MetabolicIntegra/onandOrganSpecializa/on

Whatprinciplesunderlietheintegra1onofcatabolismandenergyproduc1onwithanabolismandenergyconsump1on?Howismetabolismintegratedincomplexorganismswithmul1pleorgansystems?

TheWashington,D.C.,Metromap.Thecoordinatedflowofpassengersalongdifferenttransitlinesisanaptmetaphorformetabolicregula1on.

Severalpathwaysarecatabolicandservetogeneratechemicalenergyusefultothecell;othersareanabolicandusethisenergytodrivethesynthesisofessen/albiomolecules.Despitetheiropposingpurposes,thesereac/onstypicallyoccuratthesame0measnutrientmoleculesarebrokendowntoprovidethebuildingblocksandenergyforongoingbiosynthesis.Cellsmaintainadynamicsteadystatethroughprocessesthatinvolveconsiderablemetabolicflux.Themetabolismthattakesplaceinjustasinglecellissocomplexthatitdefiesdetailedquan/ta/vedescrip/on.However,anapprecia/onofoverallrela/onshipscanbeachievedbysteppingbackandconsideringintermediarymetabolismatasystemsleveloforganiza/on.

HowIsMetabolismIntegratedinaMul1cellularOrganism?

Incomplexmul/cellularorganisms,organsystemscarryoutspecificphysiologicalfunc/ons.Eachorganexpressesarepertoireofmetabolicpathwaysthatisconsistentwithitsphysiologicalpurpose.Suchspecializa1ondependsoncoordina1onofmetabolicresponsibili/esamongorgans.Essen/allyallcellsinanimalshavethesetofenzymescommontothecentralpathwaysofintermediarymetabolism,especiallytheenzymesinvolvedintheforma/onofATPandthesynthesisofglycogenandlipidreserves.Nevertheless,organsdifferinthemetabolicfuelstheypreferassubstratesforenergyproduc/on.ImportantdifferencesalsooccurinthewaysATPisusedtofulfilltheorgans’specializedmetabolicfunc/ons.

Wewillconsiderthemetabolicinterac/onsamongthemajororgansystemsfoundinhumans:ü  brain,ü  skeletalmuscle,ü  heart,ü  adipose1ssue,ü  andliverThemajorfueldepotsinanimalsareglycogeninliverandmuscle;triacylglycerols(fats)storedinadipose/ssue;andprotein,mostofwhichisinskeletalmuscle.Theorderofpreferencefortheuseofthesefuelsis:Glycogen>triacylglycerol>protein.Nevertheless,the/ssuesofthebodyworktogethertomaintainenergyhomeostasis(calorichomeostasis),definedasaconstantavailabilityoffuelsintheblood.

Metabolicrela1onshipsamongthemajorhumanorgans.

TheMajorOrganSystemsHaveSpecializedMetabolicRoles

BrainTworemarkablemetabolicfeatures:First,ithasaveryhighrespiratorymetabolism.Inres/ngadulthumans,20%oftheoxygenconsumedisusedbythebrain,eventhoughitcons/tutesonly2%orsoofbodymass.(thislevelofO2consump/onisindependentofmentalac/vity,con/nuingevenduringsleep.Second,thebrainhasnofuelreserves—noglycogen,noexpendableprotein,orfat.Normally,thebrainusesonlyglucoseasafuelandistotallydependentonthebloodforacon/nuousincomingsupply.Interrup/onofglucosesupplyforevenbriefperiodsof/me(asinastroke)canleadtoirreversiblelossesinbrainfunc/on.

ThebrainusesglucosetocarryoutATPsynthesisviacellularrespira/on.HighratesofATPproduc/onarenecessarytopowertheplasmamembraneNa,K-ATPasesothatthemembranepoten/alessen/alfortransmissionofnerveimpulsesismaintained.Duringprolongedfas/ngorstarva/on,thebody’sglycogenreservesaredepleted.Undersuchcondi/ons,thebrainadaptstouseβ-hydroxybutyrate,conver/ngittoacetyl-CoAforenergyproduc/onviathecitricacidcycle.β-Hydroxybutyrateisformedfromfa`yacidsintheliver.Theadapta/onofthebraintouseβ-hydroxybutyratefromfatsparesproteinfromdegrada/onun/llipidreservesareexhausted.

Thebrain’sotherpoten/alsourceoffuelduringstarva/onisglucoseobtainedfromgluconeogenesisintheliverusingthecarbonskeletonsofaminoacidsderivedfrommuscleproteinbreakdown.

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Metabolic Profile of Brain

Glucose is fuel for human brain -> consumes 120g/day -> 60-70 % of utilization of glucose in starvation -> ketone bodies can replace glucose

Muscle

Skeletalmuscleisresponsibleforabout30%oftheO2consumedbythehumanbodyatrest.Duringperiodsofmaximalexer/on,skeletalmusclecanaccountformorethan90%ofthetotalmetabolism.Metabolismisprimarilydedicatedtotheproduc/onofATPasthesourceofenergyforcontrac1onandrelaxa1on.

Musclecontrac/onoccurswhenamotornerveimpulsecausesCa2releasefromspecializedendomembranecompartments(thetransversetubulesandsarcoplasmicre1culum).Ca2floodsthesarcoplasm(thetermdeno/ngthecytosoliccompartmentofmusclecells),whereitbindstotroponinC,aregulatoryprotein,ini/a/ngaseriesofeventsthatculminateintheslidingofmyosinthickfilamentsalongac/nthinfilaments.ThismechanicalmovementisdrivenbyenergyreleaseduponhydrolysisofATP.

Thenetresultisthatthemuscleshortens.Relaxa/onoccurswhentheCa2ionsarepumpedbackintothesarcoplasmicre/culumbytheac/onofaCa2-transpor/ngmembraneATPase.TwoCa2ionsaretranslocatedperATPhydrolyzed.TheamountofATPusedduringrelaxa1onisalmostasmuchasthatconsumedduringcontrac1on.

Thestructureofaskeletalmusclecell,showingthemannerinwhichtransversetubulesenablethesarcolemmalmembranetoextendintotheinteriorofthefiber.T-tubulesandsarcoplasmicre/culum(SR)membranesarejuxtaposedatstructurestermedtriadjunc/ons(inset).

Becausemusclecontrac/onisaprocessthatoccursupondemand,musclemetabolismisdesignedforademandresponse.Muscleatrestusesfa`yacids,glucose,orketonebodiesasfuelandproducesATPviaoxida/vephosphoryla/on.Res/ngmusclealsocontainsabout2%glycogenandabout0.08%phosphocrea1nebyweight.WhenATPisusedduringmusclecontrac/on,theADPformedcanbereconvertedtoATPbycrea1nekinasefromphosphocrea/ne:

Musclephosphocrea/necangenerateenoughATPtopowerabout4secofexer/on.Duringstrenuousexer/on,suchasa100-metersprint,oncethephosphocrea/neisdepleted,musclereliessolelyonitsglycogenreserves,makingtheATPforcontrac/onviaglycolysis.Incontrastwiththecitricacidcycleandoxida/vephosphoryla/onpathways,glycolysisiscapableofexplosiveburstsofac1vity,andthefluxofglucose-6-phosphatethroughthispathwaycanincrease2000-foldalmostinstantaneously.Thetriggersforthisac/va/onareCa2andthe“fightorflight”hormoneepinefrine

Musclefa1gueistheinabilityofamuscletomaintainpoweroutput.Duringmaximumexer/on,theonsetoffa/guetakesonly20secondsorso.Fa/gueisnottheresultofexhaus/onoftheglycogenreserves,norisitaconsequenceoflactateaccumula/oninthemuscle.ItiscausedbyadeclineinintramuscularpHasprotonsaregeneratedduringglycolysis.(Theoverallconversionofglucoseto2lactateinglycolysisisaccompaniedbythereleaseof2H+)ThepHmayfallaslowas6.4.ItislikelythatthedeclineinPFKac1vityatlowpHleadstoaloweredfluxofhexosethroughglycolysisandinadequateATPlevels,causingafeelingoffa1gue.

Duringfas/ngorexcessiveac/vity,skeletalmuscleproteinisdegradedtoaa,sothattheircarbonskeletonscanbeusedasfuel.Manyoftheskeletonsareconvertedtopyr,whichcanbetransaminatedintoAlaforexportviathecircula/on.Alaiscarriedtotheliver,whichdeaminatesitbackintopyruvatesothatitcanserveasasubstrateforgluconeogenesis.Althoughmuscleproteincanbemobilizedasanenergysource,itisnotefficientforanorganismtoconsumeitsmuscleandloweritsoverallfitnessforsurvival.Muscleproteinrepresentsafueloflastresort.

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Metabolic Profile of Muscles

Major fuels are glucose, fatty acids, and ketone bodies -> has a large storage of glycogen -> about ¾ of all glycogen stored in muscles -> glucose is preferred fuel for burst of activity -> production of lactate (anaerobe) -> fatty acid major fuel in resting muscles and in heart muscle (aerobe)

Heart

Incontrastwiththeintermi`entworkofskeletalmuscle,theac/vityofheartmuscleisconstantandrhythmic.Therangeofac/vityinheartismuchlessthanthatinmuscle.Consequently,theheartfunc/onsasacompletelyaerobicorganand,assuch,isveryrichinmitochondria(halfthecytoplasmicvolumeofheartmusclecellsisoccupiedbymitochondria).Undernormalworkingcondi/ons,theheartprefersfaYyacidsasfuel,oxidizingacetyl-CoAviathecitricacidcycleandproducingATPforcontrac/onviaoxida/vephosphoryla/on.Heart/ssuehasminimalenergyreserves:asmallamountofphosphocrea/neandlimitedquan//esofglycogen.Asaresult,theheartmustbecon1nuallynourishedwithO2andfreefa`yacids,glucose,orketonebodiesasfuel.

AdiposeTissueAdipose/ssueisanamorphous/ssuethatiswidelydistributedinthebody—aroundbloodvessels,intheabdominalcavityandmammaryglands,andmostprevalently,asdepositsundertheskin.

Longconsideredonlyastoragedepotforfat,adipose/ssueisnowappreciatedasanendocrineorganresponsibleforsecre/onofavarietyofhormonesthatgovernea1ngbehaviorandcalorichomeostasis.

HumanFatDistribu1on

Itconsistsprincipallyofcellsknownasadipocytesthatnolongerreplicate,butcanincreaseinnumberasadipocyteprecursorcellsdivide,andobeseindividualstendtohavemoreofthem.65%oftheweightofadipose/ssueistriacylglycerolthatisstoredinadipocytes,essen/allyasoildroplets.Theaverage70-kgmanhasenoughcaloricreservestoredasfattosustaina6000kJ/dayrateofenergyproduc1onfor3months,whichisadequateforsurvival

Despitetheirroleasenergystoragedepots,adipocyteshaveahighrateofmetabolicac/vity,synthesizingandbreakingdowntriacylglycerol.Adipocytesac/velycarryoutcellularrespira/on,transformingglucosetoenergyviaglycolysis,thecitricacidcycle,andoxida/vephosphoryla/on.Ifglucoselevelsinthedietarehigh,glucoseisconvertedtoacetyl-CoAforfa`yacidsynthesis.However,undermostcondi/ons,freefa`yacidsfortriacylglycerolsynthesisareobtainedfromtheliver.Becauseadipocyteslackglycerolkinase,theycannotrecycleglyceroloftriacylglycerolbutdependonglycoly/cconversionofglucosetodihydroxyacetone-3-phosphate(DHAP)andthereduc/onofDHAPtoglycerol-3-phosphatefortriacylglycerolbiosynthesis.AdipocytesalsorequireglucosetofeedthepentosephosphatepathwayforNADPHproduc1on.

“BrownFat”Aspecializedtypeofadipose/ssuethatisaboundantinnewbornsandhiberna/nganimals.Theabundanceofmitochondria,whicharerichincytochromes,isresponsibleforthebrowncolorofthisfat.thesemitochondriaareveryac/veinelectrontransport–drivenprotontransloca/on,butthesepar/cularmitochondriacontainintheirinnermembranesaprotein,thermogenin(uncouplingprotein1),thatcreatesapassiveprotonchannel,permilngtheH+ionstoreenterthemitochondrialmatrixwithoutgenera/ngATP

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Metabolic Profile of Adipose tissue

Triacylglycerols are stored in tissue -> enormous reservoir of metabolic fuel -> needs glucose to synthesis TAG; -> glucose level determines if fatty acids are released into blood

LiverLiverservesasmajormetabolicprocessingcenterinvertebrates.Exceptfordietarytriacylglycerols,whicharemetabolizedprincipallybyadipose/ssue,mostoftheincomingnutrientsthatpassthroughtheintes/naltractareroutedviatheportalveintotheliverforprocessinganddistribu/on.Muchoftheliver’sac/vitycentersaroundconversionsinvolvingglucose-6-phosphate

Glucose-6-Pcanbeconvertedtoglycogen,releasedasbloodglucose,usedtogenerateNADPHandpentosesviathepentosephosphatecycle,orcatabolizedtoacetyl-CoAforfa`yacidsynthesisorforenergyproduc/onviaoxida/vephosphoryla/on.Mostoftheliverglucose-6-Parisesfromdietarycarbohydrate,fromdegrada/onofglycogenreserves,orfrommusclelactatethatentersthegluconeogenicpathway

Theliverplaysanimportantregulatoryroleinmetabolismbybufferingthelevelofbloodglucose.Liverhastwoenzymesforglucosephosphoryla/on:hexokinaseandglucokinaseTheliverisamajorcenterforfaYyacidturnover.Demandformetabolicenergyhighàtriacylglycerolsarebrokendownandfa`yacidsaredegradedinthelivertoacetyl-CoAtoformketonebodies,whichareexportedtotheheart,brain,andother/ssues.Energydemandslowàfa`yacidsareincorporatedintotriacylglycerolsandcarriedtoadipose/ssuefordeposi/onasfat.Cholesterolisalsosynthesizedintheliverfromtwo-carbonunitsderivedfromacetyl-CoA.

Livercanuseaminoacidsasmetabolicfuels.Aminoacidsarefirstconvertedtotheircorrespondingα-ketoacidsbyaminotransferases.Theaminogroupisexcretedanerincorpora/onintoureaintheureacycle.Thecarbonskeletonsofglucogenicaminoacidscanbeusedforglucosesynthesis,whereasthoseofketogenicaminoacidsappearinketonebodies.Liveristheprincipaldetoxifica1onorgan.Theendoplasmicre/culumoflivercellsisrichinenzymesthatconvertbiologicallyac/vesubstancessuchashormones,poisons,anddrugsintolessharmfulby-products.Liverdiseaseleadstoseriousmetabolicderangements,par/cularlyinaminoacidmetabolism.Incirrhosis,theliverbecomesdefec/veinconver/ngNH4toureaforexcre/on,andbloodlevelsofNH4rise.Ammoniaistoxictothecentralnervoussystem,andcomaensues.

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Metabolic Profile of the Liver (Glucose)

Essential for providing fuel to brain, muscle, other organs -> most compounds absorpt by diet -> pass through liver -> regulates metabolites in blood

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Metabolic Activities of the Liver (Amino Acids)

α-Ketoacids (derived from amino acid degradation) -> liver’s own fuel

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Metabolic Activities of the Liver (Fatty Acids)

cannot use acetoacetate as fuel -> almost no transferase to generate acetyl-CoA

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Food Intake, Starvation, and Obesity

Normal Starved-Fed Cycle: 1. Postabsorptive state -> after a

meal

2. Early fasting state -> during the night

3. Refed state -> after breakfast

-> Major goal is to maintain blood-glucose level

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Blood-Glucose

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1.  Postabsorptive state

Glucose + Amino acids -> transport from intestine to blood

Dietary lipids transported -> lymphatic system -> blood

Glucose stimulates -> secretion of insulin

Insulin:

-> signals fed state

-> stimulates storage of fuels and synthesis of proteins

-> high level -> glucose enters muscle + adipose tissue (synthesis of TAG)

-> stimulates glycogen synthesis in muscle + liver

-> suppresses gluconeogenesis by the liver

-> accelerates glycolysis in liver -> increases synthesis of fatty acids

-> accelerates uptake of blood glucose into liver -> glucose 6-phosphate more rapidly formed than level of blood glucose rises -> built up of glycogen stores

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Insulin Secretion –Stimulated by Glucose Uptake

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Postabsorptive State -> after a Meal

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2. Early Fasting State

Blood-glucose level drops after several hours after the meal -> decrease in insulin secretion -> rise in glucagon secretion

Low blood-glucose level -> stimulates glucagon secretion of α-cells of the pancreas

Glucagon:

-> signals starved state

-> mobilizes glycogen stores (break down)

-> inhibits glycogen synthesis

-> main target organ is liver

-> inhibits fatty acid synthesis

-> stimulates gluconeogenesis in liver

-> large amount of glucose in liver released to blood stream -> maintain blood-glucose level

Muscle + Liver use fatty acids as fuel when blood-glucose level drops

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Early Fasting State -> During the Night

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3. Refed State Fat is processed in same way as normal fed state

First -> Liver does not absorb glucose from blood (diet)

Liver still synthesizes glucose to refill liver’s glycogen stores

When liver has refilled glycogen stores + blood-glucose level still rises -> liver synthesizes fatty acids from excess glucose

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Prolonged Starvation Well-fed 70 kg human -> fuel reserves about 161,000 kcal

-> energy needed for a 24 h period -> 1600 kcal - 6000 kcal

-> sufficient reserves for starvation up to 1 – 3 months

-> however glucose reserves are exhausted in 1 day

Even under starvation -> blood-glucose level must be above 40 mg/100 ml

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First priority -> provide sufficient glucose to brain and other tissues that are dependent on it

Second priority -> preserve protein -> shift from utilization of glucose to utilization of fatty acids + ketone bodies

-> mobilization of TAG in adipose tissues + gluconeogenesis by liver -> muscle shift from glucose to fatty acids as fuel

After 3 days of starvation -> liver forms large amounts of ketone bodies (shortage of oxaloacetate) -> released into blood -> brain and heart start to use ketone bodies as fuel

After several weeks of starvation -> ketone bodies major fuel of brain

After depletion of TAG stores -> proteins degradation accelerates -> death due to loss of heart, liver, and kidney function

Prolonged Starvation

The fasting state computing

Presentation copyright © 2002 David A Bender and some images copyright © 2002 Taylor & Francis Ltd

glycogen

glucose

`

triacyglycerol

hormone-sensi1velipase

glycerol

faYyacidsfaYyacids

protein

aminoacids

aminoacidsglucose

ketonebodies

The fasting state

F

Starvation

Starvation in the 3rdworld

Starvation in the rich-world

50

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Mobilization at Starvation

Also at not treated diabetes

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Diabetes Mellitus – Insulin Insufficiency Characterized by: -> high blood-glucose level -> Glucose overproduced by liver

-> glucose underutilized by other organs

-> shift in fuel usage from carbohydrates to fats -> keton bodies (shortage of oxaloacetate)

-> high level of keton bodies -> kidney cannot balance pH any more -> lowered pH in blood and dehydration -> coma

Type I diabetes: insulin-dependent diabetes (requires insulin to live)

caused by autoimmune destruction of β-cells

begins before age 20

-> insulin absent -> glucagon present

-> person in biochemical starvation mode + high blood-glucose level

-> entry of glucose into cells is blocked

-> glucose excreted into urine -> also water excreted -> feel hungry + thirsty

Type II diabetes: insulin-independent diabetes

have a normal-high level of insulin in blood -> unresponsive to hormone

develops in middle-aged, obese people

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Obesity

In the U. S. -> about 70% of adults are suffering from obesity (2009)

Risk factor for: Diabetes + Cardiovascular diseases

Cause of Obesity -> more food consumed than needed -> storage of energy as fat

Two important signals for “caloric homeostasis” and “appetite” control -> insulin + leptin

Mouse lacking leptin or Leptin receptor

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The Role of Leptin and Insulin on Weight Control

Leptin (dal greco leptos, snello) is a hormone that is produced in direct proportion to fat mass (adipocytes)

Leptina regola il senso di SAZIETA’ Grelina stimola

il senso di appetito

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High Levels of Leptin and Insulin are a Signal for “caloric homeostasis”

Leptin: A Key Player In Weight Regulation

What is Leptin? •  A peptide hormone which is coded for by the obese gene

(ob) •  Influences the quantity of food consumed relative to the

amount of energy expended –  When leptin levels are high, appetite is reduced and

energy expenditure is increased •  Leptin has been found in gastric epithelium, placenta

and adipose tissue –  Most abundant in white adipose tissue

La Leptina è un ormone proteico che regola il peso corporeo, il metabolismo e le funzioni riproduttive. Essa è codificata dal gene dell’obesità (ob)

La leptina è espressa prevalentemente dagli adipociti. Piccole quantità vengono prodotte nello stomaco e nella placenta. I recettori specifici per la leptina sono espressi nell’ipotalamo, nei linfociti T e nelle cellule endoteliali

La leptina arriva nel Sistema Nervoso Centrale (SNC) attraverso la barriera ematoencefalica mediante un meccanismo di trasporto mediato da specifici recettori.

Questo segnale di natura ormonale ha lo scopo di informare il SNC sullo stato di riserve energetiche dell’individuo.

Agisce regolando l’apporto alimentare attraverso l’inibizione della sintesi e del rilascio del neuropeptide Y (NPY), sostanza stimolante l’appetito.

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The Role of Leptin and Insulin on Weight Control

Leptin (dal greco leptos, snello) is a hormone that is produced in direct proportion to fat mass (adipocytes)

Leptina regola il senso di SAZIETA’ Grelina stimola

il senso di appetito

Regulating Food Intake and Energy Expenditure

•  Leptin binds to its receptor which is expressed primarily in the brains hypothalamus region

•  In turn the hypothalamus modulates food intake and energy expenditure

•  When low leptin levels are detected, the body is warned of limited energy supplies

•  If high leptin levels are detected, the hypothalamus senses the body as being overweight –  This then trigger the body to eat less and expend more

energy •  When energy intake and output are equal, leptin reflects the

amount of triglyceride stored in the bodies adipose tissue

Metabolic Effects of Leptin

•  Decreases intracellular lipid concentration through reduction of fatty acid and triglyceride synthesis and a concomitant increase in lipid oxidation

•  It has been postulated that leptin inhibits acetyl-CoA carboxylase , enzyme involved in the committed step of fatty acid synthesis

•  This inhibition leads to decrease in malonyl-CoA levels –  Together the inhibition of acetyl-CoA to malonyl-CoA encourages the

mobilization of fatty acids from storage sites and simultaneously discourages synthesis

Experimentation on Humans •  Few experiments done at this point •  Leptin is said to circulate freely or attached to a binding protein

–  It has been found that obese individuals have more circulating bound leptin than lean individuals

•  The greater the initial level, the more it declines with dieting •  Levels tend to vary greatly from person to person •  Typically females have more leptin than males

–  Adipose tissue accounts for 20-25% of weight in females and only 15-20% in males

•  In general the greater the body mass and percent body fat, the higher the levels –  People suffering from obesity have extremely high levels

Possible Reasons For Increased Leptin In Obese Individuals

•  Differences in the fat production rate of leptin –  Some obese people may make leptin at greater rate to compensate for

faulty signaling process or action •  Resistance to leptin at its site of action

–  If resistance is partial, not complete, more leptin may be required for action

•  A combination of both could influence eating behaviors and energy use to cause obesity

•  All these possibilities indicate that obese individuals are in a state of percieved starvation