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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