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>> IT IS MY GREAT PLEASURE
TO WELCOME OUR SPEAKER,
DR. REBECCA J. BROWN.
AN LASKAR TENURE TRACK
INVESTIGATOR IN OBESITY BRANCH
AT THE NATIONAL INSTITUTE OF
DIABETES AND DIGESTIVE AND
KIDNEY DISEASES.
DR. BROWN EARNED HER MEDICAL
DEGREE FROM THE MAYO MEDICAL
SCHOOL IN 2002.
WHILE AS A STUDENT WAS A
RESEARCH FELLOW AT THE NIH
HOWARD HUGHES TRAINING PROGRAM A
PREDECESSOR OF THE RESEARCH
SCHOLARS PROGRAM.
SHE COMPLETED HER RESIDENCY AT
RAINBOW BABIES AND CHILDREN'S
HOPPED AND IN 2005 JOINED THE
NATIONAL INSTITUTE OF CHILD AND
HUMAN DEVELOPMENT AS A CLINICAL
FELLOW IN PEDIATRIC
ENDOCRINOLOGY.
AFTER COMPLETE RESEARCH FELLOW
AT NIDDK AND EARNING A MASTER'S
OF SCIENCE IN CLINICAL RESEARCH
FROM DUKE UNIVERSITY, SHE WAS
INVITED TO JOIN THE INSTITUTE AS
AN ASSISTANT CLINICAL
INVESTIGATOR BEFORE BECOMING THE
FIRST TENURED TRACK AT NIDDK IN
2015.
HER CURRENT RESEARCH FOCUSES ON
THE PATH OWE -- PATHOPHYSIOLOGY
OF THE DYSFUNCTION OF THE
INSULIN RECEPTOR.
SEEKING TO DEVELOP THERAPEUTICS
FOR THE RARE DISEASES AND
PATHWAY MAY SERVE AS DRUG
TARGETS FOR MORE COMMON DISORDER
OF INSULIN RESISTANCE.
A CURRENT FOCUS OF HER
LABORATORY IS UNDERSTANDING THE
PHYSIOLOGIC WAYS WHERE THE
LECTIN ALTERS INSULIN RESIST AND
AND ENERGY METABOLISM BOTH
DEPENDENT ON AND INDEPENDENT ON
FOOD INTAKE.
DR. BROWN IS A NATIONALLY AND
INTERNATIONALLY RECOGNIZED
INVESTIGATOR ESPECIALLY ON
LECTIN WITH 80 PEER-REVIEWED
ARTICLES AND THREE BOOK
CHAPTERS.
BOARD CERTIFIED BY THE AMERICAN
BOARD OF PEDIATRICS SERVES AS A
MEMBER OF THE BOARD OF ADVISORS
TO THE COMMITTEE AND NIDDK'S
STABLE WORKING GROUP.
DR. BROWN ALSO IS PART OF THE
DIABETES CENSUS COMMITTEE GROUP,
THE ENDOCRINE SOCIETY, OBESITY
SOCIETY AND THE EUROPE
CONSORTIUM OF DYSTROPHIES AND
PLEASE WELCOME DR. BROWN.
>> THANK YOU FOR THE KIND
INTRODUCTION.
BEFORE WE START I WANT TO
DISCLOSE THAT METRO LEPTIN THE
PHARMACEUTICAL FORM OF LEPTIN
FOR MOST THE STUDIES WAS DONATE
THE PHARMACEUTICAL COMPANIES
LISTED HERE AND UNRELATED TO THE
TALK I RECEIVED RESEARCH SUPPORT
FROM REGENERON.
AND ALL OTHER USES IN THE
PRESENTATION ARE
INVESTIGATIONAL.
OUR LEARNING OBJECTIVE HAVE TO
IDENTIFY THE BIOLOGICAL
FUNCTIONS OF LEPTIN LOOK AT
SUFFICIENCY AND EXCESS AND LOOK
AT NON-RESPONSIVE FROM
NON-RESPONSIVE LEPTIN STATES.
IN MEDICAL SCHOOL I WAS TAUGHT
LITTLE ABOUT THE FUNCTION OF
ADIPOSE TISSUE EXCEPT FOR THE
STORAGE OF AN ENERGY DEPO.
RESEARCH HAS REVEALED WHITE
ADIPOSE TISSUE ALSO FUNCTIONS AS
AN ENDOCRINE ORGAN RELEASING
HORMONES AND ONE IS LEPTIN THE
TOPIC OF TODAY'S PRESENTATION.
LEPTIN WAS DISCOVERED BY JEFF
FREEDMAN'S LAB AT THE
ROCKEFELLER IN THE 1990s AND
BASED ON THIS SPONTANEOUSLY
OCCURRING MOUSE MODEL OF OBESITY
THE OBOB MASS.
OBESITY WAS KNOWN TO FOLLOW A
RECESSIVE PATTERN LONG BEFORE
YOU CAN SEQUENCE A GENOME FOR
UNDER $1,000 AND TOOK YEARS OF
EFFORTS TO IDENTIFY THE EFFECTED
GENE AND LEARN ITS FUNCTION.
IN 1994, THE FREEDMAN LAB
REPORTED MUTATIONS IN THE GENE
ENCODING LEPTIN IN THESE
ANIMALS.
THE WORD LEPTIN WAS DERIVED FROM
THE GREEK WORD LEPTOS AND IF YOU
REPLACED THE MISSING HORMONE
LEPTIN IN THE ANIMALS IT
COMPLETELY CORRECTED THEIR
HYPERPHAGIA AND RESULTED IN A
HEALTHY LEAN MOUSE AS SHOWN
HERE.
IN 1997, A GROUP IN THE U.K.
IDENTIFIED CHILDREN FROM
CONSANGUINIOUS FAMILIES AND
FOUND SOME CHILDREN LIKE THE
OBOB MOUSE HAD A RECESSSIVE IN
LOW LEPTIN CONCENTRATIONS.
WE SEE A 4-YEAR-OLD CHILD WITH
THE CONDITION WEIGHING THREE
TIMES AS MUCH AS A TYPICAL CHILD
HIS AGE.
IN 1999, THEY SHOWED LEPTIN
ADMINISTRATION WORKED JUST AS
WELL IN THE HUMAN PATIENTS AS IT
DID IN MICE.
THIS PICTURE SHOWS THE SAME
CHILD AS ABOVE AS AGE 7 AFTER
BEING TREATED WITH LEPTIN AND
WEIGHS LESS AT AGE 7 THAN AGE 4.
NATURALLY, IT WAS THOUGHT LEPTIN
MIGHT BE THE MIRACLE CURE FOR
OBESITY.
ALSO IN 1999 THERE WAS A LARGE
CLINICAL TRIAL OF LEPTIN
ADMINISTRATION IN ADULTS WITH
COMMON FORMS OF OBESITY.
WHILE THERE WAS SOME MODEST
WEIGHT LOSS IN PATIENTS WHO WERE
TREATED WITH THE HIGHEST DOSES
OF LEPTIN THERE WERE REALLY NO
DRAMATIC EFFECTS ON BODY WEIGHT.
SO DID LEPTIN ADMINISTRATION
HAVE LITTLE EFFECT IN COMMON
FORMS OF OBESITY?
WELL, LEPTIN IS MADE BY
ADIPOSITES IN PER ASSOCIATION TO
FAT MASS.
HERE IN THE GRAPH WE SEE DATA
SHOWING PERCENT BODY FAT ON THE
Y AXIS AND LEPTIN -- PERCENT
BODY FAT ON THE Y AND LEPTIN ON
THE X FOR HUMANS ACROSS A WIDE
RANGE OF BODY FAT.
THE LOG OF SERUM LEPTIN
CORRELATES WELL WITH ADIPOSITY
AND IS REPRESENTED HERE BY FAT
STORAGE.
LEPTIN OCCURS AS A STARVATION
SIGNAL AND LOW EFFICIENCY STATES
STARVATION TO NON-STARVATION
STATES SIGNALLING AN END TO
STARVATION.
IN PATIENTS WITH NON-DEFICIENT
FORMS OF OBESITY WHICH IS ALMOST
EVERYONE SERUM LEPTIN IS ALREADY
HIGH AND WELL ABOVE THE
RESPONSIVE RANGE THUS ADDING
ADDITIONAL LEPTIN TO THESE
ALREADY HIGH LEPTIN LEVELS HAS
LITTLE CLINICAL AFFECT.
SO HOW DOES LEPTIN FUNCTION TO
MAINTAIN HOMEOSTASIS OF FAT
STORAGE?
LET'S IMAGINE YOU'RE A HEALTHY
LEAN INDIVIDUAL AND YOU'RER ADIPOSE
SITES MAYBE A NORMAL AMOUNT AND
THE LOW LEPTIN GETS SENSED BY
THE HYPOTHALAMUS AS A STARVATION
SIGNAL AND LEADS TO NUMEROUS
ADAPTATIONS TO STARVATION AND
MOST IMPORTANTLY MAKES YOU FEEL
CONSTANTLY HUNGRY.
AFTER YOU EAT A LARGE MEAL YOU
STILL WON'T FEEL SATIATED.
IF WE NOW IMAGINE THE FAMINE IS
OVER YOU'LL EAT A LOT OF FIND
YOUR LEPTIN LEVEL WILL TURN TO
NORMAL AND HOMEOSTASIS IS
RESTORED.
IT DOESN'T MEAN YOU WON'T STILL
BE HUNGRY SEVERAL TIMES A DAY
BUT AFTER YOU EAT A MEAL YOU'LL
NOW FEEL SATIATED AND MANY
THINGS REGULATE IT DURING THE
COURSE OF THE DAY AND LEPTIN IS
A LONG-TERM PLAYER.
NOW LET'S IMAGINE THE OPPOSITE.
YOU LIVE IN AN URBAN OR SUBURBAN
ENVIRONMENT AND SURROUNDED BY
CALORIE DENSE FOODS AND HAVE
LITTLE OPPORTUNITY TO EXERCISE
AND AS YOU GAIN FAT THE SERUM
LEPTIN LEVEL RISE AND IT SHOULD
SUPPRESS YOUR APPETITE AND
RESTORE HOMEOSTASIS.
WE KNOW THIS IS NOT THE CASE OR
WE WOULD NOT BE LIVING IN AN
OBESITY EPIDEMIC.
SO WHY DOESN'T HIGH LEPTIN
SUPPRESS APPETITE?
THE PRIMARY FUNCTIONAL ROLE OF
LEPTIN IS APPARENTLY TO DEFEND
NOT REDUCE BODY FAT BY
INCREASING FOOD SEEKING AND
DECREASING ENERGY EXPENDITURE
WHEN FA FAT STORES ARE
INSUFFICIENT.
SO LOW LEPTIN ACTS AS A
STARVATION SIGNAL INCREASING
APPETITE BUT HIGH LEPTIN DOES
NOT ACT AS AN OVER NUTRITION
SIGNAL AND DECREASE APPETITE.
THIS GRAPH SHOWS SERUM LEPTIN
CONCENTRATIONS ON THE X AXIS AND
DEFICIENCY ON THE Y AXIS.
LEMENTIN IS INEFFECTIVE IN HIGH
LEPTIN STATES WHERE LEPTIN
LEVELS ARE HIGH 20 TO 100
NANOGRAMS AND LEPTIN IS
INEFFECTIVE IN THESE PATIENTS.
LEPTIN THERAPY HAS DRAMATIC
AFFECTS IN SEVERELY LEPTIN
DEFICIENT PATIENTS.
THEY HAVE LEVELS LESS THAN 1
NANOGRAM.
SO IN ORDER TO UNDERSTAND THE
DIE LOGICAL ROLE OF LEPTIN WE
HAVE TO STUDY HUMANS WIN LEPTIN
DEFICIENT STATES WHO ARE LEPTIN
RESPONSIVE.
IN FACT STUDIES OF PATIENTS WITH
LEPTIN DEFICIENCY TAUGHT US A
LOT ABOUT THE BIOLOGY.
WE KNOW IT PRODUCES THE
HYPERPHAGIA OF STARVATION AND
LEPTIN RECAPITULATES THE ENERGY
CONSERVATION STATE INCLUDING
INCREASED THYROID HORMONE WHICH
IS REVERSED AND REPRODUCTION IS
ENERGY INSENSITIVE AND PATIENTS
WITH CONGENITAL LEPTIN
DEFICIENCY HAVE TAUGHT US IT'S
PERMISSIVE FOR REPRODUCTION AND
THE CHALLENGE IS THE EXTREME
RARITY OF THIS CONDITION WITH
LESS THAN 30 PATIENTS REPORTED
WORLDWIDE.
SO WHAT OTHER LOW-LEPTIN
CONDITIONS CAN WE STUDY IN
HUMANS?
STARVATION IS THE OBVIOUS CHOICE
AS THIS IS THE PHYSIOLOGIC
CONDITION OF LOW LEPTIN.
NOW, DOING STUDIES OF AN
APPETITE SUPPRESSING MEDICATION
IS CLINICALLY ETHICALLY FRAUGHT.
INTERESTING ACCUSE STARVATION
EXPERIMENTS BY WHICH I MEAN A
72-HOUR FAST HAVE BEEN DONE IN
HEALTHY VOLUNTEERS AND THEY
SHOWED LEPTIN REPLACEMENT IN
THIS CONTEXT DID SUPPRESS
APPETITE.
THERE WAS EVEN A BOLD TEAM THAT
GAVE IT TO A PATIENT WITH
ANOREXIA AND THEY FOUND
INCREASES IN THYROID AND SEX
HORMONES IN PATIENTS WITH
ANOREXIA NERVOSA.
WE CAN ADD STARVATION TO OUR
MODEL OF LEPTIN BIOLOGY AS A LOW
LEPTIN STATE RESPONSIVE TO
LEPTIN ADMINISTRATION.
HOWEVER LONG-TERM EXPERIMENTS
ARE NOT COMMONLY DONE AND WE
HAVE THIS CONDITION ASSOCIATED
WITH THE REPRODUCTIVE
DYSFUNCTION.
A GROUP AT MASS GENERAL SHOWED
LEPTIN THERAPY WITH SOME WOMEN
WITH THIS CONDITION IMPROVED
FUNCTION OF THE HYPERTHALAMIC
GONAD AXIS AND HAD SOME WEIGHT
LOSS.
WHAT OTHER LOW LEPTIN CONDITIONS
CAN WE STUDY IN HUMANS?
THE CONDITION WE STUDIED
EXTENSIVELY AT NIH IS A RARE
DISEASE CALLED LIPO DYSTROPHY.
HERE I'LL WALK YOU THROUGH THE
PATHOPHYSIOLOGY OF THIS.
THE FUNDAMENTAL PROBLEMS IS LOW
FAT MASS WHICH CAN BE GENETIC OR
ACQUIRED.
VARIETY PEOPLE WITH
LIPODYSTROPHY HAVE LOW LEVELS OF
ADIPOSEKINES.
THAT GETS SENSEDS A STARVATION
SIGNAL AND RESULTS IN
HYPERPHAGIA.
AN PATIENT WITH LIPODYSTROPHY
THEY CAN'T STORE CALORIES IN
ADIPO
ADIPOSECITES THEY GET STORED IN
THE MUSCLE AND LIVER AND FOR
COMPLICATE REASONS WE CAN CALL
LIPOTOXICITY AND IT LOODZ LEADS
TO INSULIN RESISTANCE AND CAN
LEAD TO NON-FATTY LIVER DISEASE
AND OTHERS.
THE PATHOPHYSIOLOGY IS SIMILAR
TO PATIENTS WITH LIPO DYSTROPHY.
OBVIOUSLY THERE'S MAJOR
DIFFERENCES.
AND AS A RESULT THEY HAVE HIGH
CIRCULATING LEPTIN.
THEY CAN STORE IN THEIR
ADIPOCYTES BUT THEY MAY EXCEED
THE STORAGE CAPACITY OF THEIR
ADIPOCYTES AND AT THAT POINT YOU
GET SPILLOVER EFFECTS INTO THE
ECTOPIC LIPID STORAGE DEPOTS
LIKE THE MUSCLE AND LIVER
LEADING TO INSULIN RESISTANCE
AND THE DOWN STREAM CONSEQUENCES
WE SEE.
THERE ARE TWO MAJOR CATEGORIES
OF LIPODYSTROPHY.
THOSE HERE SHOWN IN THE
ADOLESCENT ON THE LEFT ARE
MISSING NATIONALLY ALL ADIPOSE
TISSUES IN THEIR BODIES.
PATIENTS WITH LIPODYSTROPHY AS
ILLUSTRATED BY THE TEENAGE GIRL
ON THE RIGHT AND BOTH PICTURES
ARE OF THE SAME PATIENT.
THEY HAVE LOSS IN FAT IN CERTAIN
DEPOTS TYPICALLY THE EXTREMITIES
WITH INCREASED FAT IN THE HEAD,
NECK AND TRUNK.
BECAUSE LEPTIN IS SECRETED IN
PROPORTION TO FAT MASS JUST AS
IN THE GENERAL POPULATION,
LEPTIN LEVELS SHOWN IN THE GRAPH
ARE UNIFORMLY LOW IN PATIENTS
WITH GENERALIZED LIPODYSTROPHY
INDICATED BY THE BLUE DOTS BUT
LEPTIN TENDS TO BE HIGHER IN
PATIENTS WITH PARTIAL
LIPODYSTROPHY SHOWN IN THE RED
SQUARES.
IN 2000 WAS A STUDY OF HORMONE
REPLACEMENT WITH PATIENTS WITH A
MEAN SERUM LEPTIN LEVEL AND
TREATED THEM AT ESCALATING DOSES
UP TO A MAXIMUM OF TWOFOLD THE
ESTIMATED PHYSIOLOGIC
REPLACEMENT DOSE AND THE RESULTS
WERE DRAMATIC.
DIABETES IMPROVED WITH A
REDUCTION OF HEMOGLOBIN A1C FROM
9% TO NEAR BASELINE AFTER FOUR
MINUTES OF TREATMENT.
THERE WAS A 60% REDUCTION IN
SERUM TRIGLYCERIDES TO 1,000 AT
BASELINE TO UNDER 400 AND LIVER
VOLUME REDUCED BY 20% PRESUMABLY
DUE TO A REDUCTION OF FAT AND
FOOD INTAKE REDUCED BY 50% FROM
ABOUT 2700 CALORIES A DAY AT
BASELINE TO 1600 A DAY AT
FOLLOW-UP.
22 YEARS LATER, HUNDREDS OF
PATIENTS WITH THIS RARE DISEASE
HAVE BEEN TREATED WITH LEPTIN
AND WITH STUDIES LEPTIN WAS FDA
APPROVED WITH PATIENTS WITH
GENERALIZED LIPODYSTROPHY IN
2004.
THIS ILLUSTRATE THE DRAMATIC
CHANGE IN A SUBJECT WITH
GENERALIZED LIPODYSTROPHY.
THIS PATIENT CAME TO US AT AGE
21 WITH POORLY CONTROLLED
DIABETES AND HAD DIABETIC KETO A
AACIDOSIS AND THESE GRAPHS SHOW
HER LABORATORY PARAMETERS PRIOR
TO LEPTIN TREATMENT IN BLUE AND
AFTER ONE YEAR OF LEPTIN
TREATMENT IN PURPLE.
HER HEMOGLOBIN A1C DECREASED
FROM 13.1 TO THE NON-DIABETIC
RANGE OF 5.1.
THIS WAS DESPITE DISCONTINUING
INSULIN ENTIRELY FROM AN INITIAL
DOSE OF 280 UNITS PER DAY.
HER TRIGLYCERIDES DECREASED FROM
OVER 6,000 TO LESS THAN 200 AND
HER URINE PROTEIN SECRETION
DECREASED FROM OVER 6 GRAMS PER
DAY TO LESS THAN 1 GRAM PER DAY.
THIS IS A PHOTO OF THE PATIENT
PRIOR TO LEPTIN TREATMENT.
YOU CAN APPRECIATE HER
GENERALIZED LACK OF ADIPOSE
TISSUE.
SHE HAS STIGMATA OF INSULIN
RESISTANCE IN THIS AREA AND HAS
INCREASED ABDOMINAL GIRTH DUE TO
HEPATOMEGLY.
AFTER THE MOST DRAMATIC CHANGE
YOU CAN OBSERVE IS REDUCTION IN
ABDOMINAL GIRTH FROM EFFLUX OF
ECTOPIC LIPID.
THUS, WHILE WE HAVE NOT YET
CURED THE UNDERLYING PROBLEM IN
PATIENTS WITH LIPODYSTROPHY WE
CAN REPLACE A KEY MISSING
ADIPOKINE AND IT REDUCES ECTOPIC
LIPID STORAGE IN THE MUFFSCLES AND
IMPROVES INSULIN RESISTANCE AND
NON-ALCOHOL FATTY LIVER DEED.
AND AS YOU KNOW DECREASING FOOD
INTAKE WHICH WE CAN ALSO CALL
GOING ON A DIET HAS METABOLIC
BENEFITS IN PEOPLE WITH OBESITY.
THE BENEFITS OF REDUCED FOOD
INTAKE ACHIEVED THROUGH DIETING
IN PATIENTS WITH OBESITY ARE
SIMILAR TO THOSE ACHIEVED BY
LEPTIN ADMINISTRATION IN
PATIENTS WITH LIPODYSTROPHY WITH
IN INSULIN SENSITIVE AND HEPATIC
TRIGLYCERIDES.
THIS BEGS THE QUESTION ARE ALL
LEPTIN'S METABOLIC BENEFITS DUE
TO REDUCTIONS IN FOOD INTAKE OR
DOES LEPTIN HAVE METABOLIC
BENEFITS ABOVE AND BEYOND THE
EFFECTS TO REDUCE HUNGER?
HOW DO WE DETERMINE IF LEPTIN
HAS METABOLIC BENEFITS
INDEPENDENT OF ITS ACTION TO
SUPPRESS FOOD INTAKE?
STUDIES IN MICE IS EASY.
IT'S CALLED A PAIRED FEEDING
EXPERIMENT.
YOU TAKE A GROUP OF LEPTIN
DEFICIENT MICE WHO ARE HYPER
HYPERPHAGIC AND MEASURE HOW MUCH
THEY EAT AND TAKE A SECOND GROUP
OF LEPTIN DEFICIENT MICE AND
ONLY LET THEM EAT THE SAME
AMOUNT AS THE LEPTIN TREATED
MICE.
THEN YOU MEASURE DIFFERENCES IN
YOUR OUTCOMES OF INTEREST SO WE
HAVE TWO GROUPS OF MICE, ONE
WITH LEPTIN AND ONE WITHOUT
EATING THE SAME AMOUNT OF FOOD.
STUDIES HAVE SHOWN IN MICE LEAPT
INIMPROVES INSULIN RESISTANCE
BUT NOT LIPE -- DISLIPDISLIPODEMIA.
WE HAD ONE COHORT NOT PREVIOUSLY
TREATED WITH LEPTIN AND TREATED
WITH LEPTIN FOR TWO WEEKS DURING
PERIOD TWO THE LEFTIN WITHDRAWAL
COHORT HAD PATIENTS WITH
LIPODYSTROPHY ALREADY TAKING
LEPTIN.
THEY WERE STUDIED ON THEIR USUAL
DOSE OF LEPTIN IN PERIOD ONE AND
TAKEN OFF LEPTIN FOR TWO WEEKS
IN PERIOD TWO.
THE KEY TO THE STUDY DESIGN WAS
FOOD INTAKE WAS HELD CONSTANT
DURING BOTH PERIOD ONE AND TWO
AS PATIENTS WERE HOUSED
IN-PATIENT AT THE CLINICAL
CENTER ALLOWING US TO ASSESS
METABOLIC HEALTH IN ON LEPTIN
AND OFF LEPTIN CONDITIONS WITH
NO DIFFERENCE IN FOOD INTAKE.
FOR OUR RESULTS TO BE
INTERPRETABLE WE FIRST HAD TO
SHOW OUR EXPERIMENTAL DESIGN WAS
SUCCESSFUL.
THOUGH WE ASKED PATIENTS TO EAT
100% OF THE FOOD WE PROVIDED, NO
MORE, NO LESS.
WE DIDN'T FORCE FEED THEM.
INSTEAD WE MEASURED UNEATEN FOOD
AND CALCULATED ACTUAL FOOD
INTAKE.
THIS SHOWS THE MEAN DIFFERENCE
IN FOOD INTAKE BETWEEN THE ON
AND OFF LEPTIN CONDITIONS IN THE
LEPTIN INITIATION COHORT SHOWN
ON THE LEFT AND THE LEPTIN
WITHDRAWAL ON THE RIGHT.
NUMBERS GREATER THAN ZERO MEAN
SUBJECTS ATE MORE IN THE ON
LEPTIN CONDITION AND LESS THAN
ZERO MEANS THEY EIGHT MORE.
FORTUNATELY OUR PATIENTS
COMPLIED PRETTY WELL WITH THE
STUDY AND FOUND NO STATISTICAL
DIFFERENCES IN FOOD INTAKE IN
THE ON VERSUS OFF LEPTIN PERIODS
IN EITHER THE INITIATION COHORT
IN KWHOEM THE DIFFERENCE WAS
VERY CLOSE TO ZERO OR THE
WITHDRAWAL COHORT IN WHO HAD
ABOUT 60 CALORIES PER DAY LESS
FOOD INTAKE IN THE OFF LEPTIN
AVERAGE BUT WITH NO STATISTICAL
DIFFERENCE BETWEEN THE ON AND
OFF PERIODS.
THIS GRAPH SHOWS INSULIN
SENSITIVITY WITH A GLYCEMIC
CLAMP.
FOR THIS STUDY HIGHER VALUES
INDICATE GREATER INSULIN
SENSITIVITY AND LOWER VALUES
INDICATE GREATER INSULIN
RESISTANCE.
THE LEPTIN INITIATION COHORT
SHOWN ON THE LEFT AND WITHDRAWAL
COHORT ON THE RIGHT.
THE WHITE BARS SHOW THE OFF
LEPTIN CONDITIONS AND THE BLACK
BARS SHOW THE ON LEPTIN
CONDITION FOR BOTH GROUPS.
INSULIN SENSITIVITY WAS GREATER
IN THE ON LEPTIN CONDITION IN
BOTH COHORTS SHOWING THAT AS IT
DOES IN RODENTS, IT IMPROVE
SENSITIVITY INDEPENDENT OF FOOD
INTAKE IN HUMANS.
WHETHER THIS IS MEDIATED THROUGH
EFFECTS OF LEPTIN IN THE CENTRAL
NERVOUS SYSTEM OR ACTIONS IN THE
PERIPHERY REMAINS TO BE
DETERMINED.
INTERESTINGLY WE ALSO FOUND THAT
IN CONTRAST TO RODENT STUDIES,
LEPTIN ALSO IMPROVED
TRIGLYCERIDES INDEPENDENT OF
FOOD INTAKE IN HUMANS AT LEAST
WITHIN THE LEPTIN INITIATION
COHORT.
THIS IS ONLY ONE OF MANY ASPECTS
OF LEPTIN BIOLOGY THAT APPEARED
TO DIFFER IN RODENTS AND HUMANS
AND EMPHASIZES THE IMPORTANCE OF
CONDUCTING RESEARCH IN HUMAN
SUBJECTS.
SO TO RETURN TO OUR MODEL OF
LEPTIN BIOLOGY WE CAN ADD
GENERALIZED LIPODYSTROPHY WHERE
LEPTIN THERAPY DECREASES
APPETITE.
I DIDN'T SHOW THIS DATA BUT WE
FOUND IT REVERSES OTHER
ADAPTATION IN PATIENTS WITH
LIPODYSTROPHY INCLUDING
INCREASING THYROID HORMONE AND
PERMITTING NORMAL PUBERTY AND
REPRODUCTION.
IN ADDITION, PATIENTS WITH
GENERALIZED LIPODYSTROPHY ADDED
TO OUR KNOWLEDGE OF THIS BY
SHOWING IT INCREASES LEPTIN
SENSITIVITY EVEN BEYOND THE
EFFECTS TO REDUCE APPETITE AS
WELL AS DIABETES CONTROL AND
HYPERGLYCEMIA.
WE LEARN GENERALIZED
LIPODYSTROPHY IS A SEVERE LEPTIN
STATE RECEPTIVE TO LEPTIN
THERAPY.
HOW LOW DOES IT NEED TO BE AND
WHERE CAN WE DRAW THE LINE
BETWEEN LEPTIN RESPONSIVE AND
NON-RESPONSIVE STATES?
WE STUDIED PATIENTS WITH PARTIAL
LIPODYSTROPHY IN WHOM THERE'S A
LARGE RANGE OF SERUM LEPTIN
CONCENTRATIONS.
TO EVALUATE THE EFFICACY OF
LEPTIN TREATMENT IN PATIENTS
WITH GENERALIZED VERSUS PARTIAL
FORMS OF LIPODYSTROPHY WE
STUDIED 86 PATIENTS WITH
LIPODYSTROPHY AND LOOKED AT THE
EFFECT ON DIABETES CONTROL
MEASURED BY HEMOGLOBIN A1C AND
TRIGLYCERIDES IN 55 PATIENTS
WITH A MEAN SERUM LEPTIN OF 1
AND 32 WITH PARTIAL
LIPODYSTROPHY WITH A MEAN SERUM
LEPTIN OF AROUND 6.
IN THE LEFT YOU SEE REDUCTION IN
HEMOGLOBIN A1C AFTER SIX AND 12
MONTHS OF TREATMENT.
PATIENTS WITH GENERALIZED
LIPODYSTROPHY ARE IN BLUE AND
WITH PARTIAL IN RED.
THOUGH A1C DIG SIGNIFICANTLY
DECREASED IN BOTH GROUPS SOME
REACHED LEVELS LESS THAN 7%.
ON THE RIGHT YOU SEE REDUCTIONS
IN TRIGLYCERIDES SHOWING
IMPROVEMENT IN GENERALIZED AND
PARTIAL LIPODYSTROPHY GROUPS BUT
GREATER EFFICACY AMONG THOSE
WITH GENERALIZED LIPODYSTROPHY.
ARMED WITH THE KNOWLEDGE THAT
PATIENTS WITH PARTIAL
LIPODYSTROPHY HAVE SMALLER
IMPROVEMENTS, THEY SET OUT TO
ANSWER THE QUESTION HOW HIGH A
SERUM LEPTIN LEVEL IS TO HIGH TO
RESPOND TO LEPTIN TREATMENT IN
PATIENTS WITH LEPTIN DYSTROPHY.
IN COLLABORATION WITH THE
UNIVERSITY OF MICHIGAN THEY
ANALYZED DATA IN 143 PATIENTS
WITH LIPODYSTROPHY.
6 6 HAD ED AND 81 WITH PARTIAL
AND WERE TREATED WITH OPEN LABEL
LEPTIN AT NIH AND THE UNIVERSITY
OF MICHIGAN.
WE DEFINED PATIENTS AS
RESPONDERS TO LEPTIN IF THEY
ACHIEVED EITHER AN A1C REDUCTION
OF AT LEAST 1% OR TRIGLYCERIDE
REDUCTION OF AT LEAST 30%S.
PATIENTS WERE NON DEFINERS IF
THEY DIDN'T REACH EITHER OF
THOSE BENCH MARKS.
WE COMPARED SERUM LEPTIN IN
PATIENTS WITH GENERALIZED
LIPODYSTROPHY IN RED CIRCLES AND
WITH PARTIAL IN THE BLUE AMONG
NON-RESPONDERS NR ON THE LEFT
COMPARED TO RESPONDERS R ON THE
RIGHT.
NOW WHEN WE COMBINED BOTH
PATIENTS WITH GENERALIZED AND
PARTIAL LIPO DE JOE DIODYSTROPHY YOU CAN
SEE SERUM LEPTIN WAS LOWER AMONG
THE RESPONDERS COMPARED TO THE
NON-RESPONDERS.
HOWEVER, THIS IS DRIVEN BY THE
HUGE PREPONDERANCE WITH THOSE
WITH LOWER LEPTIN CONCENTRATIONS
WITHIN THE RESPONDER CATEGORY.
NOW IN THE RIGHT HAND GRAPH
WE'RE ISOLATING PATIENTS WITH
PARTIAL LIPODYSTROPHY IN BLUE
AND AMONG PATIENTS WITH PARTIAL
LIPODYSTROPHY THERE'S NO
STATISTICAL DIFFERENCE IN SERUM
LEPTIN IN RESPONDERS VERSUS
NON-RESPONDERS.
WE THEN ENDEAVORED TO FIND A CUT
POINT TO PREDICT LEPTIN
RESPONSIVENESS USING RECEIVER
OPERATOR CURVE ANALYSTS AND WE
ANALYZED EVERY POSSIBLE CUT
POINT FOR SERUM LEPTIN WITHIN
OUR DATA SET AND CALCULATE THE
SENSITIVITY AND SPECIFICITY TO
PREDICT RESPONDER VERSUS
NON-RESPONDER STATUS.
WE THEN PLOT 1 MINUS SPECIFICITY
ON THE X AND SENSITIVITY ON THE
Y AXIS.
IF LEPTIN HAS ZERO
DISCRIMINATORY POWER TO
DETERMINE RESPONDER STATUS WE'LL
SEE THE DOTTED RED LINE SHOWN ON
THE DIAGONAL.
ON THE OTHER HAND IF SERUM
LEPTIN HAD PERFECT
DISCRIMINATORY POWER WE WOULD
SEE A LINE GOING UP THE LEFT AND
ACROSS THE TOP WITH AN AREA
UNDER THE CURVE OF 1 OR 100%.
THE ACTUAL DATA IS SHOWN IN THIS
SOLID BLACK LINE HERE WHICH
REPRESENTS THE COMBINED COHORT
OF GENERALIZED PLUS
LIPODYSTROPHY.
IN THIS GROUP SERUM LEPTIN HAD
FAIR PREDICTIVE POWER WITH AN
AREA UNDER THE CURVE OF 0.74.
HOWEVER, FOR THE SUB GROUP WITH
PARTIAL LIPODYSTROPHY SHOWN IN
THE DASHED BLUE LINE THE AREA
UNDER THE CURVE WAS ONLY 6.3 AND
NOT STATISTICALLY DIFFERENT FROM
CHANCE.
THE OPTIMAL CUT POINT BASED ON
THE SUM OF SENSITIVITY AND
FESTIVITY WE CAN IDENTIFY WAS
THE SERUM LEPTIN BUT IT HAS LOW
ACCURACY WITH THE SENSITIVITY OF
ONLY 56% AND SPECIFICITY OF 78%
TO PREDICT RESPONDER STATUS.
SO WHY WAS SERUM LECTIN SUCH A
POOR PREDICTOR OF RESPONSE TO
LEPTIN TREATMENT?
WELL, ONE POTENTIAL EXPLANATION
SAID THIS DATA CAME FROM OPEN
LABEL STUDIES.
I'M SURE YOU'RE ALL FAMILIAR
WITH THE HAWTHORNE EFFECT AND
YOU BRING THEM IN WHETHER
THEY'RE GETTING DRUG NORT AND
THE LACK OF A PLACEBO GROUP
MAKES IT IMPOSSIBLE TO
DISTINGUISH HOW MUCH IMPROVEMENT
IS RELATED TO THE ACTUAL DRUG,
LEPTIN AND HOW MUCH WAS JUST
RELATED TO STUDY PARTICIPATION.
IN ADDITION, AS IN MOST STUDIES,
WE OBSERVED GREATER IMPROVEMENTS
IN METABOLIC PARAMETERS IN THE
PATIENTS WITH THE MOST EXTREME
BASELINE DISEASE AND THIS COULD
SIMPLY REPRESENT PROGRESSION TO
THE MEAN AND HAVE NOTHING TO DO
WITH LEPTIN TREATMENT.
FURTHERMORE, LEPTIN ASSAYS ARE
POORLY STANDARDIZED AND SO
VARIABILITY IN THE ASSAY ITSELF
MAY HAVE CONTRIBUTED TO OUR LACK
OF ABILITY TO DETECT THE LEPTIN
CUT POINT AND FINALLY LEPTIN IS
ACUTELY REGULATED BY ENERGY
BALANCE AS WELL AS BEING
REGULATED IN THE LONG TERM BY
FAT MASS AND THUS THE DIET THAT
PATIENTS WERE CONSUMING OVER THE
DAYS PROCEEDING THE MEASUREMENT
OF THEIR SERUM LEPTIN COULD HAVE
AFFECTED THAT MEASUREMENT.
THUS FAR, I'VE SHOWN YOU DATA ON
HOW SERUM LEPTIN CONCENTRATION
DOES OR DOESN'T PREDICT EFFECTS
OF LEPTIN TREATMENT ON APPETITE,
DIABETES AND DYSLIPIDEMIA AND
ABOUT ANOTHER COMPLICATION?
I'LL SHOW YOU DATA THAT SUGGESTS
THAT LEPTIN'S EFFECTS ON
STEATO-HEPATITIS MAY EXTEND
ACROSS A BROADER RANGE
POTENTIALLY ALLOWING US TO
EXTEND EFFICACY TO PATIENT WITH
HIGHER LEPTIN LEVELS AND COMMON
CONDITIONS.
A GROUP AT THE UNIVERSITY OF
MICHIGAN SHOWED LEPTIN TREATMENT
IMPROVED HISTOLOGY OF
NON-ALCOHOL NASH IN TWO COHORTS.
SHE TESTED EFFECTS OF LEFTIN IN
SIX MEN WITH NON-ALCOHOLIC
STEATOHEPATITIS IN THE LOWEST
QUARTILE TO THEIR BODY MASS AND
TERMED THIS LOW LEPTIN NASH.
THE MEAN CONCENTRATION IN THE
PATIENTS WAS 7 NANOGRAMS PER ML
WITH A RANGE OF 3.6 UP TO 10.9.
IN ALL SIX SUBJECTS HISTOLOGIC
NASH SCORES IMPROVED AFTER SIX
MONTHS OF LEPTIN ADMINISTRATION.
SHE ALSO STUDIED 15 SUBJECTS
WITH PARTIAL LIPODYSTROPHY WITH
A MEAN SERUM LEPTIN OF 16.2
RANGE FROM 14.8 UP TO 67.1.
THOUGH IMPROVEMENTS IN NASH
HISTOLOGY AFTER LEPTIN TREATMENT
WERE MORE VARIABLE IN THE
COHORT, AGAIN, THERE WAS
STATISTICALLY SIGNIFICANT
IMPROVEMENT SUGGESTI INING LEPTIN
MIGHT IMPROVE NASH EVEN IN
PATIENTS WITH QUITE HIGH SERUM
CONCENTRATIONS AND WELL LOOKED
AT THE MECHANISMS IN WHICH IT
IMPROVES NASH IN PATIENTS WITH
LIPODYSTROPHY.
THIS WAS DONE BY A MEDICAL
STUDENT IN MY LAB WITH
COLLABORATION WITH THE
UNIVERSITY OF MISSOURI.
TO UNDERSTAND HOW LEPTIN
IMPROVES STEATOHEPATITIS WE HAVE
TO UNDERSTAND HOW LIPPED LIPIDS
ACCUMULATE IN THE LIVER LIPE OL
SIS CAN BE TAKEN UP BY THE
LIVER.
TRIGLYCERIDES CAN BE TAKEN UP
AND ONCE IN THE HEPATOSITE LDL
CAN CONTRIBUTE TO STEATO
STEATOHEPATIT
STEATOHEPATITIS.
WHAT ARE THE MECHANISMS WHERE IT
CAN REDUCE ACCUMULATION?
OUR GROUP DEMONSTRATED LEPTIN
REDUCES FOOD INTAKE AND REDUCES
ADIPOCYTE TO REDUCE TRIGLYCERIDE
ACCUMULATION.
RODENT DATA SUPPORT ADDITIONAL
ROLES OF LEPTIN TO ENHANCE THE
LDL EXPORT FROM THE LIVER AND
DECREASE STEATOLIPOGENESIS.
WE STUDIED WHETHER IT REDUCED IT
IN PATIENTS WITH LIPODYSTROPHY.
WHAT IS DE NOVO LIPOGENESIS.
THEY'RE CARBOHYDRATE PRECURSORS.
IT OCCURS PRIMARILY IN THE LIVER
WITH A MINOR CONTRIBUTION FROM
ADIPOSE TISSUE.
CARBOHYDRATES STIMULATE THROUGH
CRHEBP AND INSULIN IS THOUGHT TO
BE NECESSARY IN INSULIN
RESISTANT STATES THROUGH
INCREASED EXPRESSION OF SREBP1 A
MAJOR TRANSCRIPTION FACTOR.
WHY DO WE CARE ABOUT DE NOVO
LIPOGENESIS.
THIS ILLUSTRATE THE RELATIVE
CONTRIBUTIONS OF DIFFERENT
SOURCES OF DLDD TRIGLYCERIDE IN
PATIENTS WITH LOW LIVER FAT
COMPARED TO THOSE WITH HIGH
LIVER FAT ON THE RIGHT.
THE ONLY SIGNIFICANT DIFFERENCE
BETWEEN THE TWO GROUPS IS
TRIGLYCERIDES DERIVED FROM DE
NOVO LIPOGENESIS.
THE AMOUNT OF THE LDL
TRIGLYCERIDE DERIVED WAS 250%
HIGHER IN SUBJECTS WITH HIGH
LIVER FAT SHOWING A ROLE OF
INCREASED DE NOVO LIPOGENESIS IN
THE PATHOGENESIS OF LIVER
DISEASE AND IN THE REPORT OF
THREE PATIENTS DE NOVO
LIPOGENESIS WAS INCREASED
SUGGESTING IT MAY PLAY A ROLE IN
LIPODYSTROPHY ASSOCIATED FATTY
LIVER DISEASE AS WELL AS OBESITY
RELATED FATTY LIVER DISEASE.
WE HYPOTHESIZED IT WOULD BE
ELEVATED IN PATIENTS WITH
LIPODYSTROPHY AND DECREASED
AFTER ADMINISTRATION RESULTING
IN STEATOLIPO GENESIS AND WE
ENRICHED THE BODY WATER POOL AND
IN THE MORNING BLOOD WAS DRAWN
AND THE INCORPORATION INTO RDLs
WAS ANALYZED AND THESE DATA WERE
USED TO CALCULATE THE PERCENTAGE
OF TRIGLYCERIDE IN VLDL THAT
DERIVED FROM DE NOVO LIPO
GENESIS.
OUR SUBJECT'S AGES RANGE FROM 14
TO 65 YEARS OLD AND THE MAJORITY
WERE FEMALE.
BECAUSE MOST PATIENTS IN THIS
GROUP HAD PARTIAL LIPODYSTROPHY,
THE MEAN LEPTIN LEVEL PRIOR TO
TREATMENT WAS 9.5 NANOGRAMS PER
ML WHICH OVERLAPS LEVELS IN THE
GENERAL POPULATION.
THE HIGHEST LEVEL WAS 32
NANOGRAMS PER ML IN THE OBESE
RANGE.
LEPTIN WAS AT MINISTERED AT A
MEAN DOSE OF ABOUT 8 MILLIGRAMS
PER DAY AND I WANT TO DWELL ON
THAT DOSE FOR A MOMENT .
I MENTIONED PREVIOUS LEPTIN
TREATMENT WORKS AT HORMONE
REPLACEMENT DOSES IN PATIENTS
WITH CONGENITAL LEPTIN
DEFICIENCY AND THE DOSE WAS WELL
A
-- ABOVE THAT.
WE FOUND LEPTIN TREATMENT
LOWERED BODY WEIGHT, IMPROVED
PERIPHERAL AND HEPATIC INSULIN
SENSITIVITY AND IMPROVED
DIABETES CONTROL AS MEASURED BY
HEMOGLOBIN A1C AND LOWERED
HEPATIC CONTENT FROM 17.6% AT
BASELINE TO 10% AFTER SIX
MONTHS.
THIS GRAPH SHOWS THE CHANGE IN
THE PERCENTAGE OF THE LDL
TRIGLYCERIDE THAT DERIVE FROM DE
NOVO LIPOGENESIS TERMED PERCENT
DNL.
AFTER SIX MONTHS THE PERCENT OF
LEPTIN OF TRIGLYCERIDES
DECREASED FROM 21% AT BASELINE
DOWN TO 7% AFTER LEPTIN
TREATMENT.
FOR COMPARISON IN LEAN HEALTHY
INDIVIDUALS, DE NOVO LIPOGENESIS
CONTRIBUTE 5% TO 10% OF THE
TRIGLYCERIDE HERE INDICATED BY
THE RED SHADING.
AND THIS SHOWS THE AMOUNT BEFORE
AND AFTER LEPTIN TREATMENT.
REMARKABLY ABSOLUTE DE NOVO
LIPOGENESIS DECREASED IN ALL
SUBJECT S WITH A MEAN 88%
REDUCTION FROM 54 TO 86 POINTS
COMPARABLE TO THE NORMAL LEVEL
OF 4 MILLIGRAMS SEEN IN LEAN
HEALTHY INDIVIDUALS AS INDICATED
BY THE RED SHADING.
AS SHOWN IN THE LEFT HAND GRAPH,
SERUM LEPTIN WAS NOT CORRELATED
WITH DE NOVO LIPO GENESIS AT
TREATMENT PRIOR TO LEPTIN
TREATMENT HOWEVER, AS SEEN IN
THE RIGHT HAND GRAPH LOWER SERUM
LEPTIN LEVELS WERE ASSOCIATED
WITH LOWER AMOUNTS OF DE NOVO
LIPO GENESIS AFTER SIX MONTHS OF
TREATMENT AND THIS IS CONSISTENT
WITH WHAT A TOLD YOU SO FAR
ABOUT LEFTIN BIOLOGY.
THE MORE LEPTIN DEFICIENCY A
PATIENT THE GREATER RESPONSE TO
LEPTIN THERAPY INDICATED HERE BY
LOWER DNL AT SIX MONTHS HOWEVER,
ALL PATIENTS SHOWED IMPROVEMENTS
IN DE NOVO LIPOGENESIS WITH
LEVELS UP TO 32 NANOGRAMS BY ML.
THIS SUGGESTS LEPTIN MAY IMPROVE
NON-ALCOHOLIC LIVER DISEASE BY
LOWERING THIS IN EVEN NON LEPTIN
PATIENTS AND WHEN DEFINING
CONDITIONS WE CAN LIKELY EXTEND
RESPONSIVENESS FOR PATIENTS WITH
LOWER LEPTINS IN THE OVER WEIGHT
RANGE.
WE DON'T KNOW IF THOSE WITH
HIGHER LEPTIN WOULD ALSO HAVE
IMPROVEMENTS IN NON-ALCOHOL
FATTY LIVER DISEASE.
TO RECAP WE HAVE SEEN LEPTIN
ADMINISTRATION HAS DRAMATIC
THERAPEUTIC AFFECTS IN PATIENTS
WITH LEPTIN DEFICIENCY INCLUDING
STATES OF LEPTIN DEFICIENCY AND
STARVATION AND GENERALIZED
LIPODYSTROPHY.
CLINICAL EFFECTS INCLUDE
REVERSAL OF ADAPTATION TO
STARVATION SUCH AS DECREASING
APPETITE AND INCREASING THYROID
HORMONES AND PERMITTING NORMAL
PUBERTY AND REPRODUCTION.
STUDIES OF PATIENT WHO'S HAVE
SEVERE INSULIN RESISTANCE HAVE
SHOWN METABOLIC BENEFITS ON
LEPTIN ON INSULIN SENSITIVITY,
DIABETES AND DISDYSLIPODEMIA AND
THOSE WITH HYPOTHALAMIC
AMENORRHEA HAVE MORE MODEST
BENEFITS FROM LEPTIN
ADMINISTRATION.
HOWEVER, BENEFITS OF LEPTIN
ADMINISTRATION MAY EXTENT TO
PATIENTS WITH HIGHER LEPTIN
CONCENTRATIONS FOR EFFECTS ON
STEATOHEPATITIS AND DE NOVO
LIPOGENESIS.
BEFORE WE CONCLUDE I WANT TO
MENTION TWO IMPORTANT STUDIES.
FIRST, SUB GROUP OF A STUDY OF
LEPTIN TREATMENT IN PATIENTS
WITH OBESITY SHOWED THOSE WITH
THE LOWEST SERUM LEPTIN LEVELS
DID HAVE MODEST BUT CLINICALLY
MEANINGFUL WEIGHT LOSS.
WE CAN CALL THESE PATIENTS LOW
LEPTIN OBESITY.
FINALLY, IN PATIENTS WITH
OBESITY WHOSE LEPTIN LEVELS WERE
REDUCED BY DIETING, LEPTIN
ADMINISTRATION RESTORED THE
METABOLIC ADAPTATIONS INCLUDING
INCREASED THYROID HORMONES AND
PUTTING THE PATIENTS INTO THE
LOW LEPTIN OBESITY CATEGORY.
IN CONCLUSION, LOW LEPTIN IS A
SIGNAL OF LONG-TERM ENERGY
DEFICIENCY AND MEDIATES
METABOLIC ADAPTATION.
MOST THE BIOLOGICAL ACTIONS ARE
IN THE TRANSITION FROM LEPTIN
DEFICIENCY TO SUFFICIENCY AND
UNDERSTANDING THE BIOLOGY
REQUIRED THE STUDY OF PATIENTS
WITH RARE DISEASES CAUSING
LEPTIN DEFICIENCY.
LEPTIN HAS LIMITED BIOLOGICAL
ACTIONS IN THE TRANSITION FROM
SUFFICIENCY TO ACCESS AND THE
ACTS MAY REQUIRE PHARMACOLOGIC
IN ADDITION TO PHYSIOLOGIC
DOSING OF LEPTIN.
I'D LIKE TO ACKNOWLEDGE THOSE
WHO CONTRIBUTED TO THE WORK AND
PHIL GORDON AND THE MEMBERS OF
MY LAB, COLLABORATORS BOTH NIH
AND OUTSIDE OF NIH, DRUG
COMPANIES THAT PROVIDED US WITH
LEPTIN OVER THE YEARS AND NONE
OF THIS WOULD HAVE BEEN POSSIBLE
WITHOUT OUR PATIENTS AND THEIR
FAMILIES.
THANK YOU VERY MUCH.
>> DR. BROWN, THANK YOU VERY
MUCH FOR YOUR PRESENTATION
OFFERING US INSIGHTS INTO LEPTIN
BIOLOGY AND PHYSIOLOGY AS WELL
AS THE BENEFITS OF IT IN LEPTIN
RESPONSIVE CONDITIONS ESPECIALLY
WITH LIPODYSTROPHY.
WE HAVE A COUPLE QUESTIONS THAT
HAVE COME IN.
ONE, WHY ARE PATIENTS WITH
OBESITY POTENTIALLY RESISTANT TO
APPETITE- SUPPRESSING EFFECTS OF
LEPTIN?
>> LEPTIN MAY BE REALLY REALLY
IRRELEVANT WHEN YOU'RE IN THE
OBESE STATE AND HAVE MANY LEPTIN
AROUND AND IT PLAYS A ROLE AS A
SIGNAL IN STARVATION.
WHY CAN'T HIGH LEPTIN SUPPRESS
APPETITE IN STATES OF OBESITY?
SOME PEOPLE CALLED IT LEPTIN
RESISTANCE.
IT MAY SIMPLY BE WE'RE ABOVE THE
AADAPTIVE LINEAR RESPONSE AND
MAY BE BEYOND THAT.
THERE'S BEEN REALLY INTERESTING
STUDIES IN RECENT YEARS FROM A
GROUP SUGGESTING YOU CAN RESTORE
LEPTIN SENSITIVITY BY
SUPPRESSING LEPTIN LEVELS.
THAT'S ONLY BEEN SHOWN IN MICE
NOT IN HUMANS.
>> THANK YOU.
AND ALONG THOSE LINES ARE THERE
ANYTHING WE CAN DO TO REVERSE
THE LEPTIN RESISTANCE YOU
MENTION?
>> THE SUPPRESSING LEPTIN LEVELS
AS I MENTIONED HAS BEEN SHOWN IN
RODENT MODELS.
THAT'S BEEN DONE WITH DIFFERENT
METHODS AND OTHER INVESTIGATORS
HAVE TRIED GIVING LEPTIN IN
COMBINATION WITH OTHER
APPETITE-SUPPRESSING HORMONES.
THE ONE THAT MADE IT FURTHEST IN
THE CLINICAL WAS LEPTIN IN
COMBINATION WITH AN ANALOG OF AN
ANALIN.
THAT WAS SUCCESSFUL IN REDUCING
OBESITY BUT THOSE WERE
TERMINATED EARLY IN THE PROCESS
BECAUSE A SUBSET OF PATIENTS
DEVELOPED NEUTRALIZING
ANTIBODIES AND PUT THEM IN A
WORSE CLINICAL SCENARIO PRIOR TO
GETTING EXPOSED TO THE DRUG.
>> THANK YOU.
ANOTHER QUESTION DOES IT MAKE
SENSE THEN TO MEASURE LEPTIN
LEVELS IN OBESITY TO DETERMINE
IF AN INDIVIDUAL BELONGED TO A
LOW-LEPTIN OBESITY GROUP?
>> INTERESTING QUESTION.
THERE'S THERAPEUTIC IMPLICATION
FOR UNDERSTANDING IF A PATIENT
HAS CONGENITAL LEPTIN DEFICIENCY
AND MEASURING IT UNDER THAT
CIRCUMSTANCE WILL BE
INFORMATIVE.
I'LL HAVE AN OBESITY PATIENT
WITH A LOW LEPTIN LEVEL.
USUALLY THEY COME FROM FAMILIES
WITH A HISTORY OF CONSANGUINITY
AND THEY'LL BE UNCOMMON.
NOW, THE PATIENTS WHO HAVE
RELATIVELY LOW LEPTIN OBESITY,
ONE CONCERN IS WHAT WAS THE
PATIENT EATING OVER THE LAST FEW
DAYS?
IF THE PATIENT WAS DIETING SAY
OVER THE THREE-DAY PERIOD PRIOR
TO COMING TO SEE YOU MAY GET A
LOW LEPTIN LEAVE OUT OF THAT
SEEMS OUT OF PROPORTION LOW
COMPARED TO THEIR OBESITY BUT
MAY BE REFLECTING THEIR DIETARY
STATE OVER THE LAST FEW DAYS AND
MAY NOT HAVE MUCH IMPLICATIONS
WITH HOW TO RESPOND TO LEPTIN
TREATMENT.
I DON'T THINK WE REALLY KNOW THE
ANSWER TO THAT AT THIS STAGE.
>> THANK YOU.
THAT APPEARS TO BE THE LAST
QUESTION THAT WE'VE GOTTEN FROM
THE NIH COMMUNITY VIEWING
AUDIENCE.
DR. BROWN, THANK YOU FOR THE
PRESENTATION.
IT WAS VERY CLEAR, CONCISE AND
COMPREHENSIVE.
THANK YOU VERY MUCH.
TO EVERYONE ELSE, THANK YOU.
YOU HAVE A GREAT AFTERNOON AND
WE'LL SEE YOU NEXT WEEK.
THANK YOU VERY MUCH.
BYE-BYE.
>> THANK YOU.