OF COURSE IN THE BIGGEST
LOSER FOLKS, THEY DID AN
ENORMOUS AMOUNT OF EXERCISE.
ONE OF THE THINGS THAT I THINK
IS INTERESTING IS THAT DURING
PERIODS OF WEIGHT LOSS, THE
EXERCISE EFFECT IS ACTUALLY
PRETTY MINIMAL COMPARED TO THE
EFFECT OF THE DIET CHANGE.
WHEREAS THINGS KIND OF FLIP
AFTER MANY, MANY YEARS AND LIKE
I SHOWED WITH THE BIGGEST LOSER
FOLKS BUT MANY OTHER PEOPLE HAVE
SHOWN THIS BEFORE, EXERCISE IS
QUITE GOOD FOR WHATEVER REASON
AT MAINTAINING PEOPLE'S WEIGHT
LOSS.
WHEREAS THE ENERGY INTAKE
DOESN'T REALLY MAKE TOO MUCH OF
AN EFFECT, AND PERHAPS THAT'S --
ONE WAY THAT YOU COULD THINK
ABOUT THAT IS THAT THE FEEDBACK
CONTROL CIRCUIT THAT'S GOVERNING
APPETITE, WHILE YOU'RE BASICALLY
ALLOWING PEOPLE TO EAT A LITTLE
BIT MORE FOOD IF THEY'RE
EXERCISING AND SO THE FEEDBACK
CONTROL STRENGTH ON THE APPETITE
SIDE IS NOT QUITE AS HIGH, IF
YOU'RE EXERCISING.
AT LEAST THAT'S ONE THEORETICAL
WAY TO LOOK AT IT AND YOU COULD
DESIGN STUDIES TO TEST THAT
HYPOTHESIS.
BUT IT'S VERY INTERESTING TO ME
THAT THE EFFECTS OF EXERCISE ARE
MINIMAL FOR WEIGHT LOSS DURING
THE ACTIVE WEIGHT LOSS PHASE AND
THEY SEEM TO REVEAL THEMSELVES
IN THE WEIGHT LOSS MAINTENANCE
PHASE AS BEING QUITE AN
EFFECTIVE TOOL TO KEEP THE
WEIGHT OFF IF YOU CAN MAINTAIN A
HIGHER LEVEL OF EXERCISE.
>>I WOULD SAY WE WERE VERY
EXCITED AT THE BEGINNING TO
THINK THAT EXERCISE COULD
INCREASE BROWN ADIPOSE TISSUE
ACTIVITY AND THEY WOULD WORK
TOGETHER, BECAUSE YOU'RE TALKING
ABOUT AN ADRENERGIC STIMULUS AND
SO YOU HAVE EPINEPHRINE OR
ADRENALINE, NOR OWE ADRENALINE
IN THE BLOOD, BUT THE LEVELS
THAT ONE FINDS IN EXERCISE ARE
NOT NEARLY ENOUGH TO ACTIVATE
THE BROWN ADIPOSE TISSUE, AND AT
ONE LEVEL -- SO NOTHING HAS BEEN
SHOWN TO REALLY BE EFFECTIVE IN
THAT WAY AND IT POSSIBLE BECAUSE
WHEN YOU EXERCISE SUFFICIENTLY,
THE CORE GETS WARM AND IT SHUTS
DOWN THE BROWN ADIPOSE TISSUE.
AND SO, THEREFORE, EXERCISE I'S
BENEFIT IN TERMS OF BROWN
ADIPOSE TISSUE FUNCTION WOULD BE
MORE INDIRECT.
IT MIGHT IMPROVE INSULIN
SENSITIVITY, IT MIGHT IMPROVE
CATECHOLAMINE SIGNALING,
SIGNALING NOREPINEPHRINE AND
EPINEPHRINE SO THAT THEY WORK
BETTER.
SO IT'S NOT GOING TO BE
SOMETHING THAT CAUSES A
SPROUTING OF BROWN FAT, BUT IT
MIGHT MAKE IT WORK BETTER, KIND
OF LIKE WHAT KEVIN WAS
DESCRIBING, THAT IT'S NOT REALLY
FOR WEIGHT LOSS THROUGH ENERGY
EXPENDITURE DIRECTLY, IT'S MORE
FOR OTHER EFFECTS.
>>SO, YO UNFORTUNATELY WE HAVEO
END, BUT WE HAVE LOTS MORE
QUESTIONS.
AND THERE'S ONE IN PARTICULAR
WHICH MAYBE IS A SUITABLE ONE TO
CONCLUDE, WE'VE GOTTEN SEVERAL
INQUIRIES ABOUT THIS.
I GUESS THE QUESTION IS, WAS
MICHAEL POLLAN RIGHT SUGGESTING
THAT WHEN PEOPLE GO TO A
SUPERMARKET, THEY SHOULD STAY IN
THE SECTION WHERE THE FRESH
PRODUCE IS AND STAY AWAY FROM
THE FROZEN, THE PROCESSED, AND
EVERYTHING, AND THEY'LL REMAIN
HEALTHIER?
IS THAT A REASONABLE SUGGESTION
REGARDING ALL THESE VARIOUS
DIETS AND UNCERTAINTY ABOUT
THEIR EFFECTIVENESS IN
EVERYBODY?
OR IS THAT JUST AN INTERESTING
IDEA?
I MEAN, CERTAINLY AS PUBLIC
POLICY, IT'S PROBABLY NOT A
GREAT IDEA BECAUSE NOT EVERYONE
HAS THE MONEY AND THE TIME, THE
EQUIPMENT, AND THE SKILL AND THE
STORAGE SPACE REQUIRED TO
PREPARE MEALS IN THAT WAY.
IT'S ONLY THE VERY PRIVILEGED
FEW WHO HAVE THAT.
SO IF WE COULD MAGICALLY MAKE
THE COUNTRY HAVE -- EVERYBODY
HAVE ALL OF THOSE THINGS, THEN I
THINK THAT WOULD BE REALLY
EFFECTIVE POLICY ADVICE.
BUT WE DON'T.
AND SO I THINK THE QUESTION IS,
HOW DO WE MAKE FOODS THAT ARE
ACTUALLY -- PROMOTE HEALTH AND
PREVENT CHRONIC DIET-RELATED
DISEASES, HOW DO WE MAKE THAT
MORE AVAILABLE TO THE REST OF
THE COUNTRY WHO DOESN'T HAVE
THAT KIND OF PRIVILEGE.
>>AARON, YOU WANT THE LAST
WORD?
>>MY LAST WORD IS THAT I AGREE
WITH DR. HALL'S DESCRIPTION OF
THE SITUATION.
I THINK THAT BEYOND THAT, I HOPE
PEOPLE ARE LISTENING, RECOGNIZE
JUST HOW FASCINATING THIS FIELD
IS, HOW MUCH WE'VE LEARNED, HOW
MUCH MORE WE STILL HAVE TO LEARN
AND THAT PEOPLE SHOULD SUPPORT
THE RESEARCH EFFORTS THROUGH ANY
WAY POSSIBLE BECAUSE WE'VE GOT
REALLY TALENTED PEOPLE WHO ARE
TRYING TO MAKE A DIFFERENCE.
>>SO ON THAT NOTE, WHICH I'M
SURE EVERYONE LISTENING WOULD
HARDLY AGREE, I'M SURE THERE ARE
HUNDREDS IF NOT MAYBE SEVERAL
THOUSAND PEOPLE WATCHING ALL
THIS FROM AROUND THE WORLD, SO
ON THEIR BEHALF, AND CERTAINLY
MY OWN, I WANT TO THANK YOU BOTH
VERY MUCH FOR AN EXTREMELY
INFORMATIVE, EXCITING
PRESENTATION, GIVING US MUCH TO
THINK ABOUT, AND INDICATING THE
IMPORTANCE OF BUILDING BRIDGES
IN ALL DIFFERENT DIRECTIONS.
SO THANK YOU AGAIN, AND WE WILL
END THE SESSION.
THANK YOU.