Tip:
Highlight text to annotate it
X
>> HI, GOOD AFTERNOON.
I'M GLAD YOU ALL MADE IT OVER
HERE.
THIS IS THE ONLY SESSION OF THE
COURSE THAT'S HERE IN WILSON
HALL.
SO STARTING NEXT WEEK, WE'LL BE
BACK AT BUILDING 50.
LAST WEEK, I RECEIVED ABOUT A
HALF DOZEN E-MAILS FROM VARIOUS
PEOPLE WITH SUGGESTIONS OF
FUTURE TOPICS, SPEAKERS, A
COUPLE OF VERY GOOD HELPFUL
CRITICISMS.
I WELCOME YOU TO DO THAT BECAUSE
IT'S VERY HELPFUL TO US.
SO, I'M GOING TO RECOMMEND A
BOOK, MANY OF YOU MAY HAVE READ
IT.
IT'S CALLED THE OMNIVORE'S
DILEMMA.
I'LL PUT IT ON THE WEBSITE.
WE'RE DISCUSSING ONE OF THE
GREAT PROBLEMS WHICH SEEMS TO BE
INCREASING OF ENORMOUS SEVERITY,
RAISES INCREDIBLE QUESTIONS.
ONE OF THEM IS, WHERE IS MY N
ONE OF THEM, IS THIS AN AMERICAN
DISEASE OR IS THIS GLOBAL
DISEASE.
WE TAKE A LOT OF HITS IN THE
CARTOONS AROUND THE WORLD WITH
THINGS LIKE THIS.
IS THIS YOUR GLOBAL PROBLEM OR
IS THIS SOMETHING THAT'S KIND OF
RESTRICTED TO COUNTRIES THAT
HAVE MORE FOOD THAN THEY KNOW
WHAT TO DO WITH AND PERHAPS MORE
POVERTY THAN THEY KNOW HOW TO
DEAL WITH.
SO THIS IS A PARTIAL LIST OF THE
RISK FACTORS OF OBESITY, AND
THERE'S GREAT CONCERN.
WE'LL HEAR A LOT ABOUT IS
WHETHER THE EPIDEMIC IN
CHILDHOOD OBESITY IS GOING TO BE
TRANSLATED IN LATER LIFE INTO
THIS INCREDIBLE ARRAY OF
PREDOMINANTLY METABOLIC-TYPE
DISORDERS, INCLUDING MORE AND
MORE INFORMATION ABOUT OBESITY
AS A RISK FACTOR IN CERTAIN
CANCERS, INFECTION AND EVEN SOME
DISORDERS THAT WE THINK OF AS
BEING PRIMARILY IN THE CENTRAL
NERVOUS SYSTEM.
BUT OF COURSE THE BIG THING THAT
ONE HERE'S MOST ABOUT ARE THE
EPIDEMICS OF TYPE TWO DIABETES,
NON-ALCOHOLIC FATTY LIVER
DISEASE, CIRRHOSIS AND
HYPERTENSION OR
ARTERIOLOSCLEROSIS, MYOCARDIAL
INFARCTION.
IT'S BETWEEN WILL AND OTHER
THINGS.
IT'S EXPRESSED IN THE POEM
INVICT TUESDAY, I AM THE FASTER
OF MY FATE, I A THE CAPTAIN OF
MY SOUL.
IS THAT TRUE WHEN IT COMES TO
OBESITY?
DOES ANYBODY ACTUALLY CONQUER
THE PROBLEM BY SHEER WILL POWER.
HOPEFULLY OUR SPEAKERS TODAY
WILL HELP BECAUSE SOME OF US
NEED THAT HELP.
ON THE OTHER HAND IS THIS
SOMETHING ELSE, IS THIS
PREDOMINANTLY A GENETIC BASIS IN
WHICH OTHER THINGS, ENVIRONMENT,
ECONOMICS AND EVERYTHING ARE
SUPERIMPOSED.
OR MAYBE IT'S ALL OF THEM.
IF THE BIG BATTLE IS CALORIE
COUNTING, WHAT GOES IN AND WHAT
GOES OUT, I JUST ARBITRARILY
ALMOST OFF THE TOP OF MY HEAD
LISTED THE THING THAT TOP IN MY
HAND THAT REPRESENT THE WARRIORS
IN THE BATTLE IS THE FOOD SUPPLY
INDUSTRY WHICH SURVIVES BY
GENERATING MORE FOOD AND KIND OF
FOOD THAT WILL APPEAL TO PEOPLE
TO EAT, PROCESSED FOOD, HEAVY
ADVERTISING OF THAT KIND OF
FOOD, SNACKS AND SO FORTH.
THIS OF COURSE IS A HUGE
COMMERCIAL VENTURE.
SOMEBODY MAKES MONEY WHEN WE
DRINK THAT COCA-COLA.
WHAT ABOUT THE DIETS, IS THERE
SUCH A THING THAT ACTUALLY WORKS
OR IS THERE SOME COMMON
DENOMINATOR MORE RELATED TO
HENRY UP ABOVE THAN TO THE
ACTUAL COMPOSITION.
SO THE OTHER THING I THOUGHT
ABOUT, THEY USED TO TALK ABOUT
GOOD CALORIES AND BAD CALORIES.
WELL THAT'S SORT OF ANCIENT
STUFF BUT IN TERMS OF ACTUAL
FOOD, ARE THERE FOODS WHERE ONE
CAN THINK OF IN TERMS OF GOOD
FOR YOU FROM A CALORIC
STANDPOINT AND OTHERS THAT ARE
PRETTY BAD.
USUALLY THE BAD ONE TASTE THE
BEST.
THEN THERE'S THE OTHER SIDE OF
THE EQUATION, CALORIES HAVE TO
BE BURNED UP.
WELL, CAN YOU REALLY BURN THEM
UP BY EXERCISE.
DOES IT REALLY WORK AND HOW LONG
DOES IT WORK FOR AND HOW MUCH
SHOULD YOU RUN OR MAYBE YOU
YOU
SHOULDN'T RUN AT ALL.
MAYBE YOU SHOULD LIFT WEIGHTS IF
YOU CAN.
WHAT ABOUT MEDICINE.
IS THE PHARMACEUTICAL INDUSTRY
GOING TO PERMIT EVERYBODY TO EAT
WHATEVER THEY WANT TO EAT AND
YET AT THE SAME TIME BY SOME
MAGIC CONTROL THE FACT THAT IT'S
NOT TURNED INTO CALORIES.
IS THERE A FUTURE FOR IT.
THIS IS SORT OF THE BATTLE
GROUND I GUESS, AND WE'RE GOING
TO HEAR ABOUT MANY MORE THINGS.
THE BIG POINT OF TODAY'S TALK IS
THAT THIS ONCE AGAIN IS A
BRIDGING OF SCIENCE AND MEDICINE
AND THE SCIENCE OF OBESITY IS
SOMETHING THAT IS RAPIDLY
EXPANDED AND CONTINUES TO ENTER
THE UNDERSTANDING OF SOME THINGS
THAT ANSWER THESE QUESTIONS SUCH
AS WHY IS IT SO DIFFICULT TO
ACTUALLY LOSE WEIGHT.
AND THIS GETS TIED INTO
METABOLISM, HORMONAL REGULATION
OF APPETITE, WHAT'S GOING ON IN
OUR HEADS.
ALL OF THIS IS PLAYED OUT
AGAINST THIS ENORMOUS SCENE OF
TREMENDOUS PUBLIC HEALTH
CONCERN.
AND IT'S TERRIFYING TO THINK
THAT IF SOME OF THE PREDICTIONS
THAT ARE BEING MADE ACTUALLY
TURN OUT TO BE TRUE, WE'RE GOING
TO HAVE A NATION THAT IS
OVERWHELMED BY THESE SERIOUS
MEDICAL DISEASES LET ALONE THE
PSYCHOLOGICAL ONES.
SO, NIH IS IN A GREAT POSITION
TO PROVIDE MAYBE NOT ALL THE
ANSWERS BUT TO STIMULATE OUR
THOUGHTS AND TELL US WHERE WE
ARE.
THE REASON WHY THEY'RE IN SUCH A
GREAT POSITION IS BECAUSE THERE
ARE INVESTIGATORS HERE WHO
REALLY ARE AT THE FOREFRONT OF
APPROACHING THESE STUDIES.
AND WE'RE FORTUNATE TO HAVE TWO
OF THEM AS PART OF THIS PROGRAM.
SO THE FIRST SPEAKER'S GOING TO
BE JACK YANOVSKI WHO GRADUATED
IN MEDICINE FROM THE UNIVERSITY
OF PENNSYLVANIA AND THEN
RECEIVED A PH.D. IN
PHYSIOLOGICAL PSYCHOLOGY.
HE THEN TRAINED IN PEDIATRICS,
CAME TO THE NIH WHERE HE BECAME
CHIEF OF PEDIATRICS AT THE
CLINICAL CENTER.
AND THEN SEVERAL YEARS AGO WAS
APPOINTED AS THE HEAD OF THE
HUMAN ON GROWTH AND OBESITY AT
NICHD'S DEPARTMENT OF
ENDROCHRONOLOGY BRANCH WHERE HE
SERVES AS THE HEAD.
WE POSTED SEVERAL OF HIS
ARTICLES, AND I WOULD URGE YOU
TO READ THEM.
I REALIZE IT WAS A LITTLE LATE
IN GETTING THEM ON THE WEBSITE
THIS WEEK.
THAT WAS MY FAULT.
BUT I WOULD URGE YOU TO READ
THEM, AT LEAST SKIM THROUGH THEM
BECAUSE THEY REPRESENT THE
HIGHEST LEVEL OF CLINICAL
INVESTIGATION DIRECTLY CONCERNED
WITH THESE QUESTIONS I'VE BEEN
ENUMERATING.
OUR SECOND SPEAKER IS KEVIN
HALL.
HE HAS DEVELOPED A MATHEMATICAL
MODEL WHICH LINKS METABOLISM
WITH OBESITY.
THIS HAS ATTRACTED ENORMOUS
INTEREST.
I POSTED, HE SENT SEVERAL
ARTICLES WHICH ARE ALSO ON THE
WEBSITE.
AND THESE STUDIES ARE
NEWMAN'S -- HIS GOAL IS TO
DEVELOP PREDICTIVE MODELS TO
ANSWER QUESTIONS LIKE HOW MUCH
WEIGHT ARE YOU GOING TO LOSE IF
YOU CLIP OFF TEN CALORIES A DAY.
OR IF YOU RUN THREE MILES.
VERY PRACTICAL QUESTIONS BUT
THEY ARE REFLECTED IN TERMS OF
THE COMPLEXITY OF METABOLIC
CONTROL.
SO OUR FIRST SPEAKER IS JACK
YANOVSKI.
THANK YOU VERY MUCH.
>> THANKS VERY MUCH FOR THE
INTRODUCTION.
TODAY WE'RE REALLY GOING TO TALK
ABOUT VERY BASIC FACTS ABOUT
OBESITY.
SOME OF CONSEQUENCES THAT HAS
ALREADY BEEN DISCUSSED WITH YOU.
THERE ARE A FAIR AMOUNT ON
CAUSES.
AND DR. HALL'S GOING TO TALK
VERY SPECIFICALLY ABOUT ENERGY
BALANCE AND HOW WEIGHT IS GAINED
AND LOST.
AND I THINK IN A VERY WONDERFUL
WAY, TO HELP US UNDERSTANDING
HOW WE REALLY FUNCTION IN THE
WORLD.
SO MY TASK IS ACTUALLY QUITE
BROAD AND I'M NOT REALLY GOING
TO TALK ABOUT TREATMENT AT ALL
ALTHOUGH I WILL BE HAPPY TO TALK
ABOUT IT IN THE QUESTIONS LATER
ON.
MY OBJECTIVE TODAY IS GOING TO
BE TO DISCUSS WHAT IS OBESITY,
THE MEDICAL CONSEQUENCES OF
OBESITY AND WHY DO SOME PEOPLE
BECOME OBESE AND OTHERS NOT.
THIS IMAGE OF A FAMILY WHERE
EVERYONE IS HEAVY, EVEN THE DOG
IS SEEN IN THE CORNER THERE IS
ONE THAT I THINK IS ACTUALLY
QUITE REASONABLE FOR TODAY.
BUT IT'S A LITTLE DECEPTIVE
BECAUSE THERE ARE MANY FAMILIES
IN WHICH THERE ARE SOME
INDIVIDUALS WHO DO NOT BECOME
HEAVY.
WE REALLY WANT TO UNDERSTAND
WHAT ARE THE DIFFERENCE BETWEEN
PEOPLE THAT ALLOW SOME FOLKS TO
THRIVE IN OUR CURRENT
ENVIRONMENT AND OTHERS NOT TO DO
SO WELL.
SO OBESITY OF COURSE IS AN
EXCESS OF BODY FAT FROM THE
LATIN OBESEITAS.
IT'S A BODY MASS INDEX WEIGHT,
IN THIS CASE KILOGRAMS HEIGHT
MEASURED IN METERS AND THAT
QUANTITY SQUARED.
FOR ADULT IT'S A VERY CONVENIENT
MEASURE BECAUSE IT SEEMS TO
REFLECT THROUGH LIFE FAIRLY WELL
UNTIL YOU GET INTO QUITE OLDER
INDIVIDUALS WHEN FOLKS BEGIN TO
LOSE MUSCLE MASS.
IT'S A MEASURE OF WEIGHT
ADJUSTED FOR HEIGHT.
IT'S HIGHLY CORRELATED WITH BODY
FAT AND WE'LL TALK ABOUT HOW THE
RELATIONSHIP DOES VARY SOMEWHAT
WITH AGE, WITH SEX, ETHNICITY
AND BODY BUILD.
IT IS QUITE EASY TO OBTAIN, YOU
JUST NEED THE WEIGHT AND HEIGHT.
IT DOESN'T DISTINGUISH RUE TAN
BODY FAST AND MUSCLE SO IT IS
POSSIBLE TO HAVE INDIVIDUALS
LIKE THIS WHO WEIGH THE SAME,
SCHWARZENEGGER ON THE RIGHT AND
FRED ANYONE -- FLINT STONE.
THERE'S A PERCENTAGE OF BODY FAT
BETWEEN MEN AND WOMEN AND IT
DIFFERS SO MUCH.
THE BODY MASS INDEX WILL TEND TO
HAVE A GREATER PERCENTAGE BODY
FAT.
SO THE NORMAL RANGE OF BODY FAT
IS HIGHER AMONG WOMEN THAN AMONG
MEN.
IF NEVERTHELESS THESE KIND OF
DATA GIVES YOU A SENSE OF WHAT
IS TRADITIONALLY CONSIDERED OR
BEASTY THE PERCENTAGE OF BODY
FAT FOR BOTH MEN AND WOMEN IS
OFTEN OVER 30% AND OFTEN MUCH
HIGHER THAN THAT IN THE 40-50%
OF TOTAL BODY WEIGHT.
IF HALF OF YOUR BODY MASS IS
FAT, THAT'S A PROBLEM.
AND WE'LL TALK ABOUT THE
PROBLEMS IN A MOMENT.
NOW IF WE USE THIS BMI STANDARD,
WE CLASSIFY MORE THAN 65% OF ALL
U.S. ADULTS AS OVERWEIGHT A BODY
MASS INDEX OVER 25 AND 30% ARE
OBESE.
THIS IS BY THE METHOD BFFS GOING
THROUGH 2010.
AS THE COLORS BECOME WARMER
TOWARDS RED THE PERCENTAGE OF
INDIVIDUALS WHO ARE OBESE
INCREASES AND SO YOU CAN SEE
THERE'S BEEN A MASSIVE INCREASE
IN THE PREVALENCE OF OBESITY,
SINCE THE 80'S AND 90'S.
SO MANY MORE RED AND ORANGE
STATES.
THIS IS NOTHING TO DO WITH THEIR
POLITICAL BACKGROUND.
THE SAME IS TRUE UNFORTUNATELY
FOR CHILDREN WHERE WE DEFINE IT
AS A BMI GREATER THAN THE 95TH
PERCENTILE STANDARD DEFINED THEM
IN THE 1970'S.
THE NUMBER OF CHILDREN WHO HAS
THIS BMI THAT'S GREATER THAN THE
STANDARD HAS INCREASED
PRECIPITOUSLY OVER THE LAST 40
YEARS.
FORTUNATELY IT'S BEEN TO
STABILIZE.
IT'S TRUE AS WELL.
BUT IT'S BECOME TO STABILIZE IN
GIRLS OVER THE LAST TEN YEARS
AND IN BOYS IT'S STILL
INCREASING TO A SMALL EXTENT BUT
IN GENERAL THE RATES ARE NOW ON
THE ORDER OF 20% OF ALL CHILDREN
ARE CONSIDERED OBESE.
NOW, THERE WAS AT ONE POINT A
FEW YEARS AGO A CONCERN THAT THE
INCREASES THAT YOU CAN SEE HERE
WERE GOING TO CONTINUE KIND OF
FOREVER.
IT'S GOING TO GO UP UNTIL A
HUNDRED PERCENT OF THE PEOPLE
WERE CONSIDERED OBESE.
BUT THAT'S NOT A REASONABLE
STATEMENT OF WHAT'S GOING ON.
WHAT WE'RE SEEING IS MOST OF THE
MOST SUSCEPTIBLE PEOPLE HAVE NOW
IN THE U.S. HAVE NOW BECOME
OBESE.
THEY MAY TEN TO GET A LITTLE BIT
HEAVIER OVER TIME, BUT CHANCES
ARE THAT WE'VE ALMOST PRESSED IT
FOR THIS VAST INCREASE IN THE
PREVALENCE OF OBESITY.
WE'RE REALLY HOPEFUL OF THE
EFFORTS THAT U.S. OR THE NATURAL
HISTORIES WE'VE REACHED THE
POINT WHERE MOST FOLKS ARE MOST
SUSCEPTIBLE TO BECOME OBESE,
WHICHEVER IS THE REAL REASON, WE
HOPE THAT WE'VE COME TO A POINT
WHERE WE CAN NOW DEAL WITH THE
PROBLEMS SUCH AS THEY ARE
WITHOUT HAVING TO DEAL WITH
GREAT INCREASES OVER THE NEXT
FEW YEARS.
NOW, IN ADULTS, BMI-ASSOCIATED
DISEASE RISK VARIES ACCORDING TO
THE DEGREE OF OBESITY.
SO THE CLASSIFIED FOLKS AS BEING
UNDER WEIGHT OR NORMAL WEIGHT OR
OVERWEIGHT OR OBESE IN THREE
DIFFERENT CLASSIFICATIONS, AND
BY THE TIME YOU HAVE CLASS THREE
OBESITY WITH A BODY MASS INDEX
OVER 40, FOLKS ARE CONSIDERED TO
HAVE EXTREMELY HIGH RISK OF THE
COMPLICATIONS OF OBESITY.
BUT YOU'LL NOTICE THAT UNDER
WEIGHT INDIVIDUALS ALSO HAVE
INCREASED RISKS OF DISEASE.
AND THAT'S FOR SEVERAL REASONS
BUT ONE OF THEM IS INSUFFICIENT
BODY LEAN MASS AND I DON'T THINK
WE'RE REALLY GOING TO TALK TOO
MUCH ABOUT THAT GROUP.
BUT ADDITIONAL RISKS BEYOND THE
CLASSIFICATION OF JUST BODY
WEIGHT INCLUDE POOR AEROBIC
FITNESS, SO HOW MUCH EXERCISE
YOU DO IS WHEN IT WAS DISCUSS
THE EARLIER.
AND IN FACT SOME DICHESDZ IN
WHAT WE CALL BODY COMPOSITION,
THOSE ARE THE LARGE WAIST
CIRCUMFERENCE AND HAVE MORE
COMPLICATIONS OF WEIGHT.
LET'S LOOK AT THAT FOR A MOMENT.
THERE'S A LOT OF DATA PUT
TOGETHER THAT SUGGESTED SOME
INDIVIDUALS WHO ARE LEAN OR
NORMAL WEIGHT MAY BE
METABOLICALLY UNFIT.
AND IT TURN OUT THAT THEY HAVE
AN INCREASED RISK OF
CARDIOVASCULAR DISEASE.
THIS IS CARDIOVASCULAR DISEASE
MORTALITY.
IF YOU DEFINE THE UNFIT FOLKS
WHO AREN'T ABLE TO EXERCISE WELL
VALUESLY INCREASED RISK COMPARED
TO THE FIFTH FOLK OF A DEGREE OF
LEANNESS.
AS THE LEVEL OF BODY WEIGHT GOES
UP, THE RISK OF CARDIOVASCULAR
DISEASE INCREASES EVEN AMONG THE
FIT FOLKS WHO ARE OBESE.
BUT YOU CAN SEE THAT'S BEING
UNFIT EVEN WHEN LEAN IS MORE
DANGEROUS FOR YOUR HEART THAN
BEING OBESE BUT FIT.
SO, PARTLY THIS IS BECAUSE THE
FOLKS HAVE A GREAT DEAL OF LEAN
MASS AND NOT AS MUCH ADIPOSE
TISSUE BUT IT'S ALSO INDEPENDENT
RISK OF THE FITNESS ITSELF.
SO NATURALLY WE PREFER TO BE
RIGHT HERE IN THIS CATEGORY IF
WE COULD.
BUT FITNESS IS CLEARLY IMPORTANT
THING WE SHOULD ALL STRIVE FOR
AT ANY DEGREE OF ADIPOSITY.
THE SECOND THING I MENTIONED IS
THE WAIST CIRCUMFERENCE MIGHT
MATTER.
WE REALLY DON'T THINK IT'S THE
FAT THAT'S MEASURED THAT'S TRULY
THE CAUSE OF COMPLICATIONS BUT
IT'S REALLY A REFLECTOR OF
METABOLIC DISEASE THAT LEADS TO
ADIPOSE TISSUE BEING DEPOSITED
INTO VISCERAL COMPARTMENT WITH 9
SO-CALLED INTERABDOMINAL FAT AND
GETS MEASURED AS AN INCREASED
WEIGHT CIRCUMFERENCE THAT'S A
MEASURE OF FAT BEING DEPOSITED
IN MANY PLACES INCLUDING THE
LIVER, INCLUDING MUSCLES,
INCLUDING THE HEART.
THIS VISCERAL ADIPOSE TISSUE
MEASUREMENT IS A MARKER FOR
METABOLIC RISK, BUT IN AND OF
ITSELF WE DON'T THINK IT'S TRULY
A CAUSE OF COMPLICATIONS.
AND THE MEDICAL COMPLICATIONS OF
OBESITY AND PARTICULARLY
VISCERAL OBESITY ARE MYRIAD.
THEY COVER EVERYBODY'S SYSTEM.
CARDIOVASCULAR DISEASE AND
STROKE IS CLEARLY INCREASED.
INCREASED PRESSURE INSIDE THE
HEAD CALLED INTRACRANIAL
APPRECIATE, CATARACTS, HEART
DISEASE, DIABETES IS A HUGE
RISK.
PROBLEMS WITH LIPIDS, HIGH BLOOD
PRESSURE, GYNECOLOGICAL
ABNORMALITIES AND POLY SIST CULL
SYNDROME WHICH AFFECTS A LARGE
MORE THAN OF WOMEN TODAY.
DISEASES OF THE BONE LIKE
OSTEOARTHRITIS WHICH CAN BE
LIMITING IN TERMS OF ABILITY TO
EXERCISE BECAUSE OF PROBLEM.
PROBLEMS WITH VEINS LIKE
PHLEBITIS.
GOUT IS MORE COMMON.
GALL BLADDER DISEASE, LIVER
DISEASE, LUNG DISEASE OF VARIOUS
SORTS, INCLUDING SLEEP APNEA
WHICH CAN HAVE EFFECTS ON THE
BRAIN AS WELL AS INDEPENDENTLY
OF OBESITY.
AND THEN THIS RISK FOR CANCER
WHERE IT LOOKS LIKE BREAST,
UTERUS, ***, PROSTATE,
KIDNEY, COLON, PANCREAS, MANY
CANCERS HAVE AN INCREASED RISK
ASSOCIATED WITH GREATER BODY
FAT.
THE REST OF THE TIME THAT WE
VERY BRIEFLY TALKED ABOUT
COMPLICATIONS OF OBESITY, I
WOULD LIKE TO DISCUSS WHY DO
PEOPLE BECOME OBESE AND HOW CAN
WE CLASSIFY THEM TO TRY TO
UNDERSTAND HOW WE MIGHT CONSIDER
TREATMENT.
AND SO WITH THE VERY BASIC LEVEL
OBESITY HAS TO BE CAUSED BY LONG
TERM POSITIVE ENERGY BALANCE
WHICH MEANS ENERGY INTAKE HAS TO
BE GREATER THAN ENERGY
EXPENSURES IN ORDER FOR FAT TO
BE STORED.
NOW, THE INTAKE CAN BE GREATER
THAN ENERGY EXPENDITURE WHEN
CHILDREN ARE GROWING.
WE KNOW FOR INSTANCE PUBITAL
BOYS PUT ON CALORIES WITHOUT
BODY FAT.
BUT IF SUFFICIENT CALORIES ARE
TAKEN IN ABOVE EXPENDITURES,
EVENTUALLY SOME FAT STORES WILL
BE DEVELOPED.
AND WE'LL HEAR A LOT I THINK
ABOUT HOW THAT HAPPENS WHEN
DR. HALL SPEAKS A LITTLE BIT
LATER.
BUT I THINK WE CAN POSSIBLY
CONSIDER EVEN IF THERE WERE THE
OTHER WEAPONS OF MASS
DESTRUCTION WE WOULD COMMONLY
HAVE IN OUR HOUSEHOLDS, THE
KNIFE, FORK AND SPOON MIGHT BE
CONSIDERED AMERICA'S WEAPONS OF
MASS DESTRUCTION.
BUT BEYOND THE FACT THAT WE KNOW
THAT FOOD INTAKE IS GOING TO
MATTER, I THINK IT'S VERY
IMPORTANT FOR US TO RECOGNIZE
THAT THERE'S A SERIOUS
CONTRIBUTION OF GENETICS TO
OBESITY.
AND PROBABLY THE CLEAREST
EXAMPLES ARE FROM TWIN STUDIES
THAT HAVE BEEN VERY ELEGANT
STUDIES EXG THE FATE OF CHILDREN
RAISED WITH OR WITHOUT THEIR
PARENTS.
THEY COME TO THE CONCLUSION THAT
MORE THAN 50% AND IN SOME
STUDIES EVEN AS HIGH AS 80%
ALTHOUGH I THINK NOW THE NUMBER
IS MORE TOWARDS THE 50% NUMBER.
BUT SOMEWHERE IN A LARGE
PROPORTION OF THE VARIANCE IN
HUMAN BODY WEIGHT CAN BE
ACCOUNTED REALLY BY GENETIC
VARIATION.
AND THEN THE REMAINDER IS
EXPLAINED BY COMMON
ENVIRONMENTAL FACTORS.
SO WHETHER WE HAVE A LOT OF FAST
FOOD RESTAURANTS PER SQUARE
INCH, SOCIETY AND OTHER FACTORS
THAT ARE ENVIRONMENTAL IN
NATURE.
AND THE CLEAREST ENVIRONMENTAL
EXAMPLE THAT MANY PEOPLE USE
THAT I LIKE TO USE ARE
GENETICALLY RELATED INDIAN
FAMILIES WHO LIVE IN MEXICO AND
THE PIMA INDIANS IN THE U.S. ARE
FOUND TO BE GENETICALLY SIMILAR.
IT'S NOT THAT THEY HAVE A DRIFT
OF THEIR GENETICS.
THE GROUP IN THE U.S. WHERE THE
GILA RIVER BECAUSE DIVERTED
MEANING THEY COULD NO LONGER
FARM SUCCESSFULLY AND DEPEND ON
HANDOUTS FROM THE U.S.
GOVERNMENT AND HAVE COME TO HAVE
A GREAT DEAL OF FONDNESS FOR
SPASM AND OTHER HIGH ENERGY
FOODS.
ALL OF THEM ARE OBESE.
THREE OF THEM HAVE DIABETES
ALREADY.
BUT THE INDIAN FAMILY FROM
MEXICO WHERE THEY LIVE A HARD
SCRABBLE FARMING LIFE,
SUBSISTENCE FARMING, NOT A LOT
OF OPPORTUNITIES TO WATCH
TELEVISION, THIS GROUP NONE OF
THEM ARE OBESE AND NONE OF THEM
HAVE DIABETES.
WE KNOW THE ENVIRONMENT HAS AN
ENORMOUS EFFECT ON THE CHANCE OF
DEVELOPING OBESITY.
THERE'S NO QUESTION WHATSOEVER
THE ENVIRONMENT IS A CAN HE
FACTOR FOR WHAT'S HAPPENED OVER
THE LAST 40 YEARS.
SO WE CAN SEE CORRELATIONS
BETWEEN PORTION SIZES IN
RESTAURANTS SCOPY BEASTY.
IT'S A BIT OF A SPECIOUS
COMPARISON BECAUSE AS PEOPLE GET
HEAVIER, THEY'RE GOING TO EAT
MORE.
BUT REGARDLESS, WE CAN SEE THAT
THE NUMBER OF, SO HERE'S THE
PERCENTAGE OF OVERWEIGHT,
OBESITY, THIS 95TH PERCENTILE
RATE INCREASING DRAMATICALLY
OVER 30 YEARS AND THE NUMBER OF
LARGE SIZE PORTIONS INTRODUCED
AT FAST FOOD RESTAURANTS
INCREASING ROUGHLY IN PARALLEL
TO WHAT IS SEEN IN TERMS OF THE
RISK OF OBESITY.
AND THERE'S SOME EXAMPLES,
MCDONALD'S FRIES HAVE INCREASED
THREE FOLD.
COCOA LAW PORTION ABOUT THREE
FOLD.
SNICKERS USED TO BE ONE OUNCE
AND NOW 4 OUNCES.
THE CALORIES INCREASE ALONG WITH
THEM.
SO CALORIE AVAILABILITY
CERTAINLY INCREASED OVER THE
YEARS.
AND THAT'S AGAIN A SUCCESS OF
ADVERTISING AS I WAS POINTING
OUT.
SOME OF YOU MAY BE AWARE OF THIS
MOVIE SUPER SIZE ME WHERE A
FILMMAKER DECIDED TO GO EAT
NOTHING BUT FAST FOOD FOR AN
ENTIRE MONTH.
AND EVERY TIME HE WAS ASKED IF
HE WANTED TO SUPER SIZE, HE HAD
TO SAY YES AND THEN CONSUME IT.
AT THE END OF HIS DATE GAINED
CONSIDERABLE 5789 AND HAD
COMPLICATIONS OF HIS OBESITY
JUST IN THAT BRIEF TIME OF OVER
NUTRITION.
WE KNOW THERE'S A POTENTIAL ROLE
THAT CAN BE PLAYED BY THE
RESTAURANTS AND OUR ENVIRONMENT
OR THE FOOD ENVIRONMENT IN
GENERAL.
BUT WE ALSO KNOW THAT THERE ARE
ENVIRONMENTAL CHANGES IN
PHYSICAL ACTIVITY THAT MAY
CONTRIBUTE TO OBESITY.
ALTHOUGH IT'S HARDER TO TEST
THOSE.
WE KNOW THERE'S DECREASED
PHYSICAL ACTIVITY IN THE SCHOOL
OR WORK PLACE SO FEWER SCHOOLS
OFFER DAILY PHYSICAL EDUCATION.
FEWER JOBS REQUIRE MANUAL LABOR
AND THERE'S CERTAINLY AN
INCREASING LACK OF SIDEWALKS IN
NEIGHBORHOODS OR SAFE AREAS
GOING OUTSIDE.
INCREASED SEDENTARY BEHAVIORS
ARE WELL ASSOCIATED WITH
OBESITY.
IN THE OFFICE IN THE HOME PEOPLE
ARE USING MORE COMPUTERS,
PLAYING VIDEO GAMES AND WATCHING
TELEVISION.
HERE ARE THE KIND OF DATA THAT
ARE SHOWN EPIDEMIOLOGICALLY, THE
RELATIVE RISK OF DEVELOPING
OBESITY INCREASES IN PROPORTION
TO HOW MUCH TV IS VIEWED BY
ADULTS.
SO HERE IS ZERO TO ONE HOURS A
WEEK UP TO GREATER TO 40 HOURS A
WEEK WHICH IS CLEARLY AN
ENORMOUS AMOUNT OF TIME SPENT
WATCHING THE *** TUBE AND THE
RELATIVE RISK FOR OBESITY
INCREASES ALONG WITH THAT TO
ABOUT TWO-FOLD.
THAT'S A MUCH GREATER INCREASE
IN THE HOURS WATCHED COMPARED TO
THE RISKS OF OBESITY.
BUT IT IS CORRELATED, IT'S AN
ASSOCIATION.
NOW SHOWING WHAT YOU CAN DO THE
REVERSE, INCREASE PHYSICAL
ACTIVITY SUFFICIENTLY TO
INDISEASE WEIGHT LOSS AND
REVERSE OBESITY IS A MUCH HARDER
THING TO DO AND TO SHOW.
AT LEAST UNLESS WE'RE LOOKING AT
FOLKS WHO ARE CONSUMING MANY
HOURS A DAY IN PHYSICAL
ACTIVITY, FOUR PLUS HOURS A DAY
IT'S HARD TO DEMONSTRATE YOU CAN
REVERSE SUCCESSFULLY WITH
EXERCISING ALONE WITHOUT
RESTRICTING FOOD INTAKE.
SO THIS IS THE SLIDE I STOLE
FROM LEN EPSTEIN.
IT'S HARDER FOR YOUR HEART
COMPARED TO A RECLINER.
THE SEASON OF THE AIR SEEMS TO
AFFECT HOW MUCH WEIGHT WITH A
GAIN.
HERE'S A PAPER WE DID A NUMBER
OF YEARS AGO.
THE WINTER HOLIDAY SEASON WHICH
FORTUNATELY JUST CONCLUDED, FROM
THANKSGIVING THROUGH NEW YEAR'S.
I GUESS WE CAN CONSIDER THROUGH
THE SUPER BOWL IS ASSOCIATED
WITH A GREATER WEIGHT CHANGE
THAN ANY OTHER PERIOD OF THE
YEAR.
THIS IS A STUDY IN WHICH WE
MEASURED ABOUT 200 FOLKS
THROUGHOUT THE ENTIRE YEAR.
THIS IS THE ONLY TIME WHERE IT
WAS ACTUALLY SIGNIFICANTLY
DIFFERENT FROM ZERO.
AND VIRTUALLY ALL THE WEIGHT
THAT'S GAINED FROM YEAR TO YEAR
CAN BE ACCOUNTED FOR BY THIS
PERIOD OF TIME IN THE HOLIDAY
SEASON.
NOW, HOWEVER, WE'RE STILL JUST
TALKING ABOUT A POUND A YEAR, A
LITTLE LESS THAN A POUND A YEAR
ON AVERAGE IN THIS STUDY.
WE KNOW MANY PEOPLE ARE GAINING
MUCH MORE THAN A POUND A YEAR
AND DEVELOPING OBESITY DOESN'T
HAPPEN EXCEPT OVER A VERY LONG
TIME FRAME WITH JUST A POUND A
YEAR CHANGE.
SO AGAIN WE'LL ASK THE QUESTION,
WHY DO PEOPLE BECOME OBESE.
WE THINK CHANGES IN OUR
ENVIRONMENT MAY EXPLAIN WHY
OBESITY IS MORE COMMON OVER THE
LAST 40 YEARS FOR SURE BECAUSE
OUR GENES DIDN'T CHANGE.
BUT OUR GENES MAKE US RESPOND TO
OUR CURRENT ENVIRONMENT BY
BECOMING OBESE.
THERE'S A FAMOUS STATEMENT
THAT'S MADE THAT THE GENETICS
THAT WE HAVE LOAD THE GUN OF
OBESITY BUT THE ENVIRONMENT
PULLS THE TRIGGER.
I THINK THAT'S A REASONABLE
SIMILE FOR WHAT'S GOING ON THAT
WE ARE BORN WITH A SET OF
PREDISPOSITIONS, INCLUDING FOR
OBESITY, FOR MANY IN THIS ROOM,
A PREDISPOSITION TO DO RESEARCH.
AND THE OPPORTUNITY BEING AT NIH
TO DO RESEARCH AND BEING IN A
CALORIE-DENSE ENVIRONMENT, THOSE
ARE BOTH FACTORS THAT LEAD US TO
CERTAIN CHOICES.
HOWEVER, WE KNOW THAT GENETICS
REALLY DO MATTER.
SO HERE ARE A GROUP OF IDENTICAL
TWINS AND FRATERNAL TWINS, SO
THESE FOLKS SHARE ALL OF THE
GENOME, FRATERNAL TWINS ONLY
ABOUT 50% ON AVERAGE OF THE
GENOMES.
YOU'LL SEE OF COURSE THAT THE
HEIGHT IS QUITE DIFFERENT IN
MANY OF THE PAIRS OF FRATERNAL
TWINS BUT SIMILAR IN THE
IDENTICAL TWINS.
NOBODY'S SURPRISED BY THAT.
LET'S LOOK AT THE OTHER
DIMENSION.
YOU SEE FOLKS THAT ARE QUITE
DISCOREDDANTS IN HOW OBESE THEY
ARE FOR THE FRATERNAL TWINS BUT
FOR THE IDENTICAL TWIN THEY DO
LINE UP VERY WELL.
THAT SPEAKS TO THAT GENETIC
IMPORTANCE FOR DETERMINING BODY
WEIGHT.
WE KNOW ANOTHER WAY OF LOOKING
AT THE RISK FOR GENETICS
AFFECTING OBESITY IS TO CONSIDER
HOW PARENTS OBESITY IS
ASSOCIATED WITH CHILDREN'S
OBESITY.
THESE ARE DATA PUT TOGETHER IN
1970'S SHOWING IF YOU HAD TWO
LEAN PARENTS YOUR TRICEPS FAT
FOLD THEREBY -- WILL BE MUCH
MORE THAN THAN TWO OBESE
PARENTS.
THIS IS IN THE FAMILY BUT MOST
HAVE BEEN GENETICALLY
DETERMINED.
LET'S FERN TO A PATIENT.
HERE'S ONE FELLOW THAT WE HAVE
SEEN AT NIH AND FOLLOWED OVER
SEVERAL YEARS.
HE'S 14 YEARS OLD.
HIS WEIGHT IS 1 6 KILOS, OVER
300 POUNDS.
HIS BODY MASS INDEX IS 56 SO
WELL OVER THAT 30 MARK FOR
OBESITY.
AND HE HAS HIGH BLOOD PRESSURE,
DISLIPID DEMIA SO HIGH
CHOLESTEROL AND SLIGHTLY HIGH
GLUCOSE LEVELS.
AND HE ALSO HAS SOME PAINS IN
HIS LOWER EXTREMITIES DUE TO HIS
WEIGHT.
WE'D LIKE TO KNOW HOW HE BECAME
SO HEAVY AT SUCH AN EARLY AGE
AND ALSO THINK ABOUT HOW WE
MIGHT BE ABLE TO REVERSE THAT.
THAT BRINGS US TO THE
DIFFERENTIAL DIAGNOSIS OF
OBESITY.
JUST BRIEFLY TALK ABOUT SOME OF
THESE OTHER CATEGORIES BESIDES
GENETICS, ARE SO THERE ARE
ENDOCRINE CANNOT DISCS THAT CAN
CAUSE OBESITY, THERE ARE
MEDICINES THAT CAN AFFECT
OBESITY, YOU CAN HAVE A DAMAGED
BRAIN THAT WE WON'T REALLY TALK
ABOUT ANYMORE AND IN TERMS OF
GENETICS WE'LL TALK ABOUT SOME
VERY ESTABLISHED SYNDROMES.
SOME OF THE NEWER SYNDROMES THAT
AFFECT THE LEPTIN SIGNALING
PATHWAY.
FIRST THE END QURAN NAWLG
DISORDERS.
THEY HIGH HYPOTHYROIDISM IS --
THE WEIGHT THAT'S ACTUALLY
GAINED IN THYROID DISEASE IS
WATER WEIGHT AND THE REVERSAL OF
THAT DOES NOT CHANGE BODY FAT
DRAMATICALLY.
HOWEVER TREATMENT DOES IMPROVE
APPEARANCE QUITE DRAMATICALLY AS
YOU CAN SEE IN THESE BEFORE AND
AFTER PICTURES.
HIGH CORTISOL LEVELS CALLED
CUSHING SYNDROME IS A VERY RARE
CONDITION.
IN CHILDREN IT'S ONE IN 10,000
AND IN ADULTS -- EXCUSE ME, ONE
IN 10 MINUTE, IN ADULTS IT'S ONE
IN A MILLION.
YOU CAN SEE IF YOU REVERSE A
TROORM THAT PRODUCES TOO MUCH
CORTISOL YOU CAN AVERT OBESITY
QUITE SUCCESSFULLY.
WE CAN ACCOUNT FOR JUST A FEW
PATIENTS IN THE WORLD.
AND THEN PEOPLE GOING HAVE A
VERY RARE CONDITION OF HIGH
BLOOD INSULIN FROM A TUMOR IN
THE PANCREAS THAT CAUSES
HYPOGLYCEMIA SO PEOPLE TRY TO
EAT TO RAISE THE BLOOD SUGAR
THAT ALSO IS ASSOCIATED WITH
OBESITY.
IT'S AGAIN A ONE IN 10 MINUTE
KIND OF DISORDER.
SO ENDOCRINE CONDITIONS, ARE
REALLY NOT THE COMMON CAUSE OF
OBESITY.
SOME MEDICINES ARE INDEED
ASSOCIATED WITH PEDIATRIC AND
ADULT OBESITY.
SO GLUCOCORTICOIDS INCREASE
CORTISOL ACTION.
A LOT OF PSYCHO TROPIC AGENTS,
ANTI-PSYCHOTIC DRUGS,
ANTIDEPRESSANTS, SOME OF THE
OLDER ONES PARTICULARLY.
ANTI-CONVULTANTS THAT ARE USED
TO TREAT EPILEPSY AND THEN OTHER
DRUGS THAT CAN CAUSE WEIGHT GAIN
INCLUDE ANTI-HYPER TENSIVE, BETA
BLOCK, THESE ARE ALL MEDICINES
WE SHOULD BE THINKING ABOUT THAT
0EU7Z MIGHT NOT HAVE A HIGH RISK
FOR IT.
THERE ARE THESE DISTINCTIVE
GENETIC SYNDROMES ASSOCIATED
WITH OBESITY, PERHAPS THE MOST
COMMON GENETIC DISORDER OF THEM
ALL, DOWN SYNDROMES, BUT SOME
OTHERS EVEN MORE RARE AND TURNER
SYNDROME, HE'LL JUST TALK ABOUT
A COUPLE OF THESE, HERE'S A
PATIENT WITH DOWN SYNDROME,
HERE'S AN EXTRA COPY OF
CHROMOSOME 21.
THEY HAVE DISTINCT EARS AND
THESE INCREASES, SPECIAL SPOTS
BUT OBESITY IS VERY COMMON.
IT'S NOT REALLY CLEAR WHY THAT
IS THE CASE.
THE -- SYNDROME IS UNIQUE
BECAUSE IT'S ASSOCIATED WITH
MOORE FEEDING AND ACTUALLY
FAILURE TO THRIVE IN THE FIRST
COUPLE YEARS OF LIFE.
AFTER ABOUT AGE TWO OBESITY AND
DEVELOPMENT OF INSATIABLE
APPETITE ASSOCIATED WITH A
PARTICULAR ABNORMALITY CAUSED BY
THE REGION OF THE PATERNAL GENE
WHO ARE WHAT CALLED -- WE HAVE
TWO COPIES OF MOTHER'S GENE
BECAUSE THE MOTHER'S GENE
USUALLY INACTIVE.
THERE CAN WE NORMAL METHYLATION.
IT GETS TO THE POINT WHERE SUCH
SEVERE OBESITY AND DRIVE TO EAT
THAT FOLKS HAVE TO LOCK THEIR
REFRIGERATORS UP TO PREVENT
FOLKS FROM EATING.
THIS IS A SEVERE HYPER PHAGIC
DIVISION.
BEETLE SYNDROME IS ANOTHER
RECOGNIZABLE CONDITION.
THERE'S RETINAL DEGENERATION,
EXTRA DIGITS IN THE HANDS AND
FEET.
SIX TOES AND EXTRA DIGITS IN THE
HAND.
AND MENTAL RETARDATION BEING
QUITE COMMON AS WELL.
THESE ARE DISTINTS SYNDROMES
RELATIVELY EASY TO RECOGNIZE IF
THEY'RE THOUGHT B SOME OF THE
NEWER GENETIC SYNDROMES
ASSOCIATED WITH OBESITY THAT
HAVE TO DO WITH THIS DRUG, THIS
HORMONE CALLED LEPTIN HAVE VERY
FEW DIFFERENCES IN PEOPLE'S
APPEARANCE.
AND SO I THOUGHT I WOULD FALK
--
TALK ABOUT A FEW OF THEM.
I'LL SWITCH NEXT TO TALKING
ABOUT LEPTIN.
IT'S A SUBSTANCE MADE BY FAT AND
CIRCULATES IN THE BODY AND IS
THE CAUSE OF THE OBESITY OF
PARTICULAR MOUSE MODEL CALLED
THE OBOB MOUSE.
THIS MOUSE WAS SUSPECTED TO HAVE
A HORMONAL CAUSE OF OBESITY
BECAUSE IF YOU LINK THE
CIRCULATION OF SUCH MICE TO
NORMAL MICE, THEY WOULD DEVELOP
NORMAL BODY WEIGHT.
SO IT WAS KNOWN THAT THERE WAS A
CIRCULATING FACTOR THAT COULD
CAUSE THIS DISORDER.
AND THE DISCOVERY THAT LEPTIN
WAS THE HORMONE THAT THESE
ANIMALS LACKED WAS A
TRANSFORMING EVENT IN OBESITY
RESEARCH HAPPENED IN 1994 THAT
REALLY OPENED UP A WHOLE SYSTEM
OF DISEASES THAT WERE CAUSED BY
DEFICIENCIES IN THE LEPTIN
SIGNALING PATHWAY IN THE BRAIN.
SO LET'S GO TO A VERY SIMPLE
VERSION OF THAT.
LEPTIN HERE IS MADE BY FAT
CELLS, CIRCULATES IN THE BLOOD.
THE MAIN PLACE IT ACTS, OUGHT
THE ONLY PLACE ABOUT MAIN PLACE
IS THE HYPOTHALAMUS WITH SPECIAL
RECEPTORS THAT ARE CYTOKIND-LIKE
RECEPTORS FOR THOSE WHO ARE
INTERESTED.
THEN THERE ARE FIRST ORDER
NEURONS THAT CONTAIN THESE
RECEPTORS BUT THEN EVENTUALLY
LEAD TO CHANGES IN OTHER
NEUROTRANSMITTERS IN THE BRAIN
LIKE ALPHA, MSH AND NEURO
PEPTIDE Y THAT COMBINED TO THEIR
OWN DISTINCT RECEPTORS AND
AFFECT THINGS LIKE APPETITE,
HORMONES, AUTONOMIC NERVOUS
SYSTEM AND ACTUALLY WORK MOSTLY
THROUGH THEIR OWN SYSTEMS.
OTHER NEURONS, THERE ARE THIRD
AND FOURTH AND FIFTH ORDER
NEURONS SOME OF WHICH ARE
BEGINNING TO BE ELUCIDATED.
WE'RE GOING TO SHOW YOU PATIENTS
WHO ARE LEPTIN DEFICIENT.
THE FIRST DESCRIPTION WAS BACK
IN 97 FROM TWO COUSINS.
THEY INHERITED THE SAME BAD
LEPTIN GENE.
NORMAL AT BIRTH BUT HAD VERY
RAPID WEIGHT GAIN AND WERE FOUND
OVER LOW LEPTIN LEVEL DESPITE A
HIGH PERCENTAGE OF BODY FAT.
AND THEY HAD A SINGLE-BASED
DELETION IN THE LEPTIN GENE
INTRODUCING A PREMATURE STOP
CODE.
THEY DIDN'T MAKE CIRCULATING
LEPTIN.
SO THIS IS WHAT THEIR BLOOD
LEPTIN LOOKED LIKE.
THEY MEASURED LEPTIN IN THE
PLASMA, THEY HAVE VERY LOW
LEVELS.
SINCE IT'S MADE BY FAT IN
PROTORTION TO HOW MUCH FAT THE
PERSON HAS NORMALLY, WE CAN SEE
WHAT NORMAL LEPTIN LOOKS LIKE IN
PROPORTION TO THESE FOLKS WHO
HAVE A LEPTIN MUTATION.
SO WE NOW KNOW ABOUT 20-25
PEOPLE WHO HAVE LEPTIN MUTATION
LEADING TO THIS LOW LEVEL
LEPTIN.
AS WE'LL TALK ABOUT, WE KNOW HOW
TO TREAT THEM AS WELL.
HERE'S A CHILD WITH LEPTIN
DEFICIENCY, SEVERE EARLY ONSET
OBESITY SO THE WEIGHT IS OUTSIDE
THE 98TH PERCENTILE BY ABOUT SIX
MONTHS OF AGE.
THIS IS WHAT'S DESCRIBED IN
GENERAL FOR THESE FOLKS.
SEVERE OBESITY.
THIS CHILD WEIGHS ALMOST OVER
200 POUNDS BEFORE THE AGE OF
TEN.
SO SEVERE EARLY ONSET OBESITY.
AND THAT CAN BE REVERSED BY
LEPTIN TREATMENT.
HASHES A LEPTIN DEFICIENT MOUSE.
THIS ONE'S BEEN TREATED WITH
LEPTIN AND IT'S A REMARKABLE
TREATMENT TO REVERSE LEPTIN
DEFICIENCY.
THE SAME IS TRUE FOR CHILDREN
WHO HAVE ALMOST CONTINUE
DEFICIENCIES THE SAME KID I
SHOWED YOU BEFORE.
A COUPLE YEARS LATER THIS CHILD
HAS LOST A GREAT DEAL OF BODY
FAST AND OF COURSE GAINED SOME
HEIGHT AS WELL BECAUSE HIS TIME
HAS PASSED.
NOW UNFORTUNATELY THERE'S LITTLE
EFFICACY OF LEPTIN IN OBESE
HUMANS WHO ARE NOT LEPTIN
DEFICIENT.
HERE'S A BIG CLINICAL TRIAL
USING SOMETHING CALLED METRO
LEPTIN A LONG ACTING FORM OF
LEPTIN PLACEBO SHOWING THAT THE
CHANGES IN BODY WEIGHT OVER TIME
ARE REALLY THE SAME IN THOSE WHO
GOT PLACEBO OR THOSE WHO GOT
LEPTIN.
THERE'S NOT A GREAT DEAL OF
EFFICACY OF LEPTIN IN
INDIVIDUALS WHO ARE ALREADY
OBESE AND THAT'S BECAUSE AS I
SHOWED YOU BEFORE THEY TEND TO
HAVE HIGH LEPTIN LEVELS ALREADY.
SO THEIR LEPTIN RE10R79S ARE
STIMULATED BY THE HIGH LEPTIN
CONCENTRATIONS.
IT DOESN'T MEAN IF THEY LOSE
WEIGHT AND LOWER THEIR
ENDOGENOUS LEPTIN LEVELS THAT
EXTRA LEPTIN WON'T CHIEN-MING
*** THEIR PHYSIOLOGY.
WE WON'T HAVE TIME TO TALK ABOUT
THOSE.
IT DOESN'T LOOK LIKE ALMOST
CONTINUE IS A REMARKABLE DRUG
FOR MOST OF US.
SO LEPTIN NOT DEFICIENT WHICH
IT'S NOT IN MOST CASES.
IT'S BINDING AT ITS OWN
RECEPTORS AND ALMOST CONTINUE
RECEPTORS ELSEWHERE.
AND YOU CAN IMAGINE THERE MUST
BE INDIVIDUALS ALSO MISSING
THOSE RECEPTORS AND SURE ENOUGH
THEY HAVE AN EARLY ONSET OBESITY
AND VERY HIGH LEPTIN LEVELS IN
THIS CASE AT LEAST IN MOST OF
THOSE PATIENTS.
AND THEY ACTUALLY FAILED TO
ENTER PUBERTY NORMALLY BECAUSE
IN THE ABSENCE OF THE LEPTIN
RECEPTOR THE HIGH THAT MUST
THINKS THE BODY IS STARVING.
ONE OF THE RESPONSES TO
STARVATION IS TO TURN DOWN
REPRODUCTION.
SO CHILDREN WITH THIS DISORDER
DON'T SPONTANEOUSLY ENTER INTO
PUBERTY.
NOW DO THEY RESPOND TO SEVERELY
RESTRICTED DIETS, PRIVATE OR
TAKEOUT DIET YES BUT AS SOON AS
THAT DIET STOPS THE WEIGHT
CONTINUES AND THIS PERSON HAS A
WEIGHT MEASUREMENT ON THE HEIGHT
CUR NOT ON THE WEIGHT CURVE.
THAT'S CONSIDERED A BAD SIGN.
NOW AS I SAID, PATIENTS WITH
LEPTIN RECEPTOR DEFICIENCY IN
GENERAL HAVE SIGNIFICANTLY
HIGHER LEPTIN LEVELS, HYPER
LEPTINNEMIA.
SO AS HIGH AS 100 VERSUS
CONTROLS EQUALLY OBESE THAT
WOULD BE ABOUT 40 OR 50.
WE'VE ACTUALLY DISCOVERED A
FAMILY LIKE THIS WITH LEPTIN
RECEPTOR DEFICIENCY.
EARLY ONSET OBESITY IS ONE OF
THE TWO KIDS, TWO SIBLINGS.
ONLY ONE OF THEIR PARENTS WAS
MODERATELY OBESE AND THEY HAD
HIGH LEPTIN EVEN FOR OBESE
CHILDREN.
SURE ENOUGH THEY CAME FROM A --
MARRIAGE WHERE THE PARENTS WERE
SECOND CUZENS.
AND TWO OF THE CHILDREN WERE
AFFECTED WITH THE SAME MUTATION.
AND I'LL SHOW YOU WHAT WE LOOKED
AT.
WHOLE SEQUENCING ACTION TO FIND
THEM.
THERE ARE A LOT OF SHARED
NUCLEOTIDE VARIANTS.
5,000 RECESSIVE CHANGES THAT
COULD HAVE BEEN EFFECTIVE.
WE WERE ABLE TO GET IT DOWN TO
IS A POTENTIALLY DAMAGING
VARIANTS AND ONE VERY REMARKABLE
HOMOZYGOUS LEPTIN RECEPTOR
CHANGE THAT CLEARLY WAS THE
CAUSE.
IT'S THIS CAUSE RIGHT HERE.
PREMATURE STOP CODE OVER
INVERSION OF NINE NOVEL AMINO
ACIDS AND THE LEPTIN RECEPTOR.
WE CAN FIND INDIVIDUALS LIKE
THIS BUT AGAIN THEY'RE RARE AND
THEY'RE LESS THAN 40 INDIVIDUALS
FAMILIES THAT HAVE BEEN
PROTECTED WITH THIS LEPTIN
RECEPTOR COMPLETE DEFESSION SEE.
HETERO ZYGOTES ARE THAT -- THERE
ARE SOME FOLKS WHO HAVE HIGH
LEPTIN LEVELS AS THOSE WITH
LEPTIN DEFICIENCY BUT THEIR
LEPTIN RECEPTORS ARE COMPLETELY
NORMAL.
SO WHO ARE THESE FOLKS?
MAYBE THEY'RE FOLKS WHO HAVE
PROBLEMS DOWN STREAM OF THE
LEPTIN RECEPTOR THAT ARE CAUSING
FEEDBACK REGULATION TROUBLES.
SO THE LEPTIN LEVELS ARE
INCREASED.
ONE SUCH CASE WE THINK MIGHT BE
THE BEIDEL SYNDROME IT HAS THIS
DEGENERATION IN THE DIGITS
CAUSED BY MANY DIFFERENT GENES.
AND THE BBS PROTEINS APPEAR TO
BE ESSENTIAL FOR NORMAL FUNCTION
WHAT'S CALLED THE PRIMARY
CILIUM.
EVERY CELL ACTUALLY HAS A LITTLE
CILIUM LIKE THIS ON IT.
IT HELPS ORIENT THE CELL
PROPERLY IN SPACE AND ALSO MOVES
THINGS AROUND THE CELL.
WHAT'S CALLED INTAW -- ONE
PARTICULAR MUTATION IS M39R
CAUSES OBESE VERSION OF THE
CILIUM HERE.
AND WHAT'S INTERESTING FOR US
WHEN YOU INACTIVATE THESE
PROTEINS IN MICE YOU LEAD TO A
RECEPTOR TRAFFICKING IN
HYPOTHALAMIC NEURONS AND
IMPAIRED LEPTIN HIGH LEVELS IN
THE MICE.
WE FOUND THE SAME TO BE TRUE
WITH THE HUMANS WITH MUCH HIGHER
LEPTIN LEVELS ADJUSTED FOR
THEIR -- THAN THE OBESE
CONTROLS.
WE THINK IT'S POSSIBLE MAYBE
SOME FOLKS WHO CAN BE IDENTIFY
BY THEIR HYPER LEPTINNEMIA FOR
HAVING DISORDERS IN THE LEPTIN
SIGNALING PATHWAYS.
OKAY.
SO IF THE LEPTIN RECEPTORS ARE
OKAY BUT THESE STILL A PROBLEM
IN THE LEPTIN SIGNALING WHERE
MIGHT IT BE?
WELL THERE'S AN ENZYME THAT,
THERE'S A GENE CALLED -- WHICH
MAKES MANY PALM KEULZ INCLUDING
THE HORMONE NEUROTRANSMITTER
ALPHA MSH AND MUTATIONS IN POMC
HAVE BEEN ASSOCIATED WITH
OBESITY.
SO IF YOU DISRUPT THE FORMATION
OF THIS ALPHA MSH, FOR INSTANCE
THESE TWO MUTATIONS, SO YOU
CAN'T MAKE ALPHA MSH, YOU CAN
DEVELOP A PERSON SUCH AS THIS
INDIVIDUAL.
NOW, ALPHA MSH CAN'T BE
PROCESSED PROPERLY NOR CAN ACTH
BE MADE OR BETA ION DOUGH --
INDOOR FIN.
IT CAUSES A PALE SKIN AND
REDDISH HAIR BECAUSE ALPHA MSH
WORKS AT A RECEPTOR CALLED
THE -- RECEPTOR IN THE BODY TO
REGULATE SKIN AND HAIR COLOR.
THESE PATIENTS HAVE ADRENAL
INSUFFICIENCY AND VERY SMALL AWE
DEANS BECAUSE A -- MAKES
CORTISOL.
BUT EVEN WHEN THEY ARE PROPERLY
REPLACED WITH CORTISOL THEY HAVE
OBESITY BECAUSE THE ALPHA MSH
DOESN'T WORK AT THE OTHER
RECEPTOR CALLED THE -- 4
RECEPTOR.
LET'S LOOK AT THESE RECEPTORS.
BEFORE WE GET THERE, ONE MORE
GENETIC DISEASE TO TELL YOU
ABOUT.
ANOTHER VERY RARE CONDITION.
THIS IS THE -- ONE, A GENE THAT
PROCESSES -- INTO ALPHA MSH BUT
ALSO PROCESSES OTHER HORMONES.
AND IF YOU DISRUPT THE NORMAL
PLACES WHERE -- PLACES THIS,
THEN YOU CAN'T MAKE ANY OF THESE
MOLECULES AND YOU HAVE A VERY
HIGH LEVEL OF -- FLOATING
AROUND.
SO THESE FOLKS HAVE EARLY ONSET
OBESITY AND ABNORMAL POST
TRANSLATIONAL HORMONE PROCESSING
LEADS TO A HOLE SERIES OF
DEFECTS, PROBLEMS WITH THE
*** AND THE CORTISOL, LOW
REGULAR INSULIN, HIGH
PROINSULIN -- AGAIN A VERY RARE
CONDITION CASE REPORT DESCRIBING
THE DISEASE.
BUT THE MOST COMMON DISORDERS OF
LIP CONTINUE PATHWAYS ARE
PROBLEMS WITH THE -- RECEPTORS.
SO BASED ON KNOCKOUT ANIMALS,
MICE ANIMALS, WE KNEW THAT IF WE
KNOCK OUT THE -- RECEPTORS IN A
MOUSE IT BECOMES AN OBESE MOUSE
AND EATS MORE CALORIES.
THERE ARE A FEW HUMANS THAT DO
THIS AS WELL.
HERE'S A NINE YEAR OLD WITH A
HOMOZYGOUS -- ACTIVATING
MUTATION AND HIS 16 YEAR OLD
NORMAL BROTHER SEVERE OBESITY
AND ACTUALLY INCREASED HEIGHT AT
LEAST EARLY ON.
THESE HAVE BEEN LOOKED FOR VERY
ACTIVITY AND IT TURNS OUT THAT
PERHAPS TWO AND-A-HALF PERCENT
OF SEVERELY OBESE INDIVIDUALS AT
LEAST EARLY ONSET OBESE
INDIVIDUALS MAY HAVE
HETEROZYGOUS MUTATIONS OF THE --
4 RECEPTORS.
SO THIS MAKES IT MOST COMMON
DISORDER WE KNOW WITH A GENETIC
CAUSE SO IS AYES OF CREATED WITH
OBESITY.
THERE'S ANOTHER RECEPTOR IN THE
BRAIN CALLED THE -- 3 RECEPTOR
WHERE THE MOUSE IS AN OBESE
MOUSE COMPARED TO THE NORMAL
MOUSE.
AND IT'S AN INTERESTING MOUSE
FROM OUR PERSPECTIVE BECAUSE IT
CHANGES BODY COMPOSITION TO HAVE
INCREASED FAT MASS AND REDUCED
LEAN MASS.
FOR THE CALORIES THEY TAKE IN
THEY DO TURN MORE OF THEM INTO
FAT.
THAT'S FEEDING EFFICIENCY AND SO
WE LOOKED FOR MUTATIONS IN THAT
AND WE FOUND A PAYER OF
POLYMORPHISMS I WON'T GO INTO
BUT IT SEEMS TO BE ASSOCIATED
WITH OBESITY.
THEY'RE MORE COMMON IN AFRICAN
AMERICANS AND CAUCASIANS.
SO WE'RE SEEING IT WITH GREATER
FAFLT AS WELL AS BODY MASS
INDEX.
WE KNOCKED THEM INTO MICE AND
NOW WE CAN SEE THAT THE MOUSE
HERE IS ALSO AN OBESE MOUSE,
THEY HAVE THIS DOUBLE MUTANT
HUMAN RECEPTOR.
SO HERE'S THE GREATER FAT MASS
IN THIS MOUSE COMPARED TO THE
SMALLER AMOUNT OF FAT IN THE
WILD TYPE HUMAN KNOCK-IN MOUSE.
AND WE'RE CURRENTLY TRYING TO
UNDERSTAND BETTER AS TO WHY THIS
MOUSE IS SO OBESE AND MAYBE I'LL
COME BACK IN A FEW YEARS AND BE
ABLE TO TELL YOU MORE ABOUT THAT
STORY.
AFTER THAT LONG DISCUSSION OF
SOME OF THE GENETIC CAUSES OF
OBESITY, JUST A FEW BECAUSE WE
THINK THERE ARE PROBABLY ON THE
ORDER OF THREE OR MORE HUNDRED
GENES THAT IMPACT ENERGY
REGULATION AND BODY WEIGHT.
LET'S COME BACK TO OUR PATIENT
AND GIVE YOU SOME DATA.
SO HERE'S OUR PATIENT'S PLASMA.
IT'S RIGHT IN LINE WITH THE
OTHER OBESE CHILDREN.
IT DOESN'T HAVE THE PROBABLE
WITH TOO HIGH OR TOO LOW LEPTIN.
IT TURNED OUT THAT THIS PATIENT
HAD A FUNCTION ALTERING VARIANT.
HAD HYPER INSULINEMIA.
ON YOU SHOULD WE TREAT THEM.
WE DON'T HAVE A TREATMENT YET
BESIDES IN THE LEPTIN DEFICIENT
INDIVIDUAL.
THE AMERICAN ACADEMY OF
PEDIATRICS RECOMMENDS THAT
PEOPLE WITH A BMI OF PERCENTILE
EVEN IF THEY HAVE SOME MILD
COMPLICATIONS SHOULD HAVE WEIGHT
LOST.
UNFORTUNATELY DOESN'T REALLY
TELL US HOW TO DO THAT.
IN MY RESEARCH GROUP WHO SPENT A
LOT OF TIME TRYING TO INDUCE
WEIGHT LOSS IN SEVERELY OBESE
CHILDREN COMPLETELY KEERTD OUT A
RANDOMIZED PLACEBO TRIAL CALLED
ORAL STAT WHICH IS A MODEST
WEIGHT LOSS INDISEASING
MEDICINE.
HERE HE LOST SEVEN KILOS OVER
THE FIRST THREE MONTHS OF
TREATMENT AND OF COURSE THE
WEIGHT LOSS SLOWS DOWN AND LOST
TWO KEY LOTION.
UNFORTUNATELY HE REGAINED HIS
LOST WEIGHT WHEN HE WAS NO
LONGER IN THE INTENSIVE PROGRAM.
AND PERHAPS KEVIAN WPEILL HAVE
SOMETHING TO SAY ABOUT WHY THAT
WOULD OCCUR.
I'M GOING TO STOP THERE.
ARE WE GOING TO DO QUESTIONS
AFTER BOTH SPEAKERS?
OR NOW?
AFTER BOTH SPEAKERS, OKAY.
SO THANK YOU VERY MUCH.
[APPLAUSE]
>> SO WHAT HAPPENS IN SOME OF
THESE PATIENTS WITH THE LEPTIN
DID HE CEPTOR DEFICIENCY.
DO THEY HAVE -- CLINICAL TRIAL
FOR FIVE YEARS.
THEY FOUND OUT THAT MY -- IS
ABOUT -- THEN AFTER FIVE YEARS
IT CAME TO OVER 1200 AS I WAS
GETTING OLDER FROM 49 TO ALMOST
74.
SO I GUESS THIS IS A LOSING
BATTLE RIGHT NOW.
IF I DON'T DO ANYTHING ELSE --
1250 SO ANYTHING ABOVE THAT I
HAVE TO BOND.
SO WHAT HAPPENS IN SOME OF THESE
PATIENTS WITH SOME OF THE
RECEPTOR MUTATIONS IN TERMS OF
THEIR RESTING METABOLISM.
>> SO THE QUESTION'S REALLY WHAT
HAPPENS WITH THESE GENETIC
ABNORMALITIES TO RESTING ENERGY
EXPEPPURES.
FIRST, JUST TO MAKE SURE
EVERYBODY KNOWS WHAT WE'RE
TALKING ABOUT.
IF YOU'RE LYING AT REST AND WE
JUST MEASURE HOW MANY CALORIES
YOU BURN, THERE WILL BE A
CERTAIN AMOUNT REQUIRED TO HAVE
YOUR HEART PUMP AND YOUR BRAIN
FUNCTION.
IF YOU'RE EATING A MEAL, YOUR
GUTS WILL HAVE TO PERISTALSIS
AND BREAK DOWN CALORIES SO THAT
BURNS DOWN CALORIES A LITTLE
HIGHER THAN JUST RESTING.
IF YOU'RE FULLY ASLEEP YOUR
BRAIN IS LESS ACTIVE AT LEAST
YOUR BODY IS SO THE SLEEPING MET
BALL IBLG RATE IS LITTLE LOWER
THAN JUST AT REST.
ANYWAY THAT TURNS OUT TO BE IN
MOST PEOPLE ABOUT TWO THIRDS BUT
ABOUT TWO 24EUR9DZ OF THE
CALORIES THAT ARE BURNED EACH
DAY.
OF COURSE THAT REALLY CAN VARY
TREMENDOUSLY DEPENDING ON
WHETHER OR NOT SOMEONE IS VERY
PHYSICALLY ACTIVE OR NOT BECAUSE
PHYSICAL ACTIVITY CAN VARY
TREMENDOUSLY FROM HOUR TO HOUR,
MOMENT TO MOMENT, FROM PERSON TO
PERSON.
AND SO RESTING ENERGY METABOLISM
IS ONE OF THE THINGS THAT PEOPLE
LOOK AT THAT MIGHT BE AFFECTED
IN SITUATIONS AND LEAD TO
OBESITY OR IN THEY WERE HIGH
ENOUGH, PREVENT OBESITY.
THE STORIES FOR RESTING ENERGY
METABOLISM IS INTERESTING.
IF PEOPLE TRY TO LOSE WEIGHT
THAT'S ONE OF THE THINGS THAT
CHANGES QUITE DRAMATICALLY AS
THEY'RE ACUTELY LOSING WEIGHT.
THE BODY IS YOU'RE NOT SUPPOSED
TO LOSE WEIGHT.
SO ALL OF THE SYSTEMS ARE TURNED
DOWN TO LEAD TO WEIGHT REGAIN
AND THOSE INCLUDE RESTING ENERGY
METABOLISM.
WE THINK ONE OF THE FACTORS,
CERTAINLY THE CHANGES AS YOU
LOSE WEIGHT VERY ACUTELY IS THE
LEPTIN CONCENTRATION IN THE
BLOOD.
AND SO IF YOU STOP EATING FOR A
DAY, LEPTIN DROPS DRAMATICALLY
RIGHT AWAY.
HOWEVER, INTERESTINGLY, ADDING
BACK LEPTIN TO THESE PEOPLE WHO
HAVE LEPTIN DEFICIENCY, GENETIC
LEPTIN DEFICIENCY DOESN'T CAUSE
TREMENDOUS CHANGES IN ENERGY
METABOLISM AS MUCH AS YOU MIGHT
IMAGINE.
IN THE MOUSE MODELS HOWEVER IT'S
PRETTY CLEAR THAT IT DOES.
NOW, THAT MAY MEAN WE DON'T HAVE
ENOUGH HUMANS WITH SUFFICIENT
PRECISION TO SEE THOSE EFFECTS.
WHERE IT HAS BEEN SHOWN TO BE
EFFECTIVE IS AFTER INDIVIDUALS
WHO HAVE HAVE THE ABILITY TO
MAKE LEPTIN LOSE WEIGHT ARE
STABILIZED AT A NEW WEIGHT IN AN
INPATIENT SETTING WHERE THEY
KNOW EXACTLY HOW MANY CALORIES
ARE CONSUMED AND HOW MUCH
ENERGY'S EXPENDING.
REPLACING OF LEPTIN DOES HAVE
SUBTLE EFFECTS ON THE ABILITY OF
THE BODY TO USE ENERGY.
SO PEOPLE BECOME VERY EFFICIENT
AT USING ENERGY WHEN THEY LOSE
WEIGHT AND LEPTIN ACTUALLY MAKES
THEM A LITTLE LESS ENERGY
EFFICIENT.
AT LEAST THAT'S THE CURRENT
BELIEF.
>> THANK YOU.
>> I THINK IT'S NOT WELL SHOWN
BUT AND IT SHOULD BE REPLICATED
IN MORE THAN ONE CENTER BUT IT'S
BELIEVED THERE MIGHT BE THIS
ROLE.
>> I CAME IN A MOMENT OR SO AGO
SO PLEASE STOP ME IF YOU
ADDRESSED THIS.
I'VE ALWAYS BEEN TAKEN WITH THE
FACT THAT BMI SEEMS TO BE A ONE
SIZE FITS ALL INDICATOR.
AND ALTHOUGH YOU CAN FIND SOME
SITES WHICH FACTOR IN AGE AND
GENDER, BODY SIZE, BONE DENSITY,
MUSCLE DENSITY SEEMS TO BE QUITE
OFF.
NOW, I NEVER CONSIDER MYSELF
TERRIBLY OBESE BUT RIGHT NOW
MIGHT BE ABOUT 20 POUNDS
OVERWEIGHT IN ORDER TO BE
NORMAL.
I DON'T LOOK AT MYSELF AS 20
POUNDS OVER WEIGHT, MAYBE SOME
DO.
I'M WONDERING WITH A YOUR VIEW
OF THE ADEQUACY OF BM.
AND THAT BY THE WAY IS ONE THAT
ADJUSTS MY AGE AND GENDER.
>> RIGHT.
SO I GUESS--
>> [INDISCERNIBLE]
>> THAT WILL HELP YOU IN THE
LONG RUN PLAYING TENNIS.
SO THE BODY MASS INDEX AS
SURROGATE MEASURE.
IT'S SUPPOSED TO BE A SCREENING
TOOL THAT WE USE IN CLINICAL
PRACTICE TO TRY TO IDENTIFY
PEOPLE WHO MIGHT BE AT GREATER
RISK.
WHAT I MENTIONED IS THAT IT'S A
MARKER OF BODY FAT BUT IT'S NOT
A VERY PERFECT MARKER.
MAYBE I CAN COME BACK TO THIS
SLIDE WHERE WE ARE JUST LOOKING
AT BODY FATNESS VERSUS BMI IN
MEN AND WOMEN.
IF WE GO TO ANY PARTICULAR BMI,
WE CAN HAVE FOLKS HERE WHO HAVE
A BODY FATNESS OF ONLY 10% OR
40%.
SO YOU KNOW THAT IT'S NOT A
WONDERFUL TOOL.
BUT ON AVERAGE, IT REFLECTS BODY
FATNESS SO IT'S A REASONABLE
SCREENING TOOL FOR US TO
CONSIDER.
NOW, IS EVERYONE GOING TO GO
HAVE A DETAILED STUDY OF THEIR
BODY FATNESS WITH EXPENSIVE
TESTS.
NO, WE'RE NOT GOING TO DO THAT.
INSTEAD WE TRY TO USE SURROGATE
MEASURES LIKE BMI TO DIRECT
OURSELVES WHO WE MIGHT WANT TO
LOOK AT.
NOW, WHEN YOU SAID YOU WERE 20
POUNDS OVERWEIGHT THAT PROBABLY
PUTS YOU IN THIS BM IT OF 25,
26, SOMETHING IN THAT RANGE.
AND SO THAT'S MAKING THE
ASSUMPTION THAT NORMAL WEIGHT IS
BMI OF 23, AND THAT THAT IS IN
FACT THE MOST ADVANTAGEOUS
WEIGHT TO HAVE IN TERMS OF YOUR
HEALTH.
I THINK MORE AND MORE DATA ARE
ACCUMULATING THAT SUGGESTS THAT
AT LEAST FOR OLDER INDIVIDUALS,
THERE ARE NO TREMENDOUS
DISADVANTAGES TO HAVING A BODY
MASS INDEX EVEN IN THE 27 RANGE
OR 28 RANGE.
IT'S REALLY WHEN YOU'RE MUCH
OVER 30 THAT YOU CAN DEMONSTRATE
THE BIG INCREASES IN MORTALITY.
NOW THAT DOESN'T MEAN THERE
AREN'T MORBID ITIES THAT DEVELOP
IN THIS CHANGE.
I DIDN'T BRING THE SLIDES WITH
ME BUT EVEN IN THE 25-30 RANGE,
THERE'S AN INCREASING RISK OF
DIABETES DEVELOPING EVEN IN THAT
VERY MILDLY OVERWEIGHT RANGE.
SO WE KNOW THERE ARE RISKS OF
COMPLICATIONS GOES OPTICALLY
DIABETES EVEN WITHIN THAT
RELATIVELY HEALTHY RANGE FOR
DYING.
SO THAT MEANS THAT WHILE WE
MIGHT NOT DIE AT HAVING A LITTLE
EXTRA WEIGHT, WE MIGHT NOT BE AS
HEALTHY AS WE'D LIKE TO BE.
THERE MAY BE OTHER CONDITIONS
LIKE ART RIFTIC CONDITIONS THAT
COULD BE REVERSED IF WE WERE AT
A LOWER BODY WEIGHT.
OF COURSE WE DON'T WANT TO GO
TOO FAR THE OTHER WAY.
THAT'S ONE OF THE PROBLEMS OF
AGING THAT EVEN SEEING EXACTLY
THE SAME BODY WEIGHT LEAN MASS
THE METABOLIC ACTIVE WEIGHT
TENDS TO DECREASE OVER TIME.
UNLESS YOU KEEP UP YOUR TENNIS
GAME.
>> LET ME ASK YOU, THERE'S
ELEGANT CELL BIOLOGY WORK DONE
HERE AT THE NIH AND ELSEWHERE
CONCERNING THE REGULATION OF
MITOCHONDRIAL STRUCTURE AND
METABOLISM IN RELATIONSHIP TO
STRESS AND CHLORIC DEPRIVATION.
HAVE ANY STUDIES OF THAT KIND
BEEN DONE WITH ANY OF THE ANIMAL
MODELS OR LET ALONE THE HUMAN
MODELS OF OBESITY SYNDROMES.
ARE THESE DIS0RDZ MAN FELSED BY
SIMILAR DISREGULATION OF
MITOCHONDRIAL STRUCTURE AND
FUNCTION.
DO WE KNOW THAT?
>> THAT'S A VERY GOOD QUESTION.
HOW MUCH DO WE KNOW ABOUT THE
LINK BETWEEN MITOCHONDRIAL
METABOLISM DYSFUNCTION AND
OBESITY.
I'M PRETTY SURE THERE'S ANIMAL
MODELS THAT HAVE BEEN DONE THAT
DEMONSTRATE THAT IT'S POSSIBLE
TO AFFECT ENERGY METABOLISM IN
THE FASCIA.
IN MOM HEUTLE IT'S NOT ANY TIME
I'VE SPENT RESEARCHING.
THERE MAY BE OTHERS IN THE
AUDIENCE ABLE TO ANSWER YET MUCH
BETTER THAN I.
ARE THERE ANY STUDIES OF USING
ANIMALS.
>> I CAN TELL YOU IT'S NOT ONE
OF THE FOLLOW HITS ON OUR
ASSOCIATIONS FOR OBESITY.
NONE OF THE MITOCHONDRIAL GENES
ARE SHOWN UP.
THE COMMON VARIATIONS WE DON'T
THINK WILL BE A MAJOR
CONTRIBUTOR.
OVER TIME WE INCREASE THE SAMPLE
SIZE TO TWO MILLION, FIVE
MILLION PEOPLE THAT WE CAN
IDENTIFY MORE GENES OR GENE LOCI
BETTER ASSOCIATED WITH BODY
WEIGHT.
REGULATION.
IT WOULDN'T SURPRISE ME IN THE
LEAST IF WE CAN DEPOSIT THAT
THAT MORE CLEARLY.
I DID TELL YOU AT ONE POINT HE
WE TRIED TO LOOK FOR VARIATIONS
IN ASSOCIATION WITH RESTING
ENERGY METABOLISM AND WERE
UNABLE TO FIND LINKS TO EXPLAIN
SOME VARIANTS WE HAD SEEN IN
ENERGY RATES BUT IT DOESN'T MEAN
IT'S NOT THERE.
>> IT SEEMS TO BE MORE TRUE IN
THE CANCER LITERATURE CELL
BIOLOGY LITERATURE RELATED TO
TUMOR LINES AND SO FORTH THE.
AT ANY RATE THERE WILL BE TIME
FOR MORE QUESTIONS SO WE SHOULD
MOVE ON.
THANK YOU VERY MUCH.
[APPLAUSE]
>> THANKS FOR THE INVITATION TO
PRESENT HERE.
WHEN I FIRST ARRIVED AT THE NIH
I HAD A PHYSICS DEGREE AND
WANTED TO LEARN MORE ABOUT THE
BROAD SCOPE OF THE KINDS OF
GROWTH THAT'S BEING DONE AT NI
HVMENT AND A LITTLE BIT OF MORE
MEDICAL KNOWLEDGE AND I ATTENDED
PRETTY REGULARLY ONE OF THE
EARLY VERSION OF THIS COURSE I
GUESS.
IT'S AN HONOR TO BE HERE AND
ALSO TO SHARE THE PODIUM WITH
JACK WHO I'VE BEEN FOLLOWING HIS
RESEARCH SINCE I GOT HERE AS
WELL.
I'VE BEEN GIVEN THE TASK OF
TALKING ABOUT WEIGHT LOST IS
DIFFICULT.
I WANTED TO SET THIS UP A LITTLE
BIT BY SOME INITIAL SURPRISE
THAT I HAD WHEN I WAS SITTING IN
ON A COUNSELLING SESSION, A
DIETARY COUNSELLING SESSION WITH
AN OBESE PATIENT AT THE CLINICAL
CENTER WITH A DIET TITION WHO
SINCE MOVED ON TO OTHER PLACES
AND SHE WAS JUST GIVING SOME
REALLY GOOD DIET ADVICE AND SHE
MADE THIS CLASS FOR THIS PERSON
WHICH I THOUGHT WAS REALLY
INTERESTING.
SHE TALKED ABOUT LOOKING AT
THEIR DIET RECORDS AND SAYING OH
WELL IT LOOKS LIKE YOU DRANK A
FEW CANS OF SODA A DAY.
IF YOU WERE JUST TO CUT THAT
DOWN INSTEAD OF DRINKING THREE
CANALS A DAY JUST DRINK ONE CAN
A DAY AND REPLACE IT WITH DIET
SODA, YOU WOULD LOSE ALL THIS
WAIT AFTER A YEAR.
AFTERWARDS I SAID WHERE DID YOU
GET THAT NUMBER FROM HOW DID YOU
CALCULATE HOW MUCH WEIGHT THIS
PERSON WOULD LOSE.
SHE SAID IT'S IN EVERY NUTRITION
TEXTBOOK, IT'S HE EVER TEXTBOOK.
IN FACT WE'RE TESTED ON THIS
IDEA OUR LICENSING EXAMS.
IT TURNED OUT THAT THIS IS
EVERYWHERE.
I LOOKED THIS UP AND THIS WAS
THE PREVIOUS GUIDE FOR THE
IDENTIFICATION OF EVALUATION OF
TREATMENT OF OBESITY FOR ADULTS.
THIS WAS JUST UPDATED AND
PUBLISHED IN THE JOURNAL OF
OBESITY, CIRCULATION I BELIEVE.
BUT THE OLD RULE OF THUMB WAS IF
YOU CUT A 500 TO A THOUSAND
CALORIES PER DAY, I SAY CALORIES
AND MOST PEOPLE TALK ABOUT
CALORIES IT'S REALLY
KILOCALORIES IN NUTRITION.
THAT WILL PRODUCE THIS
RECOMMENDED WEIGHT LOSS OF ONE
TO TWO POUNDS PER WEAK.
WEEK.
THAT'S JUST SUPPOSED TO CONTINUE
ON I GUESS.
YOU CUT IT 500 CALORIES OUTS OF
YOUR DIET YOU LOSE 50 POUNDS A
YEAR.
THAT'S GREAT, TWO YEARS THAT'S A
HUNDRED POUNDS OF WEIGHT LOSS.
IT'S GOT TO STOP SOMEWHERE RIGHT
AND SO I WAS REALLY INTERESTED
IN TRYING TO FIND OUT WHAT IS
THE, WHAT'S THE SCIENTIFIC BASIS
BEHIND IN RULE OF NUMBER.
IT'S 3500 KILOCALORIES PER
POUND.
IT TOOK ME MONTHS AND MONTHS TO
FIGURE OUT WHERE THIS NUMBER
CAME FROM AND HOW IT WAS BEING
APPLIED IN THIS WAY.
AND I FINALLY TRACKED IT DOWN TO
A PAPER THAT WAS PUBLISHED, BUY
THIS PHYSIOLOGIST -- BASICALLY
WHAT HE DID WAS TAKE BIOPSIES OF
HUMAN FAT TISSUE AND HE SAW HOW
MANY CALORIES WERE IN THE FAT
TISSUE AND HE FOUND OUT THERE
ARE 3500 CALORIES OF ENERGY
STORED IN HUMAN FAT ISSUE.
YOU MIGHT KNOW THAT THAT'S NOT
TRANSLATION INTO ACTUAL TRY
COLLISION RIDE BECAUSE FAT
TISSUE HAS WATER AND PROTEIN AND
LOTS OF OTHER STUFF IN IT.
AND SO IT'S DILUTED BY THESEMAN
CLOSURE EQUIVALENTS AND YOU GET
THE 3500 KILOCALORIES PER POUND
IDEA.
SO THE IDEAS WAS THEN OKAY WELL
WHEN YOU LOSE WEIGHT YOU JUST
LOSE FAT TISSUE.
THAT'S ASSUMPTION NUMBER ONE.
THAT'S NOT TRUE YOU USE LEAN
TISSUE AS WELL AS FAT TISSUE
WHEN YOU LOSE WEIGHT.
ASSUMPTION NUMBER TWO WHEN YOU
GO ON A DIET NOTHING HAPPENS TO
THE NUMBER HOW FAR CALORIES THAT
YOU BURN.
THOSE ARE THE TWO ASSUMPTIONS
UNDERLYING THE USE OF THIS RULE
AS STAYED IN THIS PARTICULAR
HANDBOOK AND PRACTICALLY OTHERS
AS YOU GOOGLE HOW MUCH, HOW MANY
CALORIES TO LOSE WEIGHT YOU'LL
FIND MILLIONS OF HITS THAT WILL
BASICALLY CITE THIS RULE OF
THUMB.
IT'S ACTUALLY BEEN APPLIED NUT
JUST FOR INDIVIDUAL SUBJECTS BUT
PEOPLE HAVE PUT OUT POLICY
IMPLICATIONS OF THIS.
THIS IS A 2010 RECORD THAT WAS
INVESTIGATING THE
POPULATION-WIDE IDEA THAT THIS
DIETICIAN WAS RECOMMENDING ON AN
INDIVIDUAL BASIS.
WHAT WAS HAPPENING IF WE WERE TO
SOMEHOW MAKE PEOPLE DRINK LESS
SODA.
IN FACT WE COULD TAX THEM.
THAT MIGHT BE ONE WAY WE COULD
MAKE PEOPLE DRINK LESS SODA.
AND THEY WERE ACTUALLY VERY
BRAVE BECAUSE THEY WERE
ECONOMISTS WHO WERE TALKING
ABOUT IF YOU ATTACK PEOPLE'S
SODA BY 20% THEY'LL COMPENSATE
BY DRINKING MORE OF THESE OTHER
THINGS.
IT'S A VERY FANCY ECONOMICS
ARGUMENT AND THEY CAME UP AT THE
END OF THE DAY THAT THEY WOULD
DECREASE THE ENERGY INTAKE BY 40
KILOCALORIES PER DAY.
IT DOESN'T SOUND LIKE A LOT.
WHEN YOU APPLY AS THE 3500
CALORIE PER POUND RULE TO THE
AVERAGE WEIGHT OF AN ADULT IN
RECENT YEARS, THIS IS WHAT YOU
GET.
THEY ACTUALLY SAID THIS IN THIS
REPORT.
THEY SAID THAT YOU WILL GET
ABOUT THIS RATE OF WEIGHT LOSS.
WHAT THEY DIDN'T SAY, THEY
DIDN'T PLOT THE FIGURE, I
PLOTTED THE FIGURE.
BUT BASICALLY IT MEANS YOU TAKE
THE AVERAGE WEIGHT OF ADULTS
DURING THE HEIGHT OF OBESITY.
IT ATTACKS ALL THE SODAS AND YOU
WAIT FIVE YEARS AND YOU COME
BACK TO BEFORE THERE WAS AN
OBESITY EPIDEMIC.
THAT'S CHARACTERISTIC OF THE
WEIGHT OF THE 1970'S ABOUT A 10
KILO WEIGHT LOSS.
SO SOMETHING IS WRONG WITH THIS
AND PEOPLE WERE MAKING
RECOMMENDATIONS AND PROMISING
ALL SORTS OF PUBLIC HEALTH
CONSEQUENCES TO PARTICULAR
POLICIES.
AND SO MY BACKGROUND IS IN
PHYSICS.
I BUILD MATHEMATICAL MODELS FOR
A LIVING AND I THOUGHT MAYBE IF
WE VIEWED SOMETHING ABOUT HOW
THOSE ASSUMPTIONS ARE ACTUALLY
LONG AND WE COULD ACTUALLY
QUANTIFY HOW FAR OFF THEY'RE
WRONG, HOW MUCH OAF A WEIGHT
CHANGE ACTUALLY COMES FROM FAT
TISSUE VERSUS LEAN TISSUE AND
HOW DO THOSE CHANGING BODY
COMPOSITION AND CHANGING
METABOLIC RATE THAT ACTUALLY
CHANGE OVER TIME.
HOW DOES THAT QUANTITY VIE
BELIEVE DICTATE THE DYNAMICS OF
LATE CHANGE OVER TIME FOR A
GIVEN INTERVENTION.
THAT'S THE IDEA OF MY RESEARCH
PROGRAM AND SO I BUILT A MODELS.
THESE ARE THE EQUATIONS FOR ONE
OF THE MODELS, THE MORE COMPLEX
ONE OF SEVERAL MODEL THAT WE
BUILD.
THIS ONE COUNTS FOR NUTRIENTS,
FAT AND PROTEIN HOW THEY
INTERACT IN THE BODY REGULATED
BY THE DIET AND HOW CHANGE IN
THE MACRO NUTRIENTS WILL CHANGE
VERSUS HOW MUCH FAT YOU'RE
BURNING ETCETERA ETCETERA HOW
THAT FILTERS DOWN INTO CHANGES
IN THE DETAILED CHEMICAL
COMPOSITION OF THE BODY.
I'M NOT GOING TO WALK THROUGH
ALL THIS OBVIOUSLY.
IF YOU'RE REALLY INTERESTED IN
READING BIT YOU CAN READ ABOUT
IT IN THE AMERICAN JOURNAL OF
PHYSIOLOGY PAPERS.
WHAT YOU ARE MORE INTERESTED IN
IS OKAY NOW THAT YOU BUILT THIS
MODEL CAN YOU DO ANY BETTER THAN
ACTUALLY 3500 CALORIE PERPOUND.
IN OTHER WORDS LET'S MAKE
PREDICTIONS ABOUT INDEPENDENT
EXPERIMENTS THAT WEREN'T USED TO
BUILD A MODEL BUT WE KNOW WHAT
PEOPLE WERE EATING.
DON'T CHANGE ANY PARAMETERS OF
THE MODEL AND JUST COMPARE THE
MODEL PREDEDUCTIONS TO THE
RESULTS OF THE EXPERIMENTS.
THE OCTOBER THING I'M ALLOWED TO
CHANGE IS THE INITIAL CONDITIONS
OF THE MODEL TO MATCH WHATEVER
THE SUBJECT POPULATION WAS IN
THE EXPERIMENT.
SO I'M STUDYING LEAN MEN I GET
TO STARTED THE MODEL OFF.
IT'S THE CHARACTERISTIC
COMPOSITION, RESTING METABOLIC
RATE WE TALKED BEFORE OF A LEAN
MAN.
WE SEE THAT LEAN MAN WITH
WHATEVER WAS BAD IN THE STUDY
AND COMPARED THE PREDICTIONS
WITH THE RULES.
SO WE'VE DONE THIS IN THESE TWO
PAPERS WITH OVER A DOZEN
DIFFERENT KINDS OF EXPERIMENTS.
OVER FEEDING EXPERIMENTS, UNDER
FEEDING EXPERIMENTS, MEN, WOMEN,
LEAN, OBESE, VARYING THE MACRO
NUTRIENT CONTENTS OF THE DOITD.
AND WE'VE SHOWN IT'S PRETTY
ACCURATE.
IT DOES A PRETTY GOOD JOB OF
SIMULATING THE DIFFERENCES
BETWEEN THOSE INDIVIDUALS ONCE
YOU ACCOUNT FOR THEIR BASELINE
BODY COMPOSITION CHANGES AND
METABOLIC PARAMETERS.
WHAT I WANT TO SHOW YOU IS ONE
EXAMPLE THAT'S IN THOSE TWO
PAPERS AND ACTUALLY ALLUDES TO
AN EXPERIMENT THAT JACK HAS
MENTIONED A COUPLE TIMES IN HIS
TALK.
A MUCH MORE CLASSIC BY -- AT
COLUMBIA UNIVERSITY NOW AT
COLUMBIA UNIVERSITY PUBLISHED IN
THE NEW ENGLAND JOURNAL IN 1995.
WHAT THEY DID WAS THEY TOOK SOME
FOLKS VERY OBESE FOLKS, BROUGHT
THEM IN AS INPATIENTS FOR MANY
MONTHS.
IT TOOK NINE MONTHS OF TIME.
AND FED THEM THIS, AS MICHAEL
LIKES TO CALL A HORRIBLE LIQUID
DIET.
SO THEY ONLY GET TO DRINK THIS
REALLY BLAND TASTING LIQUID DIET
AND THEY CAN KNOW EXACTLY HOW
MANY CALORIES THEY'RE CONSUMING.
BECAUSE THEY DON'T LEAVE AND
THEY KNOW THEY CAN MEASURE THE
CALORIES IN THIS LIQUID DIET
VERY EASILY.
AND SO WHAT THEY DO IS THEY
BASICALLY START THEM OFF, THEY
HAVE AROUND 3,000 CALORIES A DAY
NORMALLY AND THEY PUT THEM ON
900 CALORIES A DAY OF THIS
LIQUID DIET UNTIL THEY LOSE 10%
OF THEIR BODY WEIGHT.
THEN THEY RAMP UP THE NUMBER OF
CALORIES IN THE SAME LIQUID DIET
SO THEY MAINTAIN PERFECT WEIGHT
STABILITY FOR MANY WEEKS, OKAY
AND THEY MEASURE SOME METABOLIC
PARAMETERS IN BODY COMPOSITION.
THEY DO EXACTLY THE SAME THING
ALL OVER AGAIN UNTIL THEY LOSE
20% OF THE WEIGHT LOST AND THEN
THEY BALANCE THEM OFF.
SO WE TOOK OUR MODEL, STARTED
THEM OFF AS THE AVERAGE.
IN THIS PARTICULAR STUDY, FED
THEM THE CURVE FOR THE ENERGY
INTAKE AND COMPARE THE RESULTS.
A COUPLE THINGS I WANT TO POINT
OUT HERE.
SO THE CURVE ARE THE MODEL
PREDICTIONS, THE DATA POINTS ARE
THE BOXES.
AND A COUPLE THINGS ARE
INTERESTED AND JACK ALLUDED TO
THIS.
RIGHT AWAY WHEN YOU GO INTO THE
ENERGY DEFICIT, THE NUMBER OF
CALORIES THAT YOU'RE BURNING
SLOWS DOWN DRAMATICALLY.
THAT'S WHAT THE MODEL PREDICTS.
AND FINALLY SORT OF HAS A SLOW
PERIOD WHERE IT'S SLOWLY
DECLINING AS YOU'RE LOSING
WEIGHT.
AS YOU REESTABLISH THAT NEW BODY
WEIGHT, THAT KIND OF PICKS UP
AGAIN AND THEY DON'T HAVE A
DYNAMIC MEASUREMENT.
THIS IS KIND OF THE PERIOD OF
ACTIVE WEIGHT LOSS AND THIS IS
THE PERIOD OF WEIGHT STABILITY.
THEY DON'T HAVE THAT MEASUREMENT
DURING ACTIVE WEIGHT LOSS DURING
TOTAL ENERGY EXPENDITURE BUT
THEY DO HAVE IT FOR RESTING
METABOLIC RATE.
YOU CAN SEE THOSE SORTS OF
DYNAMICS ARE OCCURRING IN THE
DATA AS WELL.
WHEN THEY DID IT AGAIN, YOU
BASICALLY SEE THE SAME SORT OF
THINGS.
FIRST OF ALL IT'S A HORRIBLE
ASSUMPTION THAT NOTHING HAPPENS
TO THE NUMBER OF CALORIES THAT
YOU'RE BURNING WHEN YOU GO ON A
DIET RIGHT.
OTHERWISE THAT BLUE LINE AND
THAT RED LINE AND THE GREEN LINE
WHICH IS THE ENERGY COST FOR
PHYSICAL ACTIVITY SHOULD JUST BE
COMPLETELY LAWYERS.
THAT'S CLEARLY NOT WHAT'S
HAPPENING.
THE SECOND THING I WOULD LIKE TO
POINT OUT IS THE MODEL DOES A
REASONABLY GOOD JOB OF MATCHING
THE DATA HERE IN TERMS OF THE
DYNAMICS OF TOTAL ENERGY
EXPENDITURE AND RESTING
METABOLIC RATE.
IN TERMS OF BODY COMPOSITION AND
WOIRT CHANGE THE MODEL PREDICTS
BOTH THE RIGHT AMOUNT OF WEIGHT
CHANGE AND THE RIGHT COMPOSITION
OF THAT WEIGHT CHANGE THAT'S
COMING BOTH FROM FAT MASS AND
FAT FREE MASS SORT OF LEAN
TISSUES OF THE BODY IF YOU WANT
TO THINK ABOUT IT THAT WAY.
INTERESTINGLY IF YOU THEN
COMPARE WHAT THE 3500 CALORIE
PER POUND RULE WOULD PREDICT,
YOU'RE MORE THAN 40 POUNDS OFF
THE MARGIN.
IT PREDICTS MORE THAN 40 POUNDS
MORE WEIGHT LOSS AFTER THESE
SEVERAL MONTHS THAN WERE
ACTUALLY OBSERVED.
SO PRETTY POOR PREDICTION.
OKAY.
SO NOW THAT YOU'VE GOT THIS
MODEL, LET'S APPLY IT TO SOME
OTHER DATA THAT WE ACTUALLY WERE
INTERESTED IN TRYING TO
UNDERSTAND WHAT WAS HAPPENING IN
THE FOLKS WHO WERE COMPETING ON
THIS NATIONALLY TELEVISED WEIGHT
LOSS COMPETITION CALLED THE
BIGGEST LOSER.
HOW MANY PEOPLE HAVE WATCHED
THIS SHOW OR IS AN THIS SHOW.
MOW PEOPLE HAVE SEEN IT.
I'M ONE OF THE PEOPLE WHO
PROBABLY I DON'T KNOW WHERE I
FELL INTO JACK'S HOURS OF
TELEVISION ON THE X FACTOR,
PROBABLY AT THE UPPER END, NOT
QUITE 40 HOURS PER WEEK BUT IT'S
MY GUILTY PLEASURE AS REALITY
TELEVISION AND AFTER ONE DAY,
LONG DAY IN THE LAB I CAME HOME
AND I TURNED ON THE TELEVISION
AND THAT WAS AT THE TAIL END OF
THE BIGGEST LOSER COMPETITION
AND I SAW PEOPLE WERE LOSING 10,
15, 20 POUNDS PER WEEK.
WHAT THE HECK IS GOING ON IN
THIS PROGRAM.
I DON'T UNDERSTAND WHAT'S
HAPPENING HERE.
AND SO I DECIDED I'M GOING TO
MAKE A POINT OF WATCHING THIS
SHOW THE NEXT WEEK.
AND BASICALLY SHOWED A BUNCH OF
OVERWEIGHT PEOPLE GETTING YELLED
AT BY A PERSONAL TRAINERS.
WHAT I DIDN'T SEE WAS YOU KNOW
MUCH INFORMATION ABOUT WHAT THEY
WERE EATING.
BECAUSE IT'S KIND OF HARD TO
VIDEO TAPE PEOPLE NOT EATING,
RIGHT.
IT'S NOT A VERY ENTERTAINING
TELEVISION.
SO I DECIDED TO CALL UP THE, I
FOUND THE PRODUCER ON-LINE.
I DID SOME SEARCHING AND FOUND
THE NAME OF THE PRODUCER WHO
PROOGED THE SHOW AND I PHONE HIM
AND I SAID THIS IS DR. HALL FROM
THE NIH CALLING.
I WOULD LIKE TO TALK TO THE
DOCTOR WHO IS IN CHARGE OF THE
CARE OF THESE FOLKS.
ABSOLUTELY.
HE PUT ME IN TOUCH WITH ROB --
WHO IS THE MIDDLE AUTHOR ON THIS
PAPER THAT WE EVENTUALLY
PUBLISHED.
HE WAS ACTUALLY DOING VERY
CAREFUL TRACKING OF THEIR BODY
COMPOSITION CHANGE.
BUT HE DIDN'T HAVE ANY
MEASUREMENTS OF ENERGY
METABOLISM.
IN OTHER WORDS HOW MANY CALORIES
THESE FOLKS WERE BURNING, BOTH
AT REST AND DURING THESE EXTREME
AMOUNTS OF ACTIVITY.
AND ONE OF THE THINGS THAT WE
KNOW ABOUT IS THAT WHEN OR WE
THINK WE KNOW ABOUT, THIS IS ONE
OF THE THINGS ABOUT THIS AREA OF
RESEARCH, THERE'S LOTS OF
MYTHOLOGY OUT THERE AND LOTS OF
PEOPLE THINK THEY KNOW THINGS.
IT'S AN ACCEPTED FACT WHEN YOU
DIG INTO THE DETAILS YOU FILED
OUT THE BASIS FOR THESE BELIEVES
WERE NOT QUITE WHAT YOU
THOUGHTOR HOPED WOULD BE.
ONE OF THE IDEAS IS IF YOU HAVE
A LOT OF RIGOROUS EXERCISE YOU
CAN PREVENT THE LOSS OF FAT FREE
MASS.
YOU CAN KEEP YOUR LEAN TISSUES
HIGH.
AS JACK MENTIONED EARLIER, THE
METABOLIC RATE THAT SLOWS DOWN
WHEN YOU LOSE WEIGHT, ONE OF THE
THINGS THAT'S BELIEVED IS THAT
THE BIGGEST DRIVER OF THAT
RESTING METABOLIC RATE IS HOW
MUCH LEAN TISSUE YOU HAVE.
HOW MUCH LEAN ENERGY REQUIRING
TISSUES YOU HAVE.
SO THE THEORY WAS THESE FOLKS
ARE LOSING WEIGHT AND DOING ALL
THIS RESISTANCE EXERCISE GOING
FROM THIS IS BY THE WAY THE SAME
PERSON WHO LOST ABOUT 240 POUNDS
OVER SEVEN MONTHS.
THIS IS ONE OF OUR STUDY
SUBJECTS.
HE GOES FROM VERY OBESE TO
BASICALLY ONLY MOPPED RUTTILY
OVERWEIGHT ACCORDING TO THE BMI
ESTIMATES IN THE NORMAL RANGE
ACCORDING TO BODY FAT.
DOES HE PRESERVE LIEN MASS
NUMBER ONE.
AND IF HE DOES, DOES THAT
PREVENT THE FALL AND RESTING
METABOLIC RATE THAT I SHOWED YOU
IN THE PREVIOUS CASE WITH DIET
ALONE.
THAT WAS THE PURPOSE OF LOOKING
AT THESE FOLKS.
I WAS ABLE TO RECRUIT DARCY WHO
IS AT THE TIME A POST DOC OF
ERIC ROBINSON AT THE PENNINGTON
CENTER AND SHE ALONG WITH ME
HELPED KUNS VINCE ERIC IT WAS
WORTHWHILE STUDYING THESE FOLKS.
SO WE BASICALLY WENT OUT TO THIS
PLACE AND WE SAID OKAY LET'S
MEASURE METABOLIC RATE BOTH AT
REST AND THEIR TOTAL ENERGY
EXPENDITURE ALONG WITH THEIR
BODY EXOKS CHANGE.
AND LET'S SEE IF THEY'RE ABLE TO
PREVENT THIS FALL IN METABOLIC
RATE AS A RESULT OF KEEPING
THEIR LEAN TISSUE.
AND THE ANSWER WAS NO, THEY
COULDN'T.
THIS IS PLOTTING THE ADJUSTED
METABOLIC RATE ONCE YOU ADJUST
FOR AGE AND SEX AND FAT MASS
AGAINST THE BIGGEST DRIVER OF
CROSS SECTIONAL RESTING
METABOLIC RATE WHICH IS FAT FREE
MASS.
THE CLOSED CIRCLES ARE BEFORE
AND UNLESS THE REGRESSION LINE
OF THE BEFORE DATA.
AND THAT'S ACTUALLY PERFECTLY
NORMAL IF YOU PLOT THAT OVER TOP
OF THE CROSS SECTIONAL DATA
SETS, IT ALSO LOOKS VERY MUCH
LIKE THAT.
IT'S NO DIFFERENT IN TERMS OF
ITS SLOPE OR INTERCEPT.
YOU CAN SEE WITH RESPECT TO THE
LOSS IN WEIGHT ONCE THEY LOSE
WEIGHT, THEY FALL OFF THAT
CURVE.
THEY'RE ALL BELOW THE CURVE.
ONLY THIS ONE PERSON SEEMED TO
KIND OF GAIN A VERY SLIGHT
AMOUNT OF RESTING METABOLIC
RATE.
EVERYBODY ELSE DROPPED LIKE A
ROCK.
ON AVERAGE, THE DROP IN RESTING
METABOLIC RATE WAS 800 CALORIES
A DAY.
AND THAT WAS 500 CALORIES A DAY
MORE THAN WOULD BE EXPECTED
BASED ON THEIR WEIGHT CHANGE.
SO THIS IDEA OF KEEPING THEIR
LEAN TISSUE MASS UP IF IT
HAPPENED, DID NOT PREVENT THE
SLOWING OF METABOLISM THAT
OCCURRED.
SO THIS IS WHAT HAPPENED ON
AVERAGE TO THE BODY WEIGHT AND
FAT MASS OVER THE COURSE OF THIS
INTERVENTION.
AND FOR THE FIRST 13 WEEKS, THEY
ARE ISOLATED ON THIS RANCH AWAY
FROM THEIR FAMILIES, AWAY FROM
THEIR DAILY ACTIVITIES.
AND THEN THEY'RE BASICALLY TOLD
GO HOME AND KEEP THIS UP.
SO THEY'RE LOSING ABOUT A POUND
A DAY DURING THE PERIOD OF TIME
THEY'RE ON THE RANCH AND THE
RATE OF WEIGHT LOSS DECREASES TO
ABOUT HALF THAT.
BUT IT'S STILL A PRETTY GOOD
CLIP ABOUT HALF A POUND A DAY.
WHEN THEY GO HOME.
AND YOU CAN SEE THAT THE MODEL
HERE ARE THE CURVES PREDICTING
THE RIGHT AMOUNT OF FAST MASS
CHANGE AND THE RIGHT AMOUNT OF
BODY WEIGHT CHANGE OVER THIS
PERIOD OF TIME.
AND IN TERMS OF THE TOTAL ENERGY
EXPENDITURE, YOU CAN SEE THAT
THEY'RE STARTING OFF BEFORE THE
STUDY ACTUALLY HAD A MEASUREMENT
BEFORE THEY KNEW THAT THEY WERE
ON THE TELEVISION SHOW SO THEY
HAD BASELINE DATA BEFORE THEY
WERE BEING FILMED.
AND THEY WERE EATING AND BURNING
AROUND 3700 CALORIES PER DAY.
AND THAT JUMPED UP QUITE A BIT
AT SIX WEEKS INTO THE
INTERVENTION.
AND THEN BY THE END, THEY ARE
ACTUALLY QUITE A BIT LOWER THAN
THAT.
THE RESTING METABOLIC -- SO THE
EXERCISE, THEY ARE BASICALLY
SEDENTARY BEFOREHAND, THEY
DIDN'T HAVE THINK EXERCISE
PROGRAM.
WE SIMULATED THIS SORT OF SLOW
RAMP UP OF EXERCISE, RELATIVELY
SLOW RAMP UP OF EXERCISE WHICH
THEN DROPPED ONCE THEY WENT
HOME.
NOW THIS IS THE QUAL REA
EXPENDED WITH EXERCISE.
AND THAT'S A LITTLE BIT DISTINCT
FROM THE AMOUNT OF EXERCISE
BECAUSE MOST EXERCISES ARE
WEIGHT BEARING AND THEREFORE AS
YOU LOSE WEIGHT TO DO THE SAME
AMOUNT OF EXERCISE YOU ACTUALLY
COST LESS CALORIES.
REMEMBER BY THE END HERE, THERE
ARE ABOUT 60 KILOS LOWER IN BODY
WEIGHT THAN THEY WERE TO START
WITH.
THEY ARE ACTUALLY STILL DOING
ABOUT AN HOUR A DAY OF VIGOROUS
EXERCISE DURING THE AT-HOME
PERIOD WHEREAS HERE THIS
CORRESPONDS TO THREE HOURS OF
VIGOROUS EXERCISE EVERY DAY.
RESTING METABOLIC RATE, CELLS
JUST LIKE I MENTIONED BEFORE AND
THE MODEL CAPTURED THAT.
AND THEN WE COULD ACTUALLY MAKE
A PREDICTION ABOUT WHAT THEY
MUST HAVE BEEN EATING BECAUSE WE
DIDN'T VFT FACILITIES TO
ACTUALLY MEASURE DIRECTLY WHAT
THEY WERE EATING OR CONTROLLING
THE SAME WAY THAT RUDY LIBEL'S
FOLKS HAD DONE WITH THEIR
INPATIENTS.
THEY'RE EATING ABOUT 1100
CALORIES PER DAY WHILE DOING
BURNING ABOUT 5,000 CALORIES PER
DAY OVER THE COURSE OF THAT
PERIOD OF TIME.
SO VERY SEVERE NEGATIVE ENERGY
DEFICIT DURING THIS PARTICULAR
STUDY.
SO BECAUSE WE BUILT THIS MODEL,
WE COULD BE THEN DO SIMULATED
EXPERIMENTS AND ASK THE QUESTION
ABOUT WELL, WHAT WOULD HAVE
HAPPENED IF THEY HAD JUST DONE
THE DIET OR JUST DONE THE
EXERCISE SOME IT'S A
HYPOTHETICAL, SPECULATION BUT I
THOUGHT IT WAS INTERESTING TO
LOOK AT.
BECAUSE IF YOU LOOK AT DIET
ALONE, THEY DID THAT BLACK
CURVE, THAT ENERGY INTAKE
CORRESPONDS TO DIET ALONE, YOU
LOSE MORE WEIGHT THAN YOU WOULD
IF YOU DID THE EXER SIZE ALONE
AND CLAMPED YOUR DIET AT
BASELINE.
BUT THEY WOULD HAVE LOST LESS
FAT MASS.
SO THE WHITE BAR IS THE
PREDICTED FAT MASS CHANGE, THE
BLACK BAR IS THE PREDICTED BOTH
WEIGHT CHANGE.
YOU CAN SEE IN THE EXERCISE
ALONE GROUP, THEY LOSE MORE FAT
THAN THEY DO BODY WEIGHT.
SO THEY ACTUALLY GAIN SOME LEAN
MASS OKAY.
THAT'S THE COMPUTER SIMULATION.
WHEREAS WITH THE DIET ALONE,
IT'S BASICALLY TWO THIRDS IS
COMING FROM FAT MASS AND ABOUT
ONE THIRD COMES FROM LEAN MASS
LOSS.
AND THAT'S ACTUALLY WHAT'S
TYPICALLY OBSERVED IN BEAR AT
TRICK SEEING PATIENTS.
SO THEY TEND TO LOSE QUITE A BIT
OF LEAN TISSUE.
WHILE THAT DOESN'T PREVENT
PRESERVATION OF LEAN TISSUE MAY
NOT PREVENT A FALL AND RESTING
METABOLIC RATE.
THERE ARE OTHER REASONS YOU WANT
TO KEEP AROUND YOUR MUSCLE
TISSUE.
YOU WANT TO ACTUALLY BE ABLE TO
WALK AROUND AND AVOID FALLING
DOWN AS YOU GET OLDER AND VERY
PRACTICAL THINGS LIKE THAT.
SO THIS IS, THIS WAS JUST A
COMPUTER SIMULATION BUT THEN WE
DECIDED TO DO WAS GO AND DO SOME
RETROSPECTIVE PAYER MATCHING OF
BIGGEST LOSER CONTESTANTS WITH
PEOPLE WHO HAD VERY SIMILAR
INITIAL BODY COMPOSITION SEX IS
A PAYER MATCH FOR SIX, AGE AND
BODY COMPOSITION WITH FOLKS WHO
UNDERWENT GASTRIC BYPASS SURGERY
AND COMPARED THE AMOUNT OF
WEIGHT LOSS THAT WAS COMING FROM
FAST VERSUS FAST FREE MASS IN
THESE GROUPS.
SO IT TURNS OUT THAT YOU GET
SIMILAR AMOUNTS OF WEIGHT LOSS
AFTER A YEAR OF GASTRIC BY PASS
AS YOU DO IN SEVEN MONTHS ON
THIS BIGGEST LOSER PROGRAM BUT
THE PROPORTION IS QUITE A BIT
DIFFERENT.
IT'S MORE FAT FREE LOSS AFTER A
GASTRIC BYPASS COMPARED TO THIS
BIGGEST LOSER GROUP.
SO WE'RE PRETTY CONFIDENT THAT
YES, IF YOU ADD ALL THIS
VIGOROUS EXERCISE, THIS IS ONE
BIT OF MYTHOLOGY THAT WE
ACTUALLY BELIEVE IS TRUE, YOU
WILL PREVENT THE FALLING FAT
FREE MASS.
WHETHER OR NOT THAT DOES
ANYTHING FOR YOUR RESTING
METABOLIC RATE I THINK IS STILL
A QUESTION.
SO WE COULD ACTUALLY PLOT THEN
THAT METABOLIC ADAPTATION THAT
GREATER THAN EXPECTED CHANGE IN
METABOLIC RATE THAT'S OBSERVED
ONCE YOU ADJUST FOR THE CHANGE
IN WEIGHT AND THE CHANGE IN FAT
MASS AND FAT FREE MASS.
AND WE DID THIS WITH THE BEAR AT
TRICK GROUP.
YOU CAN SEE THAT BOTH GROUPS
DURING THE SORT OF ACTIVE WEIGHT
LOSS PHASE THESE PRETTY DRAMATIC
SLOWING OF METABOLISM THAT
STAKES PLACE.
ABOUT 400 CALORIES A DAY GREATER
THAN WHAT WOULD BE EXPECTED
BASED ON THE WEIGHT CHANGE AND
THE FAT MASS CHANGE ALONE.
ONCE THOSE BEAR AT TRICK FOLKS
BEGIN TO STABILIZE AFTER 12
MONTHS OR SO THAT'S REDUCED
SUBSTANTIALLY.
WHAT WE DID THEN WAS LOOK AT THE
INDIVIDUAL SUBJECTS AND TRY TO
ASK THE QUESTION WHAT ARE THE
BEST PREDICTORS OF THAT GREATER
THAN EXPECTED SLOWING OF
METABOLISM.
TWO THINGS REALLY POPPED OUT.
ONE WAS THE DEGREE OF ENERGY AND
BALANCE.
SO IN OTHER WORDS THAT WAS
ACHIEVED.
FOR SOME FOLK THAT AVERAGE
UPWARDS OF 3,000 CALORIES PER
DAY.
OTHERS IT WAS A LITTLE AS ABOUT
ON 0 CALORIES A DAY.
THERE WAS A NICE CORRELATION
BETWEEN THESE TWO FACTORS.
THE OTHER ONE THAT CORRELATED
QUITE WELL WITH THE CHANGE IN
CIRCULATING, SOMETHING WE TALKED
ABOUT BEFORE.
SO IF YOU HAVE A GREATER CHANGE
IN CIRCULATING LEPTIN YOU HAD A
GREATER METABOLIC ADAPTATION AND
THAT'S WHERE THIS IDEA COMES
FROM MAYBE IF YOU WERE TO
REPLACE THE LEPTIN DECREASING BY
QUITE A LOT IN SOME OF THESE
FOLKS, MAYBE YOU COULD SOMEHOW
MINIMIZE THE METABOLIC
ADAPTATION AND MAKE THE WEIGHT
LOSS A LITTLE BIT EASIER THAN IT
WOULD BE OTHERWISE.
WHAT I SHOWED YOU SOME
EXPERIMENTS WE LOOKED AT IN
TERMS OF MODELING METABOLIC
CHANGES THAT TAKE PLACE WHEN
PEOPLE ARE UNDER GOING WEIGHT
INTERVENTIONS IN OUR RESEARCH
SETTING.
AND SO WE'RE INTERESTED IN
DEVELOPING A TOOL FOR PEOPLE TO
USE ACTUALLY MOSTLY FOR
RESEARCHERS TO USE INITIALLY AND
PRESCRIPTIONS IN TERMS OF
IT WAS WRITTEN BY UNDERGRADUATE
MASS STUDENT SO IT'S NOT THE
MOST PRETTY LOOKING THING IN THE
WORLD BUT IT'S VERY FUNCTIONAL.
YOU BASICALLY ENTER IN YOUR
INITIAL WEIGHTS, YOUR GENDER,
YOUR AGE, YOUR HEIGHT, YOU
ANSWER A COUPLE QUESTIONS ABOUT
YOUR PHYSICAL ACTIVITY AT WORK
AND AT LEISURE TIME.
THAT'S GOING TO ESTIMATE THE
BASELINE NUMBER OF CALORIES THAT
YOU'RE EATING JUST TO MAINTAIN
THAT PARTICULAR WEIGHT.
YOU COULD ENTER WHAT YOUR GOAL
WEIGHT IS AND HOW LONG YOU WANT
TO TAKE TO ACHIEVE THAT WEIGHT.
SO FOR EXAMPLE, THIS PERSON WAS
STARTING OFF YOU PROBABLY CAN'T
READ IT AT 110 KEY ROAST.
THEY WANT TO WEIGH 80 KILOS IN
SIX MONTHS.
AND 9 MODEL WILL PREDICT WHAT
THEY HAVE TO DO TO THEIR DIET IN
ORDER TO BOTH GET TO THAT GOAL
WHICH IS RIGHT HERE AS WELL AS
THEN MAINTAIN THE GOAL ONCE THEY
GET THERE.
BECAUSE THAT'S A BIG PROBLEM AND
I'LL TALK ABOUT THAT IN A
MINUTE.
SO AT THE SAME TIME WHEN YOU'RE
PLANNING THIS WEIGHT CHANGE, YOU
CAN SAY OKAY HERE'S MY GOAL.
AM I ACTUALLY WILLING TO DO WHAT
IT'S GOING TO TAKE TO GET TO THE
GOAL.
THEN MAYBE THE MORE IMPORTANT AM
I WILLING TO DO WHAT IT'S GOING
TO TAKE TO PERMANENTLY STAY AT
THAT NEW GOAL WEIGHT.
AND THE SIMULATOR CAN HELP YOU
MAKE THOSE SORTS OF PREDICTIONS.
AND YOU CAN ALSO CHANGE THE
PHYSICAL ACTIVITY.
SO HERE WE HAVE A BOX THAT WILL
OPEN UP AND YOU CAN ADD RUNNING
OR WALKING OR CYCLING AND HOW
MANY TIMES A WEEK AND HOW MUCH
YOU WANT TO DO AND YOU CAN LOOK
AT THE TRADE OFF BETWEEN DIET
AND EXERCISE IN TERMS OF
ACHIEVING A GOAL AND THEN
MAINTAINING THAT GOAL WEIGHT.
SO THIS IS OUR ONE ANSWER TO
ADDRESSING THE 3500 CALORIE PER
POUND THAT PEOPLE HAVE BEEN
USING IN THE PAST.
THIS WILL MAKE MORE REALISTIC
PREDICTIONS.
NOW WE'RE KIND OF SURPRISED AT
HOW POPULAR THIS BECAME.
WE'VE HAD MORE THAN A MILLION
UNIQUE VISITORS ON THIS WEBSITE.
WE HAVE ABOUT 500 PEOPLE EVERY
DAY USING THIS TOOL ON-LINE
WHICH IS KIND OF SURPRISING TO
ME.
BUT WE HAVE A BIG DISCLAIMER IN
THE FRONT THAT SAYS DON'T USE
THIS FOR MEDICAL REASONS,
ETCETERA ETCETERA.
BUT I DON'T KNOW HOW EFFECTIVE
THAT IS.
ONE PERSON WHO HAD BEEN USING IT
WAS A WEIGHT LOSS DOC IN CEDAR
RAPIDS AND HE SAID I'VE BEEN
USING THIS TOOL NOW WITH SOME OF
MY PATIENTS.
I'VE INDEPENDENTLY BEEN
DOCUMENTING VERY COMPLIANT TO
THIS VERY LOW CALORIE DIET FOR
VARYING DURATIONS OF TIME.
AND LET ME SHARE SOME OF MY DATA
WITH YOU.
AND WHAT I'M PLOTTING HERE IS
THE DATA POINTS FROM TWO OF HIS
VERY ADHERENT CLIENTS WHICH HE
DECIDED WERE ADHERED BEFORE HE
SAW THE SIMULATION RESULTS.
AND YOU CAN SEE THE SOLID CURVE
HERE IS THE MODEL'S BEST
ESTIMATE AND THEN GIVEN THE
UNCERTAINTY IN SOME OF THESE
PARAMETERS, THE DASH CURVES ARE
THE SORT OF UNCERTAINTY AND THE
WEIGHT LOUSE THAT WAS THESE
FOLKS ACTUALLY ADHERED TO THIS
DIET.
YOU CAN SEE THAT THE MODEL DOES
A REASONABLY GOOD JOB OF
PREDICTING IN SORT OF REAL WORLD
CLINICAL SETTING OF HOW MUCH
WEIGHT LOSS WOULD BE EXPECTED IN
THESE DIFFERENT PEOPLE.
IN FACT, WHEN WE LOOKED AT 60 OF
HIS SUBJECTS WHO HE HAD
PREVIOUSLY DEEMED COMPLIANT TO
THE PROGRAM AND COMPARED THE
WEIGHT LOSS PREDICTED BY THE
MODEL, THEN THE WEIGHT LOSS THAT
WAS ACTUALLY MEASURED, YOU CAN
SEE THAT THERE'S A VERY HIGH
DEGREE OF CORRELATION BETWEEN
THE MODEL PREDICTIONS AND THE
DATA THAT WERE OBSERVED.
SO WE THINK THAT THIS ISN'T JUST
A RESEARCH TOOL AND A RESEARCH
SETTING BUT IT CAN ACTUALLY BE
APPLIED TO REAL LIFE WEIGHT LOSS
WHEN PEOPLE ARE ADHERENT TO THE
PROGRAM AND THAT IS THE BIGGEST
TRICK, GETTING PEOPLE TO ADHERE
TO A PROGRAM.
MOST PEOPLE'S WEIGHT LOSS LOOKS
SOMETHING LIKE THIS.
THAT THEY LOSE WEIGHT, FOR ABOUT
SIX TO EIGHT MONTHS AND THEN
THEY PLATEAU AND THEN THEY START
TO REGAIN THE WEIGHT THAT
THEY'VE LOST.
THIS IS DATA FROM -- GROUP AT
DUKE.
THIS IS ACTUALLY A STUDY
DESIGNED TO LOOK AT KEEPING
WEIGHT OFF.
SO THE INTERVENTION WAS DESIGNED
TO PREVENT THAT SLOW RISE OF
WEIGHT THAT WAS SEEN.
AND WE WERE REALLY INTERESTED IN
WHAT IS THE UNDERLYING CHANGES
OF CALORIE INTAKE THAT ARE
RESPONSIBLE FOR THIS CURVE.
I'VE TOLD YOU A LOT ABOUT THE
SLOWING OF METABOLISM AND HOW
IMPORTANT IT IS AND WHY IT MAKES
WEIGHT LOSS DIFFICULT AND IN
FACT THAT'S WHAT MOST PEOPLE SAY
IS THE REASON FOR THIS CURVE.
THEY SAY PEOPLE WHO GO ON A DIET
AND THEY START LOSING WEIGHT AND
THAT'S GREAT AND EVENTUALLY
THEIR METABOLISM SLOWS DOWN SO
IT MATCHES WHAT WAS IN THEIR
DIET.
SO THEY ARE BACK IN BALANCE
AGAIN.
THAT PLATEAUS.
OF COURSE THEY'RE STILL ON THIS
DIET BUT THEY'RE NOT GETTING ANY
MORE *** FOR THEIR BUCK ANYMORE
SO THEY SLOWLY FALL OFF THE
WAGON AND THAT'S WHAT'S
RESPONSIBLE FOR THE WEIGHT
REGAINED.
THAT'S THE SORT OF DOGMA OF
INTERPRETING THIS TYPICAL WEIGHT
LOSS CURVE AND WE ASK THE
QUESTION WELL WHAT DOES THE
MODEL SAY.
DOES THE MODEL ACTUALLY MAKE
SIMILAR SORTS OF PREDICTIONS.
WE'RE INITIALLY SURPRISED BY THE
FACT THAT NO, THAT'S NOT WHAT
THE MODEL SAYS AT ALL.
WHAT THE MODEL SAYS IS THAT
WHAT'S HAPPENING UNDERLYING THAT
CURVE IS YES YOU GET THAT
SLOWING OF METABOLISM.
THAT'S THE BLARYK.
THAT'S THE STUFF I WAS SHOWING
YOU BEFORE.
BUT TO GET THAT INITIAL WEIGHT
LOSS THEY HAVE TO CUT THEIR
CALORIES A HECK OF A LOT.
IT'S ABOUT 800 CALORIE A DAY
DEFICIT INITIALLY.
BUT THAT ONLY STAYS AROUND FOR
SIX WEEKS, OKAY.
AND THEN THEY HAVE THIS
PROGRESSIVE LOSS OF DIET
ADHERENCE.
BUT THE ENTIRE TIME THAT THE
BLACK CURVE IS BELOW THE BLUE
CURVE THEY'RE LOSING WEIGHT SO I
DON'T KNOW TWHA THAT MEANS
PSYCHOLOGICALLY TO THINK ABOUT
OKAY I CAPE CHEATING ON MY DIET
A LITTLE BIT MORE AND MORE EVERY
DAY BUT I STILL KEEP LOSING
WROTE SO THIS MUST BE A
MIRACULOUS DIET.
BY THE TIME THOSE TWO CURVES
CROSS AGAIN AT ABOUT EIGHT
MONTHS OR SO, YOU'RE ALMOST ALL
THE WAY BACK UP TO WHERE YOU
STARTED IN TERMS OF YOUR
BEHAVIOR FOR ENERGY INTAKE.
AND BY TEN MONTHS YOU'RE ALL THE
WAY BACK UP.
AND IT'S VERY SLOW SORT OF TIME
LAG BETWEEN WHAT YOU DO IN TERMS
OF YOUR BEHAVIOR AND HOW YOUR
BODY WEIGHT DYNAMICS CHANGE,
THAT'S SOMETHING THAT'S
PREDICTED BY THE MODEL.
THERE'S THIS VERY SLOW CHARACTER
OF THE TIME SCALE THAT'S
RESPONSIBLE FOR THAT WEIGHT LOSS
PLATEAU AND REGAIN.
SO WE DON'T KNOW WHETHER OR NOT
THIS IS TRUE OR NOT.
I HAVE STRONGER BELIEF THAT THIS
IS PROBABLY WHAT'S HAPPENING AND
WE'RE DOING, WE'RE STARTING THE
STUDY HOPEFULLY IN A FEW MONTHS
THAT WILL START TO ADDRESS THESE
QUESTIONS IN REAL PEOPLE BUT
WE'LL SEE WHAT HAPPENS.
JUST TO KIND OF CLOSE WE
ACTUALLY HAVE REEVALUATED THE
PREDICTIONS OF A 20% SODA TAX ON
ADULT PREVALENCE OF OVERWEIGHT
AND OBESITY.
THIS IS DINING COLLABORATION
WITH THE ECONOMISTS AT THE USDA
WHO ARE VERY OPEN TO
COLLABORATION.
AND WE PUBLISHED THIS ECONOMICS
PAPER FOR MY FIRST ECONOMICS
PAPER IN 2011 WHERE WE BASICALLY
SHOWED HOW WRONG THE 3500
CALORIE PER POUND COULD BE AND
HOW MUCH OF A MORE SUBTLE AND
STILL PERHAPS IMPORTANT EFFECT
YOU COULD GET BY TAXING SODAS.
AND WHEN A PERSON FROM COCA-COLA
SAW ME PRESENT THIS, THEY SAID
THIS IS GREAT.
WE REALLY GOT TO GET THE WORD
OUT THERE THAT TAXING OUR
PRODUCTS ISN'T GOING TO SOLVE
THE OBESITY EPIDEMIC AND THEY
SAID WELL YES THAT'S ONE WAY TO
LOOK AT IT.
MAYBE WHAT THIS MENIAL IS WE
CAN'T JUST TAX YOUR SODA WE HAVE
TO LIMIT YOUR ADVERTISING TO
CHILDREN AND DO ALL THESE OTHER
THINGS.
I DON'T THINK HE LIKED THAT
ANSWER BUT MAYBE THAT'S I'VE
NEVER BEEN INVITED TO GIVE A
TALK AT COKE.
[LAUGHTER]
SO LET ME JUST STOP BY THANKING
A LOT OF THE FOLKS WHO WERE
INVOLVED IN THESE STUDIES.
THE FOLKS IN BLUE ARE PEOPLE WHO
HAVE BEEN INVOLVED IN EITHER A
CLINICAL RESEARCH OR SOME OF THE
MATHEMATICAL MODEL.
I DIDN'T TALK AT ALL ABOUT OUR
CLINICAL STUFF TODAY AND WHAT'S
BEEN IN MY LAB.
I REALLY WANT TO THANK THE
VOLUNTEER STUDY SUBJECTS.
I BELIEVE ONE IS ACTUALLY IN THE
AUDIENCE TODAY AS WELL AS THE
NURSING STAFF AT THE METABOLIC
UNIT AT THE NIH WHO HAVE BEEN,
EVERYBODY'S BEEN REALLY HELPFUL
GETTING THE PHYSICISTS UP TO
DOING CLINICAL RESEARCH AT THE
NIH.
IT'S BEEN A STEEP LEARNING CURVE
WITH A LOT OF FUN SO THANKS.
[APPLAUSE]
>> I HAVE TWO QUESTIONS.
THE FIRST IS I KNOW A PERSON, A
DOCTOR THAT WORKS IN THIS FIELD.
HE CLAIMS IF YOU GO TO
ARTIFICIAL SWEETENER, LOW
CALORIE COLAS AND SO FORTH, HE
CLAIMS THAT THE WAY YOUR
METABOLISM REACTS TO THAT, YOUR
LIVER AND SO FORTH THAT IT
REALLY, YOU ONLY END UP WITH
THAT MUCH FEWER CALORIES, NET
CALORIE INTAKE BECAUSE YOUR
METABOLISM CHANGES IN RESPONSE
TO A VERY SWEET ARTIFICIAL
SWEETENERS.
ANYTHING ON THAT?
>> IT'S FUNNY, A LOT OF PEOPLE
HAVE REALLY STRONG OPINIONS
ABOUT THESE THINGS.
VERY LITTLE DATA TO BACK THEM
UP.
FIRST OF ALL I KIND OF SHOWED
YOU IF YOU CUT CALORIES OUT OF
YOUR DIET REGARDLESS OF HOW YOU
DO IT, YOUR METABOLISM WILL SLOW
DOWN AND YOU WOACHT GET THE SAME
NUMBER OF CHLORIC BENEFIT.
YOU IF YOU 1WEU67 AND NOTHING
CHANGES AND YOU START TO LOSE
WEIGHT YOUR METABOLISM WILL SLOW
DOWN.
IT HAS NOTHING TO DO WITH
WHETHER OR NOT THERE ARE
ARTIFICIAL SWEETENERS OR
ANYTHING ELSE.
THAT'S JUST THE BASIC FACTS OF
CUTTING CALORIES.
SO THE SHORT ANSWER'S YES,
ABSOLUTELY THAT'S RIGHT THAT
WILL HAPPEN BUT NOT FOR THE
REASONS PROBABLY THAT ARE BEING
SUGGESTED.
ALTHOUGH THERE'S SO LITTLE DATA
ON THESE THINGS.
BIGGEST PROBLEM IN THIS FIELD IN
MY OPINION IS THAT YOU CAN'T
CONTROL WHAT PEOPLE EAT WHEN
THEY'RE OUTSIDE THE LABORATORY.
AND YOU CAN'T DO EXPERIMENTS
LONG ENOUGH IN THE LABORATORY TO
GET A LOT OF MEANINGFUL DATA ON
THESE KINDS OF TOPICS.
SO YOU'RE TYPICALLY RELEGATED TO
ASKING PEOPLE WHAT THEY EAT OR
RECORDING IT IN SOME WAY.
AND THEN THERE'S LOTS OF
MISREPORTING.
SO I THINK THESE ARE VERY
DIFFICULT QUESTIONS TO ANSWER ON
THE LONG TIME PERIODS THAT ARE
CHARACTERISTIC WITH WEIGHT LOSS
AND OBESITIES.
>> THE OTHER QUESTION I HAVE IS
YOU'VE SHOWN THE WEIGHT LOSS AND
YOU GO OFF THE DIET YOU KIND OF
GRADUALLY GET BACK UP.
IF YOU DO THE MULTIPLE TIMES YOU
LOSE WEIGHT AND GRADUALLY YOU
GET BACK UP AFTER A COUPLE YEARS
AND GO ON THE DIET AGAIN LOSE
WEIGHT GO BACK UP.
THAT CYCLING UP AND DOWN, IS
THAT BAD FOR YOUR HEALTH OR ARE
YOU BETTER OFF BEING UNDER
WEIGHT FOR HALF THE TIME OR A
QUARTER OF THE TIME.
>> YES.
I'M AWARE OF SOME DATA WHERE
PEOPLE HAVE SAID OKAY WELL IF
I'VE DONE THESE YO-YOS, I END UP
AT A HIGHER WEIGHT THAN TO BEGIN
WITH.
THEY TYPICALLY DON'T TAKE INTO
ACCOUNT THAT MOST PEOPLE ARE ON
A SLOWLY INCREASING TRAJECTORY.
WHETHER OR NOT YOU OVERSHOT THAT
IS STILL AN OPEN QUESTION.
SO I WOULD TEND TO THINK THAT
THERE'S PROBABLY NOT A LOT OF
DATA THAT SUGGESTS THAT
TEMPORARY WEIGHT LOSS IS BAD FOR
YOU.
ALL OF THE POSITIVE BIOMARKERS
ASSOCIATED WITH WEIGHT LOSS AND
RISK FACTORS SEEMS TO CHANGE
DURING THOSE PERIODS OF TIME.
SO IS IT BENEFICIAL TO HAVE
TEMPORARY IMPROVEMENT IN THOSE
RISK FACTORS.
I DON'T KNOW THE ANSWER TO THAT
QUESTION.
I WISH I DID BUT I DON'T.
>> EXPERIMENTS THAT ARE HARD TO
CONDUCT.
>> EXACTLY.
>> RELATED TO THE QUESTION I
GUESS IT SEEMS LIKE IT'S A NO
BRAINER THAT OKAY IT'S GOOD FOR
YOUR HEALTH SO LOWER THE EFFECT.
BUT IS THERE ACTUALLY DATA THE
PERSON WHO IS OVERWEIGHT AND
THEN -- AND BECAME LIKE NORMAL
OR CLOSE TO NORMAL BODY MASS
INDEX AS HEALTHY AS THE PERSON
WHO WAS THERE ALL THE TIME.
AND RELATED TO KIND OF SAYING
IT'S HARD TO MAINTAIN THE
MAXIMUM WEIGHT THAT WERE
ACHIEVED.
IS THERE A PHYSIOLOGICAL
UNDERPINNING TO THAT?
>> JACK WILL PROBABLY HAVE SOME
OTHER THINGS TO ADD BUT A COUPLE
THINGS.
ONE IS THAT IT'S HARD TO DO
THOSE STUDIES LONG ENOUGH TO
HAVE PEOPLE DOWN AT A LOWER RATE
LONG ENOUGH IN ORDER TO ADDRESS
THOUGH QUESTIONS.
BUT ONE WAY YOU CAN DO IS IT IS
WITH BARIATRIC SURGERY.
THE ONE THING THAT'S PRETTY
CLEAR IS THAT THERE IS REDUCED
MORTALITY AS A RESULT OF LOSING
WEIGHT BY BARIATRIC SURGERY.
WHETHER OR NOT THERE'S SOMETHING
SPECIAL ABOUT BARIATRIC SURGERY
OTHER THAN THE FACT YOU CAN
ACTUALLY MAINTAIN THAT WEIGHT
LOSS I THINK IS A WE.
THERE HAVE BEEN OTHER ANALYSES
OF THAT SAME DATA THAT SUGGESTED
THAT IT'S REALLY THE FOLKS WHO
HAVE TYPE TWO DIABETES BEFORE
THE SURGERY THAT HAD, THAT DROVE
MOST OF THE IMPROVED MORTALITY
ESTIMATES BUT I DON'T THINK THAT
THERE'S REALLY DEFINITIVE
ANSWERS TO THAT.
THERE'S OTHER REALLY DISTURBING
DATA THAT COMES FROM DENMARK
THAT HAS SUGGESTED THAT LOSING
WEIGHT BY NON-BARIATRIC SURGERY
ACTUALLY INCREASES MORTALITY.
I THINK THAT'S PRETTY SUSPECT
AND IF IT'S TRUE THAT'S A MAJOR
NEWS.
THESE ARE THE SORT OF HARD END
POINTS OF MORTALITY NOT JUST
IMPROVEMENT OF RISK FACTORS.
EVERYBODY KNOWS THAT YOU IMPROVE
YOUR RISK FACTORS WHEN YOU LOSE
WEIGHT.
HOW THAT TRANSLATES INTO THESE
HARD ENDPOINTS IS I THINK STILL
PART OF AN OPEN QUESTION.
JACK, DO YOU HAVE SOMETHING TO
ADD TO THAT?
OKAY.
>> KEVIN I NOTICED NORA -- IS
DIRECTOR OF THE NATIONAL
INSTITUTE OF DRUG ADDICTION AND
ONE OF YOUR COLLABORATORS.
>> YES.
>> SO THAT PROMPTS THE QUESTION
OF WHETHER OBESITY AND THIS
COMPULSION TO EAT HAS THE SAME
IMAGING CHARACTERS AS LET'S SAY
*** ADDICTION.
>> SO THE PAPER THAT I TOLD YOU
THAT I WAS WRITING ON THE WAY
OVER HERE IS GOING TO ADDRESS
THOSE THINGS.
SO NORA HELPED US GET SET UP IN
OUR STUDY THAT'S WRAPPING UP NOW
LOOKING AT DOPAMINE RECEPTOR
AVAILABILITY MEASURED BY A PET
IMROI EMISSION TOMOGRAPHY IN A
CROSS-SECTION OF SUBJECTS.
AND WE WERE INTERESTED IN
REPLICATING HER INITIAL FINDINGS
FROM BACK IN 2001 WHICH SHOWED
THAT OBESE INDIVIDUALS HAD
HIGHER, SORRY, LOWER LEVELS OF
DIP MEAN RECEPTOR AVAILABILITY
COMPARED TO LEAN INDIVIDUALS AND
THEY WERE DECREASED TO A SIMILAR
EXTENT AS PEOPLE WHO ARE
ADDICTED TO DRUGS AND ABUSE.
AND SO WE DID THAT ON A LARGER
NUMBER OF SUBJECTS.
AND WE ACTUALLY FOUND THE
OPPOSITE RESULT.
AND WE LOOKED AT SPECIFIC
REGIONS WITHIN THE STRIATUM
WHICH IS THIS REGION THAT IS
BELIEVED TO BE RESPONSIBLE FOR
REWARD, MOTIVATION, MOTOR
CONTROL, AS WELL AS HABIT
FORMATION AND WHAT WE FOUND WAS
INTERESTINGLY THAT WHEN YOU
LOOKED AT THESE SUBSTRIDAL
REGIONS OBESITY OR ADDED POSTIE
EAT BY BMI OR FAT MASS
MEASUREMENTS WAS POSITIVELY
ASSOCIATED WITH REGIONS OF THE
STRIATUM WITH HABIT FORMATION.
DOPAMINE PLAYS A ROLE IN
ACCELERATING THE PROCESS OF
HABIT FORMATION, AND U SHOW THIS
IN ANIMAL MODELS.
AND SO, BUT WHAT WE DID
REPLICATE WITH NORA REGION IS --
STRIATUM THAT PEOPLE OFTEN
TALKED ABOUT IN THE -- REGION
THAT IT WAS DECREASED IN OBESE
INDIVIDUALS.
AND CORRELATED WITH NEGATIVELY
CORRELATED WITH BMI.
AND ADIPOSITY.
THAT'S WHERE NORA'S GROUP HAD
FOCUSED MOST OF THEIR ATTENTION
ON PREVIOUSLY WAS THIS REWARD
AND MOTIVATION REGION SUGGESTING
THAT OBESITY IS A STATE OF HYPO
FUNCTIONING REWARD.
AND THE IDEA WAS THAT MAYBE THAT
LEADS PEOPLE TO EAT MORE TO GET
THE SAME REWARD AS THEY DID
BEFORE THAT PROCESS.
SO, OUR DATA SUGGESTS THAT THESE
DORSAL LATERAL STRIDAL REEDGES
THESE RABBIT FORMING REGIONS
MIGHT BE MORE IMPORTANT THAN --
STRIDAL REGIONS BUT WE DON'T
KNOW.
I THINK IT'S INTERESTING AND
WE'RE LOOKING TO SEE NOW HOW
DIET ACTUALLY IMPACTS DOPAMINE
BINDING IN THESE REGIONS.
BECAUSE LIKE I SAID THAT BLACK
CURVE MOVING UP, THAT'S A FOOD
INTAKE EFFECT, RIGHT.
WE THINK WE UNDERSTAND THE BLUE
CURVE WELL NOW BUT SLOWING OF
METABOLISM THESE METABOLIC A
ADAPTATIONS, WHY PEOPLE EAT WHAT
THEY EAT AND WHAT INFLUENCES IN
THE ENVIRONMENT INFLUENCE WHICH
PEOPLE TO EAT, HOW MUCH AND WHAT
THEIR FOOD CHOICE IS.
THAT'S THE BIG MYSTERY IN MY
OPINION AND THAT'S KIND OF WHERE
OUR RESEARCH IS STARTING TO
FOCUS.
>> SO IS THERE DEVELOPMENT OF
THE OF RESTING METABOLISM WITH
AGE.
THAT'S ONE THING FROM MY
EXPERIMENT I FOUND OUT THAT MY
RESTING -- WAS DECREASING AS I'M
GETTING OLDER.
SO I GUESS -- WHY RESTING
METABOLISM ALSO DECREASE AS
YOU'RE CUTTING DOWN YOUR CALORIE
INTAKE.
>> RIGHT.
SO THE AGING PROCESS I THINK IS
REALLY INTERESTING.
WE HAVEN'T DONE A LOT OF
MODELING OF AGING YET ALTHOUGH
WE'D LIKE TO AND TAMMY HARRIS
FROM NIH IS ALWAYS ENCOURAGING E
STRONGLY TO DO THAT.
AND WE'LL MOVE THERE NOW.
WE PUBLISHED A CHILDHOOD MODEL
LAST YEAR NOW WE CAN MOVE ON TO
THE AGING PROBLEM.
BUT ONE OF THE THINGS THAT WE
KNOW ABOUT AGING AND JACK
MENTIONED THIS IS THAT EVEN IF
YOUR WEIGHT IS STABLE, YOU CAN
BE BEGINNING FAT AND LOSING LEAN
TISSUE.
AND EVEN THOUGH THERE CAN BE A
DISCONNECT BETWEEN RESTING
METABOLIC RATE LEAN TISSUE LIKE
I SHOWED YOU WITH THESE DRAMATIC
WEIGHT CHANGES, LEAN TISSUE IS
STILL THE PRIMARY DRIVER OF YOUR
RESTING METABOLIC RATE.
SO EVEN IF YOUR WEIGHT STAYS THE
SAME AND ESPECIALLY ONCE YOU
KIND OF PASS INTO THE SORT OF
70'S OR SO, YOU CAN START TO SEE
THIS DISASSOCIATION BETWEEN BODY
WEIGHT AND BODY COMPOSITION SO
YOU CAN MAINTAIN THE SAME BODY
WEIGHT OR EVEN LOSE WEIGHT AND
BE LOSING QUITE A LOT OF LEAN
TISSUE.
THAT WILL DRIVE YOUR METABOLIC
RATE LOWER.
>> HOW MANY PEOPLE
[INDISCERNIBLE]
>> SO THE QUESTION WAS HOW MANY
FREE PARAMETERS DO YOU HAVE IN
THE MODEL.
SO IT'S A GOOD QUESTION.
THE MOST COMPLICATED MODEL THAT
I SHOWED YOU, I HAD FIVE FREE
PARAMETERS.
I FIT THOSE FIVE FREE PARAMETERS
TO A LIST OF DATA THAT INCLUDED
MORE THAN A HUNDRED DATA POINTS.
SO THAT WAS JUST THE CAL BASIC
PHASE.
THEN I WENT ON TO VALIDATE THAT
MODEL WITHOUT CHANGING ANY
PARAMETERS IN DOZEN OF HE CAN
PARMTS.
SO THIS IS THE QUESTION ARE YOU,
GIVE ME ENOUGH FREE PARAMETERS I
CAN FIT AN ILL OF ELEPHANT SO
YOU CAN DESCRIBE ANYTHING OR IF
YOU WANT TO DESCRIBE ANY SORT
RANDOM SERIES OF DATA YOU CAN
FIT A POLYNOMIAL AND DIMENSIONS
INTO THAT THING AND YOU
DESCRIBED THE DATA.
THE REAL TRICK ONCE YOU
DESCRIBED THE DATA IS CAN YOU
PREDICT NEW DATA.
CAN YOU PREDICT THE RESULTS OF
AN EXPERIMENT THAT'S NEVER BEEN
DONE BEFORE AS I SHOWED YOU WITH
THE BIGGEST LOSER EXPERIMENT.
WE HADN'T DONE THAT WHEN WE
DEVELOPED THE MODEL OR DATA THAT
WEREN'T USED TO BUILD THE MODEL
AND WE'VE DONE BOTH OF THOSE
THINGS.
>> ARE ALL THESE POPULAR DIETS,
EAT THIS DON'T EAT THAT AVOID
THIS EAT A LOT OF THAT.
DOES THAT, DO YOU HAVE A FACTORS
IN THAT IN YOUR MODEL.
>> YES.
SO THE COMPLICATED MODEL THE ONE
WITH THE FIVE FREE PARAMETERS
THAT I TOLD YOU ABOUT, BASICALLY
IT'S AT THE LEVEL OF DIETARY
CARBOHYDRATE FAT AND PROTEIN.
IT DOESN'T DISTINGUISH BETWEEN
DIETARY CARBOHYDRATES OTHER THAN
IN THE DIGESTIBILITY SO IF YOU
HAVE A LOT OF HIGH FIBER DIET
NOT ALL OF THOSE CALORIES ARE
DIGESTIBLE.
SO THAT PART IS IN THERE BUT IT
DOESN'T FOR EXAMPLE SAY WHETHER
OR NOT YOU HAVE A LOT OF MONO
UNSATURATED FATTY ACIDS VERSUS
OMEGA THREE FATTY ACIDS.
IT DOESN'T DISTINGUISH THAT
LEVEL OF DETAIL.
BUT WE'RE REALLY INTERESTED IN
THIS QUESTION NOW OF YOU KNOW I
LIKE TO THINK OF THE HUMAN BODY
AS AN ENGINEERING, FROM AN
ENGINEERING ANALOGY.
YOU'RE BASICALLY A FLEX FIELD
AUTOMOBILE.
YOU RUN ON THREE DIFFERENT KINDS
OF FUEL.
YOU CAN BASICALLY PUT IN YOUR
GAS TANK WHATEVER'S THE CHEAPEST
ON THAT PARTICULAR DAY.
YOU'RE GOING TO RETURN
RELATIVELY WELL BUT ACTUALLY
YOU'RE NOT, YOU DON'T HAVE A GAS
TING.
YOUR CAR IS BUILT OUT OF THE
FUEL.
AND IT'S CONSTANTLY TURN OVER
ITS PARTS.
HOW IS IT THAT THIS MACHINE CAN
ADAPT SO WELL TO DRAMATIC SWINGS
IN THE COMPOSITION OF THE FUELS
THAT ARE COMING IN.
THAT WAS REALLY THE BASIS FOR
BUILDING THAT VERY COMPLICATED
MODELS TO UNDERSTAND THE
PHYSIOLOGY AND THE FACT THAT SO
MANY GOOD EXPERIMENTS LOOKING AT
DIFFERENT KINDS OF DIETS AND
THEIR IMPACT ON PHYSIOLOGY HAVE
BEEN DONE BEFORE ALLOWED US TO
BUILD THAT MODEL.
THE EFFICACY OF ALL OF THESE
KINDS OF DIETS I THINK BOILS
DOWN TO WHETHER OR NOT YOU STICK
TO THEM.
AND ALSO POSSIBLY WHETHER
THERE'S SOME METABOLIC ADVANTAGE
OF ONE DOITD OVER ANOTHER.
I HAPPEN TO BELIEVE THE BIGGEST
IMPACT IS WHETHER OR NOT YOU'RE
STICKING TO YOUR DIET.
BUT WE'RE DESIGNING STUDIES AND
DOING STUDIES AS WE SPEAK WHERE
WE CAPE PEOPLE AND ONE OF THEM
IS IN THE AUDIENCE RIGHT NOW,
SPHAIG AT THE NIH CLINICAL
CENTER FOR TWO MONTHS
CONTINUOUSLY AND WE VERY
CAREFULLY FEED THEM A DIET WHERE
THEY HAVE TO EAT EVERYTHING
THAT'S THERE AND WE ARE GOING TO
DRAMATICALLY CHANGE THE MACRO
NUTRIENT COMOTION OF THE DIET
AND SEE IF THERE IS METABOLIC
CHANGES THAT TAKE PLACE AS A
RESULT OF THAT.
WE'RE REALLY INTERESTED IN THOSE
QUESTIONS BUT WE DON'T HAVE AN
ANSWER FOR YOU.
>> I NOTICE THERE'S LITTLE TALK
OF BROWN FAT FOR EXAMPLE COLD --
IF THAT'S STILL A SUBJECT.
AND THE OTHER PART IS WHAT ABOUT
THE STORY ABOUT THE BACTERIAL
FLORA OF LEAN PEOPLE VERSUS FAT
PEOPLE.
>> SO TWO EXCELLENT QUESTIONS
AND VERY HOT TOPICS IN THE
RESEARCH, NO PUN INTENDED.
WITH RESPECT TO BROWN ADD DOSE
TISSUES I THINK JACK'S DONE
SIMILAR WORK ON THIS.
OBESE PEOPLE TEND TO HAVE LOWER
AMOUNT OF BROWN ADD POTION
TISSUE.
WHETHER OR NOT IT'S BECAUSE THEY
DOAMENTD NEED IT BECAUSE FAT IS
A REALLY GOOD INSULATOR OR
WHETHER THAT WAS CAUSATIVE, WE
DON'T KNOW THE ANSWER TO THAT
QUESTION YET.
WE ALSO DON'T REALLY KNOW HOW
MUCH ENERGY, PENDURE IS EXPECTED
TO CHANGE BY ACTIVATING THAT
BROWN ADIPOSE TISSUE.
WE CAN SIMULATE LOTS OF THINGS.
ONE OF THE THINGS, AND THERE'S A
VERY NICE PAPER THAT RECENTLY
CAME OUT LOOKING AT COLD
EXPOSURE IN HUMANS TO LOOK TO
SEE HOW MUCH ENERGY EXPENDITURE
GOES UP.
A LOT OF THE PREVIOUS STUDIES
HAVE LOOKED AT THAT AND HAVE
ALLOWED PEOPLE TO EAT WHATEVER
THEY WANT HAVE FOUND THAT THE
COLD EXPOSURE YES CAUSES A
SLIGHT INCREASE IN METABOLIC
RATE OF WHICH THEY ATE MORE THAN
THAT WENT UP.
SO -- IS DOING A REALLY NICE
STUDY RIGHT NOW LOOKING AT COLD,
PORTION AT VARIOUS DIFFERENT
TEMPERATURES AND TRYING TO DRAW
THE CURVE OF METABOLIC RATE AS A
FUNCTION OF AMBIENT TEMPERATURE
AND MEASURED IN METABOLIC
CHAMBERS AT THE SEVENTH FLOOR OF
THE CLINICAL CENTER.
I THINK LOTS OF INTERESTING WORK
NEEDS TO BE DONE IN THAT AREA.
AS OF YET WE HAVE NOT MODELED
ACTIVATION OR INACTIVATION OF
BROWN ADIPOSE TISSUE AS PART OF
OUR MODEL.
YOU ALSO ALLUDE TO A LOT OF THE
INTERESTING WORK ON GUT MICRO
BIOME AND MICRO FLORA THAT HAVE
BEEN SHOWN TO CHANGE WHEN YOU
CHANGE YOUR DIET AND HAVE BEEN
SHOWN TO BE DIFFERENT IN OBESE
INDIVIDUALS VERSUS LEAN
INDIVIDUALS.
A LOT OF THE MECHANISMS BY WHICH
THAT HAS BEEN PURPORTED TO TAKE
PLACE HAVE BEEN INVOLVING
ALTERED BASICALLY ABSORBABILITY
OF FOOD.
MOSTLY IN RODE EBILITY MODELS
WHERE IT'S ACTUALLY VERY
DIFFICULT TO DO THOSE
MEASUREMENTS CAREFULLY AS MY
FORMER POST DOC WHO MEASURED
DAILY FOOD INTAKE CORRECTED FOR
SPILLAGE OVER MANY MANY WEEKS
KNOWS.
SO IT'S ACTUALLY HARD TO
INTERPRETER THOSE STUDIES IN MY
OPINION.
AND ANOTHER INTERESTING QUESTION
IS HOW MUCH ENERGY DOES THIS
MICRO BIOME REQUIRE.
ANOTHER ORGAN IN SOME SENSE THAT
REQUIRES ENERGY AND ARE THEY
REALLY LIVING JUST OFF THE STUFF
THAT WE WOULDN'T NORMALLY DIGEST
ANYWAY.
I THINK THOSE ARE INTERESTING
QUESTIONS.
ONE THING I THINK IS TRUE IS
THAT THE AMOUNT OF BACTERIA IN
YOUR GUT THAT'S OFTEN TALKED
ABOUT HALF A KILOGRAM OR A
KILOGRAM, I THINK THOSE ARE
DRAMATIC OVERESTIMATES IS
PROBABLY LESS THAN 50 GRAMS OR
SO WHEN YOU DO THE MATH
CORRECTLY.
SO THAT KIND OF LIMITS THE
AMOUNT OF ENERGY EXPENDITURE
THAT ORGAN CAN POSSIBLY
GENERATE.
BUT I THINK THESE ARE
INTERESTING QUESTIONS.
DID YOU HAVE ANYTHING.
>> I WANT TO BRING THE -- ON THE
STAGE AGAIN.
>> GOOD.
>> WE HAVE BASICALLY TWO WAYS OF
INDUCED CALORIE RESTRICTION IN A
MOUSE MODEL.
AND ONE IS TO GIVER THEM A
RESTRICTED DIET WITH SOME LOW
CHLORIC CONTENT.
ONE IS TO BASICALLY TAKE AWAY
THE FOOD.
AT THE END OF THE DAY IT'S VERY
SIMILAR.
CAN YOU COMMENT ON THAT AND
PERHAPS SOME EXTRAPOLATION TO
HUMAN STUDIES.
>> WELL, SO THIS IS A VERY
INTERESTING AREA ABOUT ALTERNATE
DAY FASTING I THINK IS WHAT
YOU'RE SUGGESTING IS THAT
THERE'S SOME NOW DEVELOPING
HUMAN DATA THAT IT MAY NOT BE AT
LEAST IN THE SHORT TERM
METABOLICALLY DETRIMENTAL.
AND WHETHER IT'S, I WOULD SAY
FOR MYSELF PERSONALLY I WOULD
RAFT REDUCE SOME EVERY DAY THAN
TO HAVE 24 HOUR FACES
INTERMITTENTLY.
BUT IT DOESN'T MEAN IT'S NOT A
SUCCESSFUL STRATEGY.
I MEAN AS DR. HALL ALLUDED TO
THE FACT THAT DIETS OF ANY SORT
WORK WHEN YOU HEAR OF THEM AND
IF IT'S EASIER TO BE COMPLETELY
INHERENT TO A 24 HOUR FAST WITH
FOOD INTAKE IN BETWEEN THAT'S
GOOD REDUCED OVERALL OPEN TAKE
IT'S FABULOUS.
IT'S INTERESTING TO SPECULATE
THAT COULD BE METABOLIC
ADAPTATIONS TO THAT APPROACH
THAT WOULD LEAD TO COMPLETE
COMPENSATION ON THE INNER TAKEN
IN ON THE FASTING DAY.
OWE CHANGES IN METABOLIC
PARAMETERS THAT WOULD IN FACT
LEAD TO LESS ACTIVE UTILIZATION
OR STORAGE OF THE CALORIES WHEN
FOOD IS TAKEN IN.
I THINK THAT YOU DON'T HAVE
ENOUGH INFORMATION ABOUT IT IN
HUMANS CERTAINLY BUT MAYBE KEVIN
IS GOING TO COLLECT THOSE DATA
NEXT YEAR.
>> BASICALLY IN A MONTH.
>> LISTEN I WEUNLT TO THANK BOTH
OF YOU.