Obesity in aging: Hormonalcontribution

Hormonal issues in obesity andagingnn Hormonal role in regulation of energyHormonal role in regulation of energy

balancebalancenn Genetic component in hormonal regulationGenetic component in hormonal regulationnn Life style contribution to hormonal changesLife style contribution to hormonal changesnn Age-associated hormonal changesAge-associated hormonal changesnn Hormonal solutions to obesityHormonal solutions to obesity

Hormonal role in regulation ofenergy balancenn Oscillations around energy balance lead toOscillations around energy balance lead to

compensatory behaviors and hormonecompensatory behaviors and hormonesecretionsecretion

nn InsulinInsulinnn Insulin, GH, IGF-IInsulin, GH, IGF-Inn Counter-regulatory hormonesCounter-regulatory hormonesuu glucagonglucagon,, catecholamines catecholamines, GH,, GH, cortisol cortisol

nn LeptinLeptin

Energy regulation= oscillationsaround energy balance

nn Energy expenditure triggersEnergy expenditure triggersenergy release throughenergy release throughcounter-regulatory hormonescounter-regulatory hormonesuu GH,GH,cortisolcortisol,,catecholaminescatecholamines

forfor lipolysis lipolysis and andglycogenolysisglycogenolysis

nn Energy intake triggersEnergy intake triggersnutrient absorption andnutrient absorption andglycogen, protein and fatglycogen, protein and fatsynthesissynthesisuu insulin (with GH,I)insulin (with GH,I)

Metabolic effects of GH

nn Carbohydrate metabolismCarbohydrate metabolismuu increased plasma glucoseincreased plasma glucoseuu decreased cellular glucose utilizationdecreased cellular glucose utilization

nn Lipid metabolismLipid metabolismuu lipolysislipolysis after 1 hr delay after 1 hr delayuu abdominal (visceral) depotabdominal (visceral) depot

nn Protein metabolismProtein metabolismuu IGF-I and growth factorsIGF-I and growth factors

Metabolic effects of cortisol

nn Anabolic andAnabolic andcatabolic actionscatabolic actions

nn GlucoregulatoryGlucoregulatoryactionsactionsuu gluconeogenesisgluconeogenesisuu glycogen synthesisglycogen synthesis

nn Lipid metabolismLipid metabolismuu lipolyticlipolytic with GH with GHuu lipogeniclipogenic with with

insulininsulin

Cortisol and obesity

nn Cushing’sCushing’s syndrome syndromenn OversecretionOversecretion of of

cortisolcortisolnn Fat depositionFat deposition

uu visceralvisceraluu facialfacialuu back of the neckback of the neck

Metabolic effects ofcatecholamines

nn Lipid metabolismLipid metabolismuu lipolysislipolysis

FF beta1beta1FF beta2beta2FF beta3beta3 adrenergic adrenergic receptors receptors

uu inhibition ofinhibition of lipolysis lipolysisFF alphaalpha adrenergic adrenergic receptors receptorsFF adenosine receptorsadenosine receptors

uu increased lipid oxidationincreased lipid oxidation

nn Carbohydrate metabolismCarbohydrate metabolism

Metaboliceffects ofinsulinnn increased nutrientincreased nutrient

intakeintakenn increased CHOincreased CHO

metabolismmetabolismnn hexosehexose

monophosphatemonophosphate shunt shuntnn reducing equivalentsreducing equivalents

for fat synthesisfor fat synthesisuu NADPHNADPH

Genetic component in hormonalregulation of energy balancenn Pima Indians Pima Indiansuu obesity in USAobesity in USAuu lean phenotype in Mexicolean phenotype in Mexico

nn Insulin response and sensitivityInsulin response and sensitivitynn LeptinLeptin genotypes genotypesuu obob//obob obesity due to lack of obesity due to lack of leptin leptinuu dbdb//dbdb obesity due to lack of obesity due to lack of leptin leptin receptor receptor

Insulin response and sensitivity

nn Genetic variation in Genetic variation inuu responsiveness to food (“externality”)responsiveness to food (“externality”)uu insulin response to foodinsulin response to fooduu cell sensitivity to insulincell sensitivity to insulin

Leptin: adipocyte hormonecommunicating with the brain

nn LeptinLeptinuu secretory secretory product of the product of the adipocyte adipocyteuu circulates in the blood at concentrations incirculates in the blood at concentrations in

proportion to the amount of adipose tissue.proportion to the amount of adipose tissue.nn Modulated byModulated byuu metabolic hormonesmetabolic hormonesuu gendergenderuu development stagedevelopment stageuu current body energy requirements. current body energy requirements.

Leptin: postulated signaling role

nn The primary role of the hormone The primary role of the hormone leptin leptin is to is toprovide information to the central nervous system,provide information to the central nervous system,primarily hypothalamic areas, about the amount ofprimarily hypothalamic areas, about the amount ofenergy stored in the adipose tissueenergy stored in the adipose tissue

nn In the brain,In the brain, leptin leptinuu inhibitsinhibits neuropeptide neuropeptide Y Yuu activates energy expenditureactivates energy expenditure

FF physical activityphysical activityFF metabolismmetabolism

Leptin

Adipose Tissue

WEIGHT GAIN

ParasympatheticTone

WEIGHT LOSS

LEPTIN

Hypothalamus

NPY Y5 Receptor

Response to Starvation

TemperatureReproductiveFunction

EnergyExpenditure

FoodIntake

LEPTIN

Hypothalamus

MSHMC-4 Receptor

Response to Obesity

Food Intake

Energy Expenditure

SympatheticTone

nn Upon receipt of theUpon receipt of theleptinleptin signal, the signal, theneural networksneural networksresponsible forresponsible forenergy homeostasisenergy homeostasismake appropriatemake appropriatechanges in energychanges in energyintake or energyintake or energyexpenditure toexpenditure tomaintain the bodymaintain the bodyin energy balance.in energy balance.

Leptin: Food > Energy Intake Expenditure

Leptin: Energy > Food Expenditure Intake

Leptin

db

Fat Stores

Controller -Hypothalamus

Mutations ofleptin andleptin receptorgenes lead toobesity.nn LeptinLeptin is is

produced byproduced bythe the OB OB genegene

nn obob//obob mutation mutationlackslacks leptin leptinand is obeseand is obese

Leptin receptors

nn LeptinLeptin receptor is coded by the receptor is coded by the DBDB gene.gene.nn dbdb//dbdb mutation results in abnormalmutation results in abnormal mRNAs mRNAs

made coding for a nonfunctional receptormade coding for a nonfunctional receptornn db db//dbdb mice become fat because they can’t mice become fat because they can’t

respond to the weight-regulating product ofrespond to the weight-regulating product ofthethe obob gene,gene, leptin leptin..

Leptin receptors (continued)nn Abnormal RNA splicing ofAbnormal RNA splicing of noncoding introns noncoding introns in in

obob//obob genotype genotypenn mRNAmRNA produces the long form of the receptor produces the long form of the receptor

interrupted by an abnormal insert.interrupted by an abnormal insert.nn The extra piece of RNA contains a signal thatThe extra piece of RNA contains a signal that

prematurely stops production of the receptorprematurely stops production of the receptorproteinprotein

nn Instead of the long form of the receptor, it makes aInstead of the long form of the receptor, it makes ashort form that lacks signaling abilityshort form that lacks signaling ability

nn Truncated receptors can not produce STAT signalsTruncated receptors can not produce STAT signals

Mutation of the db gene

Ob-R gene

Ob-R mRNA

Ob-Rprotein

Intracellularsignals

Ob No Intracellularsignals

Ob

Point mutation

StopStop

Normal db/db Mutant

Stop

Role of leptin in micenn Mutations in theMutations in the obob gene block the synthesis ofgene block the synthesis of leptin leptin

inin obob//obob and wild-type mice and wild-type micenn InjectingInjecting obob//obob and wild-type mice with and wild-type mice with leptin leptin resulted resulted

in a dose and time-dependent decrease in body weightin a dose and time-dependent decrease in body weightnn LeptinLeptin-induced weight loss in-induced weight loss in ob ob//obob mice was due to mice was due touu increased oxygen consumptionincreased oxygen consumptionuu higher body temperaturehigher body temperatureuu increasedincreased locomotor locomotor activity activityuu decreased food intake.decreased food intake.

Role of leptin in humans

nn In most cases theIn most cases the obob gene is functionally normal in gene is functionally normal inhuman obesity.human obesity.

nn Obese humans have highObese humans have high leptin leptin levels and are levels and areinsensitive toinsensitive to leptin leptin..

nn A mutation in theA mutation in the dbdb gene, which causes a defect gene, which causes a defectin the receptor may interfere with peripheralin the receptor may interfere with peripheralsignals of the level of obesitysignals of the level of obesity

nn LeptinLeptin probably plays a minor role in probably plays a minor role inhuman obesityhuman obesity

Life style contribution to obesityin aging

nn Meal eatingMeal eatingnn Secular changes in nutrient intakeSecular changes in nutrient intakenn InactivityInactivitynn StressStress

Meal eating

nn Inverse relationshipInverse relationshipbetween meal size andbetween meal size andbody fatnessbody fatness

nn Societal pressure toSocietal pressure toeat spaced large mealseat spaced large meals

nn Meal sizes in USAMeal sizes in USA vs vsEuropeEurope

nn Large meals lead toLarge meals lead tooversecretionoversecretion of ofinsulininsulin

Huge and calorically dense servingsoffered commercially

nn Au Bon PainAu Bon PainBlueberryBlueberrymuffinmuffin

nn 430 Kcal and 18430 Kcal and 18grams fatgrams fat

Huge and calorically dense servingsoffered commercially

nn CinnabonCinnaboncinnamon rollcinnamon roll

nn 670 Kcal and 34670 Kcal and 34g of fatg of fat

Huge and calorically dense servingsoffered commercially

nn Pizza HutPizza HutPepperoniPepperoniLover’s PanLover’s PanPizza, 2 slicesPizza, 2 slices

nn 700 Kcal and 34700 Kcal and 34grams of fatgrams of fat

Huge and calorically dense servingsoffered commercially

nn Deli tuna saladDeli tuna saladsandwich withsandwich withmayomayo

nn 833 Kcal and 56833 Kcal and 56grams of fatgrams of fat

Fat synthesis due to large mealsnn RQ > 1 indicates fat synthesisRQ > 1 indicates fat synthesisnn Only when carbohydrate load/meal is excessiveOnly when carbohydrate load/meal is excessive

Secular trend in food and nutrientintakenn Calories levelCalories levelnn Fat intake onFat intake on

the risethe risenn CarbohydrateCarbohydrate

intake inintake indeclinedecline

Fatintake:addedfats

nn Fat intakeFat intakecontinues to risecontinues to rise

nn Fat accumulationFat accumulationis largely due tois largely due toincreased fatincreased fatintakeintake

Age-associated hormonalchangesnn Insulin Insulin oversecretion oversecretion and resistance and resistancenn GHGH undersecretion undersecretionnn Thyroid hormoneThyroid hormone undersecretion undersecretionnn Menopause andMenopause and andropause andropausenn AdrenopauseAdrenopausenn Changes in the pattern of hormone secretionChanges in the pattern of hormone secretionnn New hormoneNew hormone synergisms synergisms

Insulin oversecretion andresistance nn Aging is oftenAging is often

asociatedasociated with obesity with obesitynn Reduced insulin-Reduced insulin-

induced glucoseinduced glucoseuptake is seen both inuptake is seen both inaged and obeseaged and obese

nn This is due to reducedThis is due to reducedperipheral sensitivityperipheral sensitivityto insulin, principallyto insulin, principallyin the musclein the muscle

Insulin oversecretion andresistance

nn Aging is oftenAging is oftenasociatedasociated with obesity with obesity

nn OversecretionOversecretion of ofinsulin is seen in bothinsulin is seen in bothaged and obeseaged and obese

nn High fasting plasmaHigh fasting plasmainsulininsulin

Age-associated hormonalchangesnn GHGH undersecretion undersecretion is a manifestation of is a manifestation of

somatopausesomatopauseuu reducedreduced lipolysis lipolysisuu reduced IGF-I and lean tissue growthreduced IGF-I and lean tissue growth

nn Thyroid hormoneThyroid hormone undersecretion undersecretionuu About 10% of older women areAbout 10% of older women are hypothyroid hypothyroiduu reduced T3/T4 isreduced T3/T4 is asociated asociated with reduced with reduced

mitochondrialmitochondrial oxidative metabolism oxidative metabolism

Age-associated hormonalchangesnn Menopause andMenopause and andropause andropauseuu sex hormonessex hormones supress supress LPL (dietary lipid LPL (dietary lipid

uptake)uptake)uu visceral fat has more androgen receptors thanvisceral fat has more androgen receptors than

E2 receptorsE2 receptorsuu sex hormones stimulate IGF-I secretionsex hormones stimulate IGF-I secretionuu sex hormones influence levels of physicalsex hormones influence levels of physical

activityactivity

nn Reduced sex hormone binding globulinReduced sex hormone binding globulin

Age-associated hormonalchangesnn AdrenopauseAdrenopauseuu secretion ofsecretion of glucocorticoids glucocorticoids remains normal remains normaluu secretion of DHEA orsecretion of DHEA or DHEAs DHEAs declines declines

nn Changes in the pattern of hormone secretionChanges in the pattern of hormone secretionuu less distinct hormone pulses produce lessless distinct hormone pulses produce less

distinct biological effectsdistinct biological effects

Age-associated hormonalchangesnn New hormoneNew hormone synergisms synergisms::nn Reduced GH secretionReduced GH secretionuu reduced jointreduced joint lipolytic lipolytic effect with effect with cortisol cortisol

nn Life stressesLife stressesuu increased troughincreased trough cortisol cortisol values are associated values are associated

with increased abdominal fatwith increased abdominal fat

nn Increased insulin secretionIncreased insulin secretionuu increasedincreased lipogenic lipogenic effect with effect with cortisol cortisol

Hormonal solutions to obesity:the magic bullet

nn CholecystokininCholecystokinin injections injectionsuu increased satiety signalincreased satiety signal

nn Insulin receptor drugsInsulin receptor drugsuu increased tissue sensitivity in spite ofincreased tissue sensitivity in spite of

obesityobesity

nn GH, GHRH/GHRP injectionsGH, GHRH/GHRP injectionsnn ArginineArginine intake intakeuu increased IGF-I andincreased IGF-I and lipolysis lipolysis