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Adipose Tissue: Not Just Fat

Introduction to Adipose Tissue: WAT and BAT Regulation of Adipogenesis Regulation of Lipid Metabolism in Adipocytes Table of Adipose Tissue Hormones and Cytokines Leptin Adiponectin Resistin Inflammatory unctions of Adipose Tissue Metabolic unctions of Bro!n Adipose Tissue" BAT

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Introduction to Adipose Tissue

Adipose tissue is not merely an organ designed to passi/ely store e0cess carbon in t#e form of fatty acids esterified to glycerol 1triacylglycerols2, Mature adipocytes synt#esi3e and secrete numerous en3ymes" gro!t# factors" cytokines and #ormones t#at are in/ol/ed in o/erall energy #omeostasis, Many of t#e factors t#at influence adipogenesis are also in/ol/ed in di/erse processes in t#e body including lipid #omeostasis and modulation of inflammatory responses, In addition" a number of proteins secreted by adipocytes play important roles in t#ese same processes, In fact recent e/idence #as demonstrated t#at many factors secreted from adipocytes are pro4inflammatory mediators and t#ese proteins #a/e been termed adipocytokines or adipokines, T#ere are currently o/er 5* different adipokines recogni3ed as being secreted from adipose tissue, T#ese adipokines are implicated in t#e modulation of a range of p#ysiological responses t#at globally includes appetite control and energy balance, 6pecific metabolic processes regulated by adipose tissue include lipid metabolism" glucose #omeostasis" inflammation" angiogenesis" #emostasis 1regulation of blood coagulation2" and blood pressure,

T#e ma7or form of adipose tissue in mammals 1commonly referred to as 8fat82 is !#ite adipose tissue" WAT, 6peciali3ed adipose tissue t#at is primarily tasked !it# t#ermogenesis" especially in t#e neonate" is bro!n adipose tissue" BAT, BAT is so4called because it is darkly pigmented due to t#e #ig# density of mitoc#ondria ric# in cytoc#romes, BAT speciali3es in t#e production of #eat 1adapti/e t#ermogenesis2 and lipid o0idation,

Histological section of adipose tissue demonstrating distincti/e morp#ology of WAT and BAT, W#ite adipocytes occupy t#e left side of t#e image and bro!n adipocytes t#e rig#t side, As described belo! !#ite adipocytes are generally rounded !it# o/er &*9 of t#e cell /olume taken up by a single fat droplet, T#e fe! small mitoc#ondria and t#e nucleus are compressed to t#e /ery edge of t#e !#ite adipocyte, T#e bro!n adipocytes are smaller in o/erall si3e" polygonal in s#ape" contain se/eral small lipid droplets and #ig# numbers of large mitoc#ondria !#ic# imparts t#e bro!n color to t#ese cells, Image from :un;ueira<s Basic Histology" %)t# ed, by Ant#ony L, Mesc#er" Mc=ra!4Hill >rofessional ?i/ision" reproduced !it# permission, WAT is composed of adipocytes #eld toget#er by a loose connecti/e tissue t#at is #ig#ly /asculari3ed and inner/ated, W#ite adipocytes are rounded cells t#at contain a single large fat droplet t#at occupies o/er &*9 of t#e cell /olume, T#e mitoc#ondria !it#in !#ite adipocytes are small and fe! in number, T#e mitoc#ondria and nucleus of t#e !#ite adipocyte is s;uee3ed into t#e remaining cell /olume, Molecular c#aracteristics of !#ite adipocytes include e0pression of leptin but no e0pression of uncoupling protein %" @C>% 1designated @C>%(" leptinA2, Bro!n adipocytes are smaller in o/erall si3e compared to !#ite adipocytes, Bro!n adipocytes are polygonal in s#ape and contain numerous large mitoc#ondria packed !it# cristae, W#ereas" !#ite adipocytes contain a single large fat droplet" bro!n adipocytes contain se/eral small lipid droplets, Bro!n adipocytes are molecularly @C>%A and leptin(, BAT is primarily /isceral !it# #ig#est concentrations around t#e aorta, BAT is #ig#y /asculari3ed and contains a /ery #ig# density of noradrenergic ner/e fibers, In addition to adipocytes" WAT contains macrop#ages" leukocytes" fibroblasts" adipocyte progenitor cells" and endot#elial cells, T#e presence of t#e fibroblasts" macrop#ages" and ot#er leukocytes along !it# adipocytes" accounts for t#e /ast array of proteins t#at are secreted from WAT under /arying conditions, T#e #ig#est accumulations of WAT are found in t#e subcutaneous regions of t#e body and surrounding t#e /iscera 1internal organs of t#e c#est and abdomen2, Alt#oug# WAT can be found associated !it# numerous organs its functions are more t#an 7ust insulation of t#e organ and a ready reser/oir of fat for energy production, ?epending on its location WAT ser/es speciali3ed functions, T#e WAT associated !it# abdominal and t#oracic organs 1e0cluding

t#e #eart2" t#e so4called /isceral fat" secretes se/eral inflammatory cytokines and is t#us in/ol/ed in local and systemic inflammatory processes, WAT associated !it# skeletal muscle secretes free fatty acids" interleukin4' 1IL4'2 and tumor necrosis factor4B 1TC B2 and as a conse;uence plays a significant role in t#e de/elopment of insulin resistance, Cardiac tissue associated WAT secretes numerous cytokines resulting in local inflammatory e/ents and c#emota0is t#at can result in t#e de/elopment of at#erosclerosis and systolic #ypertension, Didney associated WAT plays a role in sodium reabsorption and t#erefore can affect intra/ascular /olume and #ypertension, T#e ma7or focus of t#is discussion !ill be on t#e biological acti/ities associated !it# WAT" #o!e/er" discussion of BAT is included at t#e end of t#is page, WAT ser/es many functions including insulating t#e /iscera" storing e0cess carbon energy in t#e form of triacylglycerols and mediating glucose #omeostasis, WAT also plays important roles as an endocrineEimmune organ by secreting adipokines t#at includes inflammatory cytokines" complement4like factors" c#emokines" and acute p#ase proteins, T#e endocrine functions of WAT regulate appetite" energy metabolism" glucose and lipid metabolism" inflammatory processes" angiogenesis" and reproducti/e functions, back to t#e top

Regulation of Adipogenesis
T#e process of adipocyte differentiation from a precursor preadipocyte to a fully mature adipocyte follo!s a precisely ordered and temporally regulated series of e/ents, Adipocyte precursor cells emerge from mesenc#ymal stem cells 1M6Cs2 t#at are t#emsel/es deri/ed from t#e mesodermal layer of t#e embryo, T#e plutipotent M6Cs recei/e e0tracellular cues t#at lead to t#e commitment to t#e preadipocyte lineage, >readipocytes cannot be morp#ologically distinguis#ed from t#eir precursor M6Cs but t#ey #a/e lost t#e ability to differentiate into ot#er cell types, T#is initial step in adipocyte differentiation is referred to as determination and leads to proliferating preadipocytes undergoing a gro!t# arrest, T#is initial gro!t# arrest occurs coincident !it# t#e e0pression of t!o key transcription factors" CCAATEen#ancer binding protein alp#a 1CEFB>B2 and pero0isome proliferator4acti/ated receptor gamma 1>>ARG2, ollo!ing t#e induction of t#ese t!o critical transcription factors t#ere is a permanent period of gro!t# arrest follo!ed by e0pression of t#e fully differentiated adipocyte p#enotype, T#is latter p#ase of adipogenesis is referred to as terminal differentiation, Alt#oug# >>ARG and CEFB>B are t#e most important factors regulating adipogenesis additional transcription factors are kno!n to influence t#is process, T#ese additional factors include sterol4 regulated element binding protein %c 16RFB>%c" also kno!n as A??% for adipocyte differentiation4%2" signal transducers and acti/ators of transcription 5 16TAT52" A>4% and members of t#e DrHppel4like factor 1DL I" DL 5" and DL %52 family as !ell as CEFB> beta 1J2 and CEFB> delta 1K2, More information about t#e roles of >>ARG and 6RFB> in metabolic #omeostasis can be found in t#e >>AR page as !ell as t#e C#olesterol page, Alt#oug# t#ese numerous transcription factors #a/e been s#o!n to influence o/erall adipogenesis" eit#er positi/ely or negati/ely" >>ARG is t#e only one t#at is necessary for adipogenesis to take place, In fact" in t#e absence of >>ARG" adipocyte differentiation fails to occur and as yet no factor #as been identified t#at can rescue adipogenesis in t#e absence of >>ARG, In spite of t#is fact" e0pression of >>ARG does not commence during t#e initial acti/ation of adipocyte differentiation but only after t#e responses elicited by 6TAT5" DL I" DL 5" A>4%" 6RFB>%c" and CEFB>J and CEFB>K are e0erted, >>ARG !as originally identified as being e0pressed in differentiating adipocytes and as indicated abo/e it is no! recogni3ed as a master regulator of adipogenesis, >>ARG !as identified as t#e target of t#e

t#ia3olidinedione 1TL?2 class of insulin4sensiti3ing drugs, T#e mec#anism of action of t#e TL?s is a function of t#e acti/ation of >>ARG and t#e conse;uent induction of genes necessary for differentiation of adipocytes, T#e #uman >>ARG gene 1symbol >>AR=2 is located on c#romosome +p)5 spanning o/er %**kb and composed of & e0ons encoding t!o biologically acti/e isoforms as a conse;uence of alternati/e mRCAs and translational start codon usage, T#e principal protein products of t#e >>AR= gene are identified as >>ARG% and >>ARG), >>ARG% is encoded for by e0ons A% and A) t#en common e0ons % t#roug# ', >>ARG) is encoded by e0on B and common e0ons % t#roug# ', >>ARG) is almost e0clusi/ely e0pressed in adipocytes, Like all nuclear receptors t#e >>ARG proteins contain a ?B? and a LB?, In addition" like >>ARB" t#e >>ARG proteins contain a ligand4dependent acti/ation function domain 1identified as A 4)2 and a ligand4independent acti/ation function domain 1identified as A 4%2, T#e A 4) domain resides in t#e LB? and t#e A 4% domain is in t#e C4terminal region of t#e >>ARG proteins, >>ARG) protein contains an additional +* C4terminal amino acids relati/e to >>ARG% and t#ese additional amino acids confer a 5('4fold increase in t#e transcription4stimulating acti/ity of A 4% !#en compared to t#e same domain in t#e >>ARG% protein, F0pression of >>ARG% is nearly ubi;uitous, >>ARG) is e0pressed near e0clusi/ely in !#ite adipose tissue 1WAT2 !#ere it is in/ol/ed in lipid storage and in BAT !#ere it is in/ol/ed in energy dissipation, As indicated abo/e" during adipocyte differentiation se/eral upstream genes are re;uired for t#e acti/ation of t#e >>AR= gene, T#ese include CEFB>J and CEFB>K" 6RFB>4%c" DL 5" DL %5" 3inc4 finger protein I)+ 1LfpI)+2" and early B4cell factor 1Fbf%2, In t#e process of adipocyte differentiation >>ARG acti/ates nearly all of t#e genes re;uired for t#is process, T#ese genes include a>) !#ic# is re;uired for transport of free fatty acids 1 As2 and perilipin !#ic# is a protein co/ering t#e surface of mature lipid droplets in adipocytes, Additional genes regulated by >>ARG t#at are in/ol/ed in lipid metabolism or glucose #omeostasis include lipoprotein lipase 1L>L2" acyl4CoA synt#ase 1AC62" acetyl4 CoA acetyltransferase % 1ACAT%2" se/eral p#osp#olipase A 1>LA2 genes" adiponectin" t#e gluconeogenic en3yme >F>CD" and glycerol4+4p#osp#ate de#ydrogenase 1=>?%2, >>ARG also functions in macrop#age lipid metabolism by inducing t#e e0pression of t#e macrop#age sca/enger receptor" C?+', T#e C?+' receptor is also kno!n as fatty acid translocase 1 AT2 and it is one of t#e receptors responsible for t#e cellular uptake of fatty acids, T#e role of 6RFB>4%c in acti/ation of adipocyte differentiation is t#oug#t to be t#e result of t#is transcription factor initiating t#e e0pression of genes t#at" as part of t#eir acti/ities" generate >>ARG ligands, T#is fact e0plains t#e necessity for 6RFB> e0pression to precede t#at of >>ARG, In spite of t#is fact it #as been s#o!n t#at mice lacking 6RFB>4% do not display significant reductions in t#e amount of WAT, Ho!e/er" le/els of 6RFB>4) are increased in t#ese animals indicating t#at t#is may be a compensatory mec#anism, Alt#oug# loss of 6RFB>4% e0pression does not result in a significant deficit in adipose tissue de/elopment" ectopic o/ere0pression of 6RFB>4%c does en#ance t#e adipogenic acti/ity of >>ARG, T#e CEFB> family of transcription factors !ere among t#e first to be s#o!n to play a role in o/erall adipocyte differentiation, T#e t#ree members of t#e family 1CEFB>B" CEFB>J and CEFB>K2 are #ig#ly conser/ed basic4leucine 3ipper containing transcription factors, T#e importance of t#ese factors in adipogenesis #as been demonstrated in knockout mouse models, for e0ample !#ole body disruption of CEFB>B e0pression results in deat# s#ortly after birt# due to li/er defects" #ypoglycemia" and failure of WAT or BAT accumulation, @sing knockout mice it #as been determined t#at t#e roles of CEFB>J and CEFB>K are e0erted early in t#e process of adiopcyte differentiation !#ereas t#ose of CEFB>B are re;uired later, In fact" e0pression of CEFB>B is induced late in adipogenesis and is most abundant in mature adipocytes, T#e e0pression of bot# CEFB>B and >>ARG is" in part" regulated by t#e actions of CEFB>J and CEFB>K, Mne of t#e ma7or effects of t#e e0pression of CEFB>B in adipocytes is en#anced insulin sensiti/ity of adipose tissue, T#is later fact is demonstrated by t#e fact t#at CEFB>B knockout

does not abolis# adipogenesis but t#e WAT is not sensiti/e to t#e actions of insulin, T#e general model of transcription factor acti/ation of adipogenesis indicates t#at A>4%" 6TAT5" DL I" and DL 5 are acti/ated early and result in t#e transacti/ation of CEFB>J and CEFB>K, T#ese latter t!o factors in turn acti/ate t#e e0pression of 6RF>B4% and DL %5 !#ic# leads to t#e acti/ation of >>ARG and CEFB>B, It is important to keep in perspecti/e t#at it is not only transcription factor acti/ation of adipocyte precursors t#at controls adipogenesis, T#ere is also a balance e0erted at t#e le/el of transcription factor4mediated in#ibition of adipogenesis, 6ome of t#e factors t#at are anti4adipogeneic include members of t#e DrHppel4like factor family" DL ) and DL +, =ATA) and =ATA+ also e0ert anti4adipogenic acti/ity, =ATA factors are so4called because t#ey bind ?CA elements t#at contain a core =ATA se;uence, T!o of t#e interferon regulatory factor family of transcription factors" IR + and IR I" oppose t#e process of adipogenesis as !ell, T#e c#anges in t#e pattern of e0pression of transcription factors t#at control t#e o/erall process of adipogenesis is associated !it# c#anges in c#romatin dynamics, T#ese c#anges in c#romatin dynamics in/ol/e bot# #istone protein met#ylation and ?CA met#ylation e/ents, T#e c#romatin in pluripotent cells displays a #ig#ly dynamic nature !it# a #ig# le/el of decondensed ?CA, Mnce differentiation is induced t#ere is a c#ange in t#e o/erall pattern of met#ylated genes, Lineage4specific genes are demet#ylated !#ereas pluripotency genes are met#ylated resulting in transcriptional acti/ation and silencing" respecti/ely, As t#e process of adipocyte differentiation proceeds t#e genes encoding >>ARG and CEFB>B are obser/ed to be repositioned into t#e interior of t#e nucleus coincident !it# t#eir increased rates of transcription, 6ince M6Cs can be induced to differentiate into bone and muscle" as !ell as adipocyte" it is necessary t#at adipocyte differentiation genes suc# as >>ARG and CEFB>B be silenced if t#e induced pat#!ay is to bone or muscle, Associated !it# transcriptional silencing are protein comple0es termed co4repressors and associated !it# transcriptional acti/ation are comple0es termed co4acti/ators, W#en M6Cs are induced do!n t#e bone lineage t#e #istone + proteins in t#e >>ARG promoter region are met#ylated on lysine & 1identified as H+D&2 by a co4repressor comple0 t#at includes t#e #istone met#yltransferase 6FT?B% and t#e associated proteins CLD 1Cemo4like kinase2 and CH?N 1c#romodomain #elicase ?CA binding protein4N2, In addition to silencing of t#e >>ARG promoter" t#e acti/ity of t#e >>ARG protein on its target genes is also restricted by association !it# co4repressor comple0es, In preadipocytes >>ARG acti/ity is repressed by association !it# pRB and H?AC+ 1#istone deacetylase +2, T#e induction of differentiation results in t#e p#osp#orylation of pRB !#ic# leads to its release from t#e repressi/e comple0, T#is in turn results in t#e recruitment of #istone acetyltransferases 1HATs2 and t#e co4 acti/ator protein CB>Ep+** 1CB> is CRFB binding protein" !#ere CRFB is cAM>4response element4 binding protein2 to t#e >>ARG comple0 resulting in acti/ation of >>ARG target gene transcription, Cumerous e0periments #a/e begun to define t#e large array of #istone modifications t#at regulate t#e e0pression of genes in/ol/ed in o/erall adipogenesis particularly t#e e0pression of >>ARG, T#ese #istone modifying comple0es include HATs" H?ACs" #istone met#yltransferases 1HMTs2" and #istone demet#ylases 1H?Ms2, T#e general conse;uences of acti/ation of HATs and HMTs is t#e acti/ation of >>ARG e0pression andEor en#ancement of >>ARG acti/ity at its target gene promoters, Con/ersely" as e0pected" H?AC acti/ation results in in#ibited >>ARG acti/ity at its target gene promoters, back to t#e top

Regulation of Lipid Meta olism in Adipocytes

T#e triacylglycerols 1TA=2 found in WAT represent t#e ma7or energy reser/es of t#e body, T#e pool of

TA= is in a constant state of flu0 t#at is regulated by food intake and fasting and t#e conse;uences of t#ose dietary states on t#e le/els of pancreatic #ormones, In addition" adipose tissue fat pools c#ange as a result of ot#er #ormonal fluctuations" inflammatory processes" and pat#op#ysiology, T#e o/erall bioc#emistry of TA= metabolism is co/ered in t#e Lipid 6ynt#esis page and t#e atty Acid M0idation page, T#e aim of t#is section is to discuss in more detail t#e en3yme acti/ities t#at regulate o/erall adipose tissue TA= #omeostasis as !ell as t#e p#ysiological and #ormonal regulation of t#ese processes, It !as originally belie/ed t#at t#e liberation of fatty acids from adipose tissue TA= stores !as triggered e0clusi/ely /ia #ormonal acti/ation of #ormone4sensiti/e lipase 1H6L2, Ho!e/er" !#en H6L4null mice !ere generated it !as disco/ered t#at t#e process in/ol/es additional adipocyte H6L4independent TA= lipase acti/ities, 6ubse;uent researc# #as led to t#e identification of at least fi/e adipose tissue TA= lipases in addition to H6L, H6L #as demonstrated acti/ity !it# a !ide /ariety of substrates t#at includes TA=" diacylglycerols 1?A=2" and c#olesterol esters 1CFs2, W#en assayed in vitro t#e acti/ity of H6L is at least %*4fold #ig#er against ?A= t#an TA=, W#en acting on TA= or ?A= t#e acti/ity of H6L is greatest against fatty acids t#at are in t#e sn4% or sn4+ position of t#e glycerol backbone, @ntil recent e0periments in knock4out mice demonstrated ot#er!ise" H6L !as belie/ed to be t#e principle en3yme in/ol/ed in adipocyte TA= and ?A= #ydrolysis as !ell as t#e primary neutral c#olesteryl ester #ydrolase 1CCFH2 acti/ity, Alt#oug# H6L4null mice still e0#ibit TA= #ydrolase acti/ity" results from studies in t#ese mice indicate t#at H6L4mediated lipolysis is a significant contributor to o/erall fatty acid liberation from adipocytes, In mice lacking H6L t#ere is a reduced le/el of circulating free fatty acids and TA=s as !ell as reduced #epatic storage of TA=, T#ese results indicate t#at in t#e absence of H6L t#ere is insufficient adipose tissue lipolysis to support t#e normal cellular demands for energy from fatty acids nor for ade;uate OL?L synt#esis in t#e li/er, Results of studies on t#e role of H6L in o/erall adipose tissue lipolysis demonstrate t#at it is not strictly re;uired for t#e initiation of TA= #ydrolysis as originally t#oug#t, Ho!e/er" in H6L4null mice t#ere is an accumulation of ?A=s indicating t#at t#e critical role for H6L is in t#e liberation of fatty acid from ?A= !#ic# in turn generates monoacylglycerols 1MA=s2, T#e rate of fatty acid release from ?A=s is on t#e order of %*4 to +*4 times t#at t#e rate of release from TA=, To date t#e only ?A= lipase identified in adipose tissue is H6L, urt#er understanding of t#e role of H6L in o/erall adipose tissue lipolysis came from t#e identification of an additional TA= lipase t#at !as originally termed desnutrin, T#e o/erall structure of desnutrin indicates t#at it contains typical domains found in many ot#er lipases, 6ubse;uent to t#e identification of desnutrin anot#er lipase !as c#aracteri3ed and called adipose triglyceride lipase 1AT=L2, ?esnutrin and AT=L are t#e same protein so it is often designated desnutrinEAT=L, T#e desnutrinEAT=L gene is e0pressed predominantly in adipose tissue but also at muc# lo!er le/els in cardiac and skeletal muscle and t#e testes, T#e intracellular location of desnutrinEAT=L is t#e cytosol as !ell as in tig#t association !it# lipid droplets, T#e acti/ity of desnutrinEAT=L is specific for TA= as e/idenced in cell culture e0periments !#ere o/er4e0pression of t#e gene results in increased free fatty acid release !it# no effect on p#osp#olipid stores, In addition" desnutrinEAT=L #as limited acti/ity against ?A= since in t#ese and similar in vitro e0periments t#ere is a significant accumulation of ?A= compared to t#e same types of e0periments carried out !it# H6L, F0pression of desnutrinEAT=L is under t#e influence of dietary status, In fasting animals t#e le/el of desnutrinEAT=L increases and t#en declines follo!ing re4feeding, T#is dietary regulation of desnutrinEAT=L suggests t#at it may play a contributory role in t#e de/elopment of obesity" a #ypot#esis supported by t#e fact t#at in genetically obese mice 1obEob and dbEdb2 t#e le/el of desnutrinEAT=L e0pression is reduced, W#en e0periments are performed t#at artificially reduce t#e

le/el of desnutrinEAT=L RCA or protein t#ere is a significant drop in t#e le/el of free fatt acid release, ?emonstrating a synergy bet!een H6L and desnutrinEAT=L acti/ity" in cells !#ere bot# en3ymes are reduced t#ere is an additi/e le/el of reduction in free fatty acid release, A critical role for desnutrinEAT=L in TA= #ydrolysis in tissues ot#er t#an adipose tissue !as s#o!n by results of desnutrinEAT=L knock4out in mice, T#esse animals died at around %)4!eeks of age due to increased ectopic fat stores particularly in t#e #eart, In addition" total lipase acti/ities in se/eral tissues in addition to WAT and BAT !ere altered in t#e desnutrinEAT=L4null mice, T#ese data point to a critical role for desnutrinEAT=L in TA= #ydrolysis and fatty acid release not only from adipose tissue but also from tissues suc# as t#e #eart" skeletal muscle" and testes, In addition to H6L and desnutrinEAT=L" adipose tissue e0presses a number of ot#er TA= #ydrolases, Adipose tissue microsomes contain a non4H6L TA= lipase t#at is identified as triacylglycerol #ydrolase 1T=H" also called carbo0ylesterase +2, T=H contains typical lipase motifs and displays catalytic acti/ity against long4" medium4" and s#ort4c#ain TA=s as !ell as neutral c#olesteryl esters, Ho!e/er" T=H does not #ydroly3e p#osp#olipids , F0pression of T=H is seen predominantly in t#e li/er !#ere its primary functions are to mobili3e intracellular TA= stores and participate in t#e synt#esis of TA=4ric# OL?Ls, T=H e0pression is also seen in adipocytes and t#e le/el of its e0pression increases dramatically !#en preadipocytes differentiate into mature adipocytes, T#e adipose tissue regulation of T=H e0pression is effected" in part" /ia t#e action of CEFB>B, A related protein" identified as T=H4)" #as also been found predominantly e0pressed in t#e li/er but is also present in adipose tissue and kidney, T#ere is anot#er interesting protein e0pressed predominantly in adipose tissue !it# a significant degree of #omology to desnutrinEAT=L, T#is protein is called adiponutrin, W#ereas" adiponutrin s#o!s TA= lipase acti/ity !#en assayed in vitro" !#en it is o/er4e0pressed in cells it #as no effect on TA= #ydrolysis, In addition" !#ereas desnutrinEAT=L 1as !ell as most ot#er lipases2 e0pression is increased in t#e fasting state and decreased follo!ing re4feeding" adiponutrin e0pression e0#ibits t#e opposite pattern, In fasted animals adiponutrin mRCA is essentially undetectable and its le/els increase dramatically in t#e re4fed state, It appears t#at alt#oug# t#is en3yme is a member of t#e lipase family of en3ymes it plays an anabolic rat#er t#an a catabolic role in adipocyte lipid metabolism, T#e final step in t#e complete #ydrolysis of TA=s occurs !#en glycerol and t#e last fatty acid are released from MA=s by MA= lipase, T#is en3yme possesses no catalytic acti/ity to!ards TA=s or ?A=s nor c#olesteryl esters, Cumerous ot#er proteins in addition to t#e lipases are in/ol/ed in o/erall TA= #omeostasis in adipose tissue, 6e/eral of t#ese ot#er proteins are associated !it# t#e lipid droplets inside t#e cell suc# as t#e perilipins" adipose fatty acid4binding protein 1a AB>2" and ca/eolin4%, Additional proteins important in o/erall TA= metabolism include a;uaporin N 1a !ater and glycerol transport protein2 and lipotransin, T#e perilipins play a role in restricting access of TA= lipases to substrates in order to pre/ent unrestrained #ydrolysis in t#e un4stimulated state, T#e role of a AB> is to carry free fatty acids from t#e fat droplet to t#e plasma membrane !#ere t#ey can be released to t#e plasma, T#e glycerol t#at is released from TA=s is e0ported /ia t#e action of a;uaporin N as s#o!n by e0periments in mice lacking e0pression of t#is gene, T#ese mice release free fatty acids upon stimulation of adipose tissue !it# catec#olamines but no glycerol is released, T#e role of lipotransin is belie/ed to be in s#uttling H6L from t#e cytosol to t#e lipid droplet upon stimulation of adipocytes, W#et#er adipose tissue stores fatty acids as TA=s or releases t#em for energy production by ot#er tissues is dependent upon t#e dietary" #ormonal and p#ysiological status of t#e organism, T#e primary mec#anism for t#e stimulation of adipose tissue TA= #ydrolysis is discussed in t#e fatty acid o0idation page, In brief" catec#olamines suc# as epinep#rine and norepinep#rine" as !ell as t#e pancreatic #ormone glucagon" bind to t#eir cognate receptors on adipocytes triggering acti/ation of adenylate cyclase resulting in increased le/els of cAM>, In turn t#e cAM> acti/ates >DA !#ic# t#en

p#osp#orylates and acti/ates H6L, Mf significance is t#e fact t#at acti/ation of >DA in H6L4null mice also results in en#anced TA= #ydrolysis albeit at a le/el muc# lo!er t#an in t#e presence of acti/e H6L, T#is indicates t#at t#ere are >DA4mediated e/ents in adipose tissue TA= lipolysis t#at are distinct from t#e classic H6L4mediated process, T#e primary c#ange in adipose tissue TA= lipolysis follo!ing feeding is e0erted /ia t#e actions of insulin, T#e cAM>4dependent c#anges t#at occur in response to insulin binding are effected by acti/ation of p#osp#odiesterase +B !#ic# #ydroly3es cAM> rendering >DA muc# less acti/e, T#e acti/ation of p#osp#odiesterase +B occurs /ia >DBEAkt4mediated p#osp#orylation !#ic# itself is acti/ated follo!ing insulin binding its receptor, T#e principle cAM>4independent mec#anism for insulin4mediated reduction in TA= lipolysis is due to t#e stimulation of protein p#osp#atase4% !#ic# remo/es t#e p#osp#ate from H6L rendering it muc# less acti/e, T#e acti/ity of H6L is also affected /ia p#osp#orylation by AM>D, In t#is case t#e p#osp#orylation in#ibits t#e en3yme, In#ibition of H6L by AM>D may seem parado0ical since t#e release of fatty acids stored in TA=s !ould seem necessary to promote t#e production of AT> /ia fatty acid o0idation and t#e ma7or function of AM>D is to s#ift cells to AT> production from AT> consumption, T#is paradigm can be e0plained if one considers t#at if t#e fatty acids t#at are released from TA=s are not consumed t#ey !ill be recycled back into TA=s at t#e e0pense of AT> consumption, T#us" it #as been proposed t#at in#ibition of H6L by AM>D mediated4 p#osp#orylation is a mec#anism to ensure t#at t#e rate of fatty acid release does not e0ceed t#e rate at !#ic# t#ey are utili3ed eit#er by e0port or o0idation, back to t#e top

Ta le of Adipose Tissue !ormones and "yto#ines

Adipose tissue produces and releases a /ast array of protein signals including gro!t# factors" cytokines" c#emokines" acute p#ase proteins" complement4like factors" and ad#esion molecules, T#e Table belo! describes se/eral of t#e adipocyte proteins in more detail !it# leptin" adiponectin" and resistin discussed in greater detail in t#e follo!ing sections, T#e proteins of t#e /arious signaling processes are listed belo!, Cot all WAT secretes t#e same adipokines as is e/ident from studies of differences in adipose tissue function in /arious anatomical regions of t#e body as described abo/e, T#is is most significant !#en considering t#e clinical risks associated !it# increased adipose tissue mass, or e0ample" increases in /isceral WAT" e/en !#en subcutaneous fat depots are not increased" carry a greater metabolic risk for insulin resistance and diabetes and cardio/ascular disease, $ro%th and angiogenic factors: fibroblast gro!t# factors 1 = s2" insulin4like gro!t# factor4% 1I= 4 %2" #epatocyte gro!t# factor 1H= 2" ner/e gro!t# factor 1C= 2" /ascular endot#elial cell gro!t# factor 1OF= 2" transforming gro!t# factor4J 1T= J2" angiopoietin4%" angiopoietin4)" tissue factor 1T " factor +2 "yto#ines: IL4%J" IL4I" IL4'" IL4P" IL4%*" IL4%P" TC B" macrop#age migration in#ibitory factor 1MI 2 "omplement&li#e factors: adipsin" adiponectin" acylation stimulating protein 1A6>2 Adhesion molecules and '"M components: B)4macroglobulin" /ascular cell ad#esion molecule4% 1OCAM4%2" intercellular ad#esion molecule4% 1ICAM4%2" collagen I" collagen III" collagen IO" collagen OI" fibronectin" matri0 metalloproteinase % 1MM>%2" MM>N" MM>&" MM>%*" MM>%%" MM>%I" MM>%5" lysyl o0idase

Acute phase proteins: C4reacti/e protein 1CR>2" serum amyloid A+ 16AA+2" plasminogen acti/ator in#ibitor4% 1>AI4%2" #aptoglobin "hemo#ines: c#emerin" monocyte c#emotactic protein4% 1MC>4%2" macrop#age in#ibitory protein4% alp#a 1MI>4%B2" regulated upon acti/ation" normally T cell e0pressed and secreted 1RACTF62 Meta olic processes: adipocyte fatty acid binding protein 1a>)2" apolipoprotein F 1apoF2" resistin" omentin" /aspin" apelin" retinol binding protein I 1RB>I2" /isfatin" leptin (ther processes: CMQ pat#!ay products >=F) and >=I) 1prostacyclin2" nitric o0ide synt#ase pat#!ay" renin4angiotensin system" tissue in#ibitors of metalloproteinases 1TIM>s2 In addition to t#ese secreted factors adipose tissue produces se/eral plasma membrane and nuclear receptors t#at can trigger c#anges in adipose tissue function, >lasma membrane receptors include t#ose for insulin" glucagon" gro!t# #ormone" adiponectin" gastrin" and angiotensin4II, Cuclear receptors include pero0isome proliferator4acti/ated receptor4G 1>>ARG2" estrogens" androgens" /itamin ?" t#yroid #ormone" progesterone" and glucocorticoids, actor adiponectin also called adipocyte complement factor %;4related protein 1ACR>+*2" and adipoR adipsin 1also called complement factor ?2 >rincipal 6ource Ma7or Action

adipocytes

see belo!

adipocytes" li/er" monocytes" macrop#ages

rate limiting en3yme in complement acti/ation le/els increase !it# increased insulin" e0erts positi/e #emodynamic effects" may regulate insulin resistance by facilitating e0pression of BAT uncoupling proteins 1e,g, @C>%" t#ermogenin2 modulates e0pression of adipocyte genes in/ol/ed in glucose and lipid #omeostasis suc# as =L@TI and fatty acid synt#ase 1 A62S potent anti4 inflammatory effects on macrop#ages e0pressing t#e c#emerin receptor 1c#emokine4like receptor4%" CMDLR%2 is a member of t#e pentra0in family of calcium4dependent ligand binding proteinsS assists complement interaction !it# foreign and damaged cellsS

apelin

adipocytes" /ascular stromal cells" #eart

c#emerin

adipocytes" li/er

C4reacti/e protein 1CR>2

#epatocytes" adipocytes

en#ances p#agocytosis by macrop#agesS le/els of e0pression regulated by circulating IL4'S modulates endot#elial cell functions by inducing e0pression of /arious cell ad#esion molecules" e,g, ICAM4%" OCAM4%" and selectinsS induces MC>4 % e0pression in endot#eliumS attenuates CM production by do!nregulating CM6 e0pressionS increase e0pression and acti/ity of >AI4% adipocytes" #epatocytes" acti/ated T#) cells" and antigen4 presenting cells 1A>Cs2 predominantly adipocytes" mammary gland" intestine" muscle" placenta

IL4'

acute p#ase response" B cell proliferation" t#rombopoiesis" synergistic !it# IL4% and TC on T cells

leptin

see belo!

monocyte c#emotactic protein4% 1MC>4%2

leukocytes" adipocytes

is a c#emokine defined as CCL) 1C4C motif" ligand )2S recruits monocytes" T cells" and dendritic cells to sites of infection and tissue in7ury t#e omentum is one of t#e peritoneal folds t#at connects t#e stomac# to ot#er abdominal tissues" en#ances insulin4 stimulated glucose transport" le/els in t#e blood in/ersely correlated !it# obesity and insulin resistance

omentin

/isceral stromal /ascular cells of omental adipose tissue

plasminogen4acti/ator in#ibitor4 % 1>AI4%2

adipocytes" monocytes" placenta" platelets" endometrium adipocytes" spleen" monocytes" macrop#ages" lung" kidney" bone

see t#e Blood Coagulation page for more details

resistin

see belo!

marro!" placenta induces e0pression of ot#er autocrine gro!t# factors" increases cellular responsi/eness to gro!t# factors and induces signaling pat#!ays t#at lead to proliferation is a serine protease in#ibitor" le/els decrease !it# !orsening diabetes" increase !it# obesity and impaired insulin sensiti/ity conflicting results relati/e to insulin receptor binding but blocking insulin receptor signaling interferes !it# effects of eCamptS c#anges in eCampt acti/ity occur during fasting and positi/ely regulate t#e acti/ity of t#e CA?A4dependent deacetylase 6IRT% leading to alterations in gene e0pression

TC B

primarily acti/ated macrop#ages" adipocytes

/aspin

/isceral and subcutaneous adipose tissue

/isfatinS also called pre4B cell4 en#ancing factor 1>BF 2S reported to be t#e e0tracellular /ersion of t#e en3yme nicotinamide p#osp#oribosyltransferase 1Campt or eCampt2" #o!e/er" t#e original paper claiming t#is #as been retracted back to t#e top /isceral !#ite adipose tissue

Leptin
Leptin is %'k?a peptide !#ose central function is t#e regulation of o/erall body !eig#t by limiting food intake and increasing energy e0penditure, Ho!e/er" leptin is also in/ol/ed in t#e regulation of t#e neuroendocrine a0is" inflammatory responses" blood pressure" and bone mass, T#e #uman leptin gene is t#e #omolog of t#e mouse 8obese8 gene 1symbol MB2 t#at !as originally identified in mice #arboring a mutation resulting in a se/erely obese p#enotype, Leptin4deficient 1obEob2 and leptin receptor4deficient 1dbEdb2 mice e0#ibit numerous disruption in energy" #ormonal" and immune system balance, T#ese mice are obese" display #ormonal imbalances" #a/e defects in t#ermoregulation" #a/e #ematopoietic defects and are infertile, Le/els of leptin increase in t#e serum in obese indi/iduals and drop during !eig#t loss, T#ere is a direct correlation bet!een t#e amount of body fat an indi/idual carries and t#e circulating le/els of leptin, Leptin acti/ates t#e anore0igenic a0is 1appetite suppression2 in t#e arcuate nucleus 1ARC2 of t#e #ypot#alamus by increasing t#e fre;uency of action potentials in t#e #ypot#alamic >MMC neurons by depolari3ation t#roug# a nonspecific cation c#annel and by reduced in#ibition by local ore0igenic neuropeptide4T 1C>T2 neurons, Leptin functions by binding to its receptor !#ic# is a member of t#e cytokine receptor family, Leptin and its receptors possess structural similarities to t#e IL4' family of cytokines and t#e class I cytokine receptor family, T#e leptin receptor mRCA is alternati/ely spliced resulting in si0 different products, T#e leptin receptors are named Mb4R" MB4Rb" MB4Rc" Mb4Rd" Mb4Re" and Mb4Rf, T#e MB4Rb mRCA

encodes t#e long form of t#e leptin receptor 1also called LF>R4B2 and is e0pressed primarily in t#e #ypot#alamus but is also e0pressed in cells of t#e innate and adapti/e immune systems as !ell as in macrop#ages, T#e ot#er receptor subtypes are e0pressed in numerous tissues including muscle" li/er" kidney" adrenal glands" leukocytes" and /ascular endot#elium, Acti/ation of t#e receptor leads to increased p#osp#atidylinositol4+4kinase 1>I+D2 and AM>D acti/ity /ia acti/ation of t#e :akE6TAT signaling pat#!ay, Mne effect of t#e acti/ation of t#e :akE6TAT pat#!ay is acti/ation of suppressor of cytokine signaling + 16MC6+2 !#ic# t#en in#ibits leptin signaling in a negati/e feed4back loop, Leptin binding its receptor also results in t#e acti/ation of mTMR bot# in t#e #ypot#alamus and in perip#eral tissues, T#e role of mTMR in t#e regulation of protein synt#esis is co/ered in bot# t#e >rotein 6ynt#esis page as !ell as in t#e Insulin unctions page, T#e role of leptin in t#e acti/ation of mTMR function is an important factor in t#e ability of leptin to acti/ate macrop#ages, An interesting aspect of t#e role of leptin in mTMR function is t#at !it#in mature adipocytes leptin synt#esis itself is dependent on mTMR acti/ation, =i/en t#at leptin le/els rise in t#e serum of obese indi/iduals and t#at leptin interaction !it# macrop#ages leads to increased macrop#age inflammatory processes" it is not surprising t#at t#ere is a direct correlation bet!een leptin le/els and t#e de/elopment of at#erosclerosis,

W#en leptin binds to its receptor 1LF>R4B2 t#e receptor undergoes a conformational c#ange t#at acti/ates t#e receptor4associated :ak) tyrosine kinase, Acti/ated :ak) !ill autop#osp#rylate itself as !ell as p#osp#orylate t#e tyrosine 1T2 residues in LF>R4B at positions &P5" %*NN" and %%+P, >#osp#orylated T4&P5 ser/es as a docking site for 6H>) 16H) domain containing protein tyrosine p#osp#atase" also called >T>%?2, T#e gene t#at encodes 6H>) is identified as >T>C%%, >#osp#orylated T4%*NN ser/es as a docking site for 6TAT5 1signal transduction and acti/ation of transcription 52, >#osp#orylated T4%%+P ser/es as a docking site for 6TAT+, W#en 6H>)" 6TAT5" and 6TAT+ bind to p#osp#orylated LF>R4B t#ey t#emsel/es are acti/ated by :ak)4mediated p#osp#orylation, Acti/ated 6H>) in turn acti/ates t#e FRD%E) 1e0tracellular4regulated kinase %E)2 signal pat#!ay t#at results in increasd transcription of t#e F=R4% gene, Acti/ated 6TAT+ in turn acti/ates t#e transcription of 6MC6+ 1suppressor of cytokine signaling +2, 6MC6+ !ill t#en interact !it# T4&P5 and attenuate signaling from 6H>) as !ell as interact !it# :ak) and attenuate its tyrosine kinase acti/ity resulting in a negati/e feed4back loop, Leptin e0pression is under comple0 control and a number of transcription factor binding sites #a/e been identified in t#e promoter region of t#e leptin gene, Leptin le/els are #ig#er in age and !eig#t4 matc#ed females compared !it# males, T#is is partially due to t#e in#ibition of leptin e0pression by androgens and t#e stimulation of e0pression by estrogens, Leptin e0pression #as been s#o!n to be increased by se0 steroids" glucocorticoids" cytokines" and to0ins released during acute infection, T#e sympat#etic ner/ous system triggers a reduction in circulating leptin le/els /ia t#e release of catec#olamines, T#is effect of catec#olamines #as been s#o!n to be due to acti/ation of J4adrenergic receptor signaling, In addition to effects on appetite e0erted /ia central ner/ous system functions" leptin is also kno!n to e0ert effects on inflammatory processes, Leptin modulates perip#eral T cell function leading to increased le/els of T #elper cell type % cytokines, In addition leptin reduces t#ymocyte apoptosis and increases t#ymic cellularity, T#ese result correlate !ell !it# obser/ations demonstrating a reduced capacity for immunologic defense !#en leptin le/els are lo!, Ho!e/er" too muc# leptin is not beneficial as #ig# concentrations can result in an abnormally strong immune response !#ic# predisposes an indi/idual to autoimmune p#enomena, Acute stimulation !it# pro4inflammatory cytokines results in increased serum le/els of leptin" !#ereas" c#ronic stimulation by IL4%" IL4'" or TC B leads to reduced le/els of serum leptin,

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Adiponectin
Adiponectin !as independently isolated by four different laboratories leading to different names, Ho!e/er" adiponectin is considered t#e standard name for t#is adipose tissue4specific protein, Mt#er names include adipocyte complement related protein of +*k?a 1ACR>+*2 because of its #omology to complement factor %; 1C%;2" adipoR" gelatin4binding protein )Pk?a 1B=>)P2" and adipocyte most abundant gene transcript % 1apM%2, T#e ma7or biological actions of adiponectin are increases in insulin sensiti/ity and fatty acid o0idation, T#e adiponectin gene is located on c#romosome +;)N,+ spanning %' kbpand composed of + e0ons, T#e adiponectin gene does not contain a typical typical TATA4bo0 promoter element upstream of t#e transcriptional start site, Adiponectin contains a C4terminal globular domain !#ic# #arbors t#e #omology to C%; and an C4terminal collagen4like domain, T#e globular domain allo!s for a #omotrimeric association of t#e protein forming t#e functional structure of t#e protein, T#e association of t#e subunits is suc# t#at t!o trimeric globular domains interact !it# a single stalk of collagen domains formed from t!o trimers, T#is comple0 structure is similar to t#e TC superfamily of proteins despite t#ere being no amino acid se;uence #omology bet!een adiponectin and TC proteins, Wit#in t#e circulation" adiponectin e0ists in bot# a full4lengt# form as !ell as a globular form t#at is t#e result of proteolytic clea/age of t#e full4lengt# protein, T#e #ormone forms comple0 structures suc# t#at it can be found as a trimer" #e0amer" and as t#e #ig# molecular !eig#t oligomer, In addition to t#e comple0 structure" adiponectin is glycosylated" a modification t#at is essential to its acti/ity, Adiponectin acti/ity is in#ibited by adrenergic stimulation and glucocorticoids, F0pression and release of adiponectin is stimulated by insulin and in#ibited by TC 4B, Con/ersely" adiponectin e0erts inflammatory modulation by reducing t#e production and acti/ity of TC 4B and IL4', @nlike leptin" le/els of adiponectin are reduced in obese indi/iduals and increased in patients !it# anore0ia ner/osa, T#ere are se04related differences in adiponectin le/els as !ell similar to t#at seen for leptin !#ere age and !eig#t matc#ed males #a/e lo!er le/els t#an females, In patients !it# type ) diabetes" le/els of adiponectin are significantly reduced, Adiponectin functions by interaction !it# specific cell4surface receptors and at least t!o receptors #a/e been identified, AdipoR% is e0pressed at #ig#est le/els in skeletal muscle and AdipoR) in primarily e0pressed in t#e li/er, F0pression of adiponectin receptors is also seen in /arious regions of t#e brain, AdipoR% is #ig#ly e0pressed in t#e medial prefrontal corte0" #ippocampus" and t#e amygdala, W#ereas" AdipoR) e0pression in t#e brain is restricted to t#e #ippocampus and specific #ypot#alamic nuclei, AdipoR% is a #ig#4affinity receptor for globular adiponectin and #as lo! affinity for t#e full4 lengt# adiponectin, In contrast" AdipoR) #as intermediate affinity for globular and full4lengt# adiponectin, Alt#oug# t#ese receptors contain se/en transmembrane domains typical of t#e serpentine family of =4protein coupled receptors 1=>CRs2" t#ey are structurally distinct from t#e =>CR class, T#e AdipoRs stimulate t#e p#osp#orylation and acti/ation of AM>D, T#e adiponectin4mediated acti/ation of AM>D results in increased glucose uptake" increased fatty acid o0idation" increased p#osp#orylation and in#ibition of acetylCoA carbo0ylase 1ACC2 in muscle, In t#e li/er t#e result is reduced acti/ity of gluconeogenic en3ymes and glucose output, Adiponectin also plays an important role in #emostasis by suppressing TC B4mediated inflammatory c#anges in endot#elial cell responses and in#ibiting /ascular smoot# muscle cell proliferation, Acti/ation of AM>D acti/ity in endot#elial cells results in increased fatty acid o0idation and acti/ation

of endot#elial CM synt#ase 1eCM62, back to t#e top

Resistin
Resistin is a %) k?a protein t#at !as originally identified in mice in a screen for genes suppressed by an agonist of t#e pero0isome proliferator4acti/ated receptor4G 1>>ARG2, T#e name resistin deri/es from t#e original obser/ation t#at t#is protein induced insulin resistance in mice, Resistin belongs to a family of four proteins referred to as ILL proteins for 8found in inflammatory 3one8, Resistin is t#us" also referred to as ILL+, Alt#oug# resistin is e0pressed in adipocytes" in #umans it appears t#at macrop#ages may be t#e most important source of t#e protein, In mice resistin e0pression increases during adipocyte differentiation and le/els of resistin increase in diet4induced obesity, Reduction in resistin le/els is associated !it# increased AM>D acti/ity in t#e li/er !#ic# leads to decreased e0pression of gluconeogenic en3ymes and conse;uent reduction in #epatic glucose production, Con/ersely" ele/ation in resistin le/els is associated !it# increased #epatic glucose production and glucose intolerance, W#et#er t#ese same responses to resitin are e/ident in #uman is still under in/estigation, W#at is kno!n is t#at o/ere0pression of resistin in #uman #eptocytes impairs insulin4stimulated glucose uptake and glycogen synt#esis, >art of t#e mec#anism for impaired glycogen synt#esis is t#at resistin decreases t#e e0pression of one of t#e insulin receptor substrates 1IR64)2 !#ic# is in/ol/ed in t#e acti/ation of >I+D, T#e >I+D4acti/ated signal pat#!ay leads to t#e p#osp#orylation and in#ibition of glycogen synt#ase kinase +J 1=6D+J2, @n4 p#osp#orylated =6D+J !ould normally p#osp#orylate and in#ibit glycogen synt#ase acti/ity, Loss of t#is pat#!ay t#en leads to a #ig#er rate of glycogen synt#ase in#ibition by =6D+J4mediated p#osp#orylation, Resistin also e0erts effects on t#e immune system and t#e /asculature, Resistin modulates endot#elial cell function by en#ancing e0pression of t#e cell ad#esion molecule OCAM4% and t#e c#emoattractant MC>4%, Resistin #as also been s#o!n to e0ert a pro4inflammatory effect on smoot# muscle cells, back to t#e top

Inflammatory Functions of Adipose Tissue

T#e significance of inflammatory responses elicited /ia secretion of adipose tissue4deri/ed 1WAT2 cytokines relates to t#e fact t#at t#eir production and secretion is increased in obese indi/iduals, T#ere is a gro!ing body of e/idence t#at demonstrates a direct link bet!een t#e c#anges in adipose tissue function in obesity and t#e de/elopment of type ) diabetes and t#e metabolic syndrome, Mne key c#ange in adipose tissue during obesity is an increase in t#e percentage of macrop#ages resident !it#in t#e tissue, Macrop#ages are a primary source of pro4inflammatory cytokines secreted by adipose tissue, T#e primary adipokine responsible for t#is infiltration is monocyte c#emotactic protein4% 1MC>4%2, As t#e le/el of macrop#ages increases in adipose tissue t#e le/el of pro4inflammatory cytokine secretion by t#e tissue increases, Circulating le/els of bot# TC 4B and IL4' increase as adipose tissue e0pands in obesity and t#ese c#anges are directly correlated !it# insulin resistance and t#e de/elopment of type ) diabetes, As indicated abo/e adiponectin plays an important anti4inflammatory role by suppressing t#e production of bot# TC 4B and IL4', Ho!e/er" as t#e le/el of macrop#age

infiltration increases in obesity t#e increased secretion of TC 4B results in suppression of adiponectin production and secretion, Adipose tissue4deri/ed IL4' accounts for appro0imately +*9 of t#e circulating le/el of t#is pro4inflammatory cytokine, Oisceral WAT #as been s#o!n to secrete a #ig#er percentage of t#e circulating IL4' t#an subcutaneous WAT and t#is fact correlates !it# t#e negati/e effects of a pro4inflammatory status 1as is t#e case !it# obesity2 on t#e organs, As WAT density increases t#ere is an associated increase in IL4' secretion !#ic# is correlated to an increase in t#e circulating le/els of acute4p#ase proteins suc# as CR>, In addition to t#e effects of TC 4B on adiponectin production t#e cytokine also directly affects insulin sensiti/ity by in#ibiting insulin receptor signaling, T#is effect of TC 4B is t#e result of increased insulin receptor serine p#osp#orylation, TC 4B 1as !ell as IL4'2 trigger t#e release of pro4inflammatory cytokines suc# as :@C C4terminal kinase 1:CD2 and nuclear factor kappa B 1C UB2, Acti/ation of :CD leads to t#e insulin receptor serine p#osp#orylation as !ell as insulin receptor substrate 1IR62 serine p#osp#orylation, Bot# of t#ese TC 4B4mediated serine p#osp#orylations lead to impaired insulin receptor signaling, :CD and C UB acti/ate pro4inflammatory genes !#ic# results in a self4perpetuating cycle of increased inflammatory cytokine release, TC 4B also decreases endot#elial nitric o0ide synt#ase 1eCM62 resulting in decreased le/els of CM as !ell as decreased e0pression of mitoc#ondrial o0idati/e p#osp#orylation genes, T#is leads increased o0idati/e stress" accumulation of reacti/e o0ygen species 1RM62" and increased endoplasmic reticulum stress, T#e responses of t#e cell to t#e increased o0idati/e stress is furt#er increases in C kB releases and t#us" increased inflammatory processes, T#e effects of adipocyte4deri/ed TC 4B and IL4' demonstrates a clear correlation bet!een obesity and a pro4inflammatory role for adipocytes, Alt#oug# lymp#ocytes 1T4cells and B4cells2 are not constituents of adipose tissue t#ey are p#ysically associated !it#in t#e lymp# nodes, Lymp# tissue is surrounded by pericapsular adipose tissue !#ic# increases in density !it# increasing obesity, T#is close association allo!s for )4!ay paracrine interactions bet!een t#e lymp# and adipose tissues, Mne important interaction bet!een lymp# tissue and WAT in/ol/es leptin, As indicated abo/e" leptin plays a ma7or role in t#e regulation of appetite and energy balance and t#e circulating le/els of leptin increases as adipose tissue mass increases, Leptin #as also been s#o!n to modulate T4cell function" t#us demonstrating a pro4inflammatory role for leptin, Leptin protects T4cells from apoptosis and en#ances t#e s!itc#ing of T4cells to a T#% response, >ro4 inflammatory cytokine production and release from T4cells is increased as a result of leptin action, Leptin induces a number of signal transduction pat#!ays in immune and endot#elial cells as outlined abo/e, Leptin effects on t#e /ascular endot#elium are also pro4inflammatory, F0pression of ad#esion molecules is increased by leptin binding its receptor on endot#elial cells, T#is results in an increased ability of neutrop#ils and ot#er leukocytes to ad#ere to t#e endot#elium leading to increased local inflammatory processes, back to t#e top

Meta olic Functions of Bro%n Adipose Tissue) BAT

It !as originally t#oug#t t#at BAT !as present in #umans only during t#e neonatal period, Ho!e/er" recent e/idence #as demonstrated t#at adults retain some metabolically acti/e BAT deposits t#at respond to cold and sympat#etic ner/ous system acti/ation, T#e most studied regulator of t#e action of BAT is norepinep#rine,

Wit#in BAT" norepinep#rine interacts !it# all t#ree types of adrenergic receptors 1B%" B)" and J2 eac# of !#ic# acti/ates distinct signaling pat#!ays in t#e bro!n adipocyte, Wit# respect to t#e J4 adrenoreceptors" t#e J+ subtype is t#e most significant" J% receptors are e0pressed in bro!n preadipocytes but not mature adipocytes and J) receptors are e0pressed in BAT but not bro!n adipocytes t#emsel/es, Mf significance to t#e role of BAT in t#ermogenesis and t#e ma7or role of J+4 adrenoreceptors is t#e fact t#at t#ese receptors are not sub7ect to desensiti3ation as are t#e J% and J) receptors, Ho!e/er" t#is is not to say t#at continuous adrenergic stimulation #as no negati/e effect in BAT, Indeed" t#e le/el of J+ receptor e0pression is do!nregulated during continuous adrenergic stimulation, Ho!e/er" t#is effect is transient and t#e mRCA rapidly re4accumulates after termination of t#e stimulatory signal, 6ignal transduction e/ents triggered by adrenergic stimulation of BAT are effected /ia t#e acti/ation of =s type =4proteins, =s proteins couple to t#e acti/ation of adenylate cyclase resulting in increased cAM> production and acti/ation of >DA, or more information on t#e types of =4proteins /isit t#e 6ignal Transduction page, Acti/ation of H6L leads to release of free fatty acids !#ic# are taken up by t#e mitoc#ondria similarly as t#ey !ould be for purposes of o0idation" #o!e/er" in BAT t#ey interact !it# and acti/ate t#e proton gradient uncoupling acti/ity of uncoupling protein % 1@C>%" also kno!n as t#ermogenin2, @ncoupling t#e proton gradient releases t#e energy of t#at gradient as #eat, T#e t#ermogenic function of BAT is outlined in t#e igure belo!, In addition to stimulating #eat production in BAT" norepinep#rine promotes t#e proliferation of bro!n preadipocytes" promotes t#e differentiation of mature bro!n adipocytes" in#ibits apoptosis of bro!n adipocytes" and regulates t#e e0pression of t#e @C>% gene,

!ormonal generation of heat in ro%n fat

Interestingly" norepinep#rine stimulation of B)4adrenergic receptors on BAT #as t#e opposite effect to J+ receptor acti/ation, T#is is due to t#e fact t#at t#e B) receptors are coupled to =i type =4proteins !#ose acti/ation results in in#ibition of adenylate cyclase, T#e precise p#ysiological significance of t#is parallel response of BAT to norepinep#rine is as yet not fully appreciated, It is unclear #o!" or !#en" BAT balances t#e t#ermogenic stimulatory actions of J+ receptors !it# t#e in#ibitory actions of B) receptors but it may allo! t#e cells to modulate t#eir responses to norepinep#rine under /arying p#ysiological conditions, 6imilar to t#e endocrine role of WAT" BAT also synt#esi3es and secretes numerous factors, Ho!e/er"

due to t#e relati/ely small o/erall si3e of bro!n fat compared to !#ite fat t#e role of factors secreted from BAT ser/e many autocrine and paracrine roles, T#is is not to say t#at BAT doesnVt #a/e a potential endocrine role it is 7ust not as !ell establis#ed as t#e endocrine role of WAT, 6e/eral proteins produced from BAT ser/e autocrine functions suc# as adipsin" fibroblast gro!t# factor ) 1 = )2" insulin4like gro!t# factor4% 1I= 4%2" prostaglandins" and adenosine, Adipsin 1also kno!n as complement factor ?2 clea/es t#e complement protein C+ into C+a and C+b, C+a is inacti/ated to C+desArg !#ic# is more commonly referred to as acylation4stimulating protein 1A6>2, A6> stimulates TA= synt#esis and glucose uptake in WAT, T#e le/el of C+ e0pression is muc# #ig#er in WAT t#an in BAT and A6> #as not been found in BAT so t#e precise function of adipsin in BAT is not clear alt#oug# it could be functional !#en BAT is in a t#ermogenically inacti/e state and is functioning in an anabolic state to store TA=s, Acute and c#ronic cold e0posure results in increased = ) e0pression in BAT as does norepinep#rine, T#e = receptor % 1 = R%2 gene is also e0pressed in BAT and t#e result of = ) acti/ation of t#e receptor is increased bro!n adipocyte cell density, 6imilarly" during cold e0posure t#e le/els of I= 4% mRCA increase and I= 4% receptors are #ig#ly e0pressed on bro!n adipocytes, I= 4% action can pre/ent TC 4B4induced apoptosis in bro!n fat, >aracrine factors synt#esi3ed by BAT include ner/e gro!t# factor 1C= 2" /ascular endot#elial cell gro!t# factor 1OF= 2" angiotensinogen" and CM, T#e secretion of C= occurs primarily from proliferating bro!n preadipocytes and in t#is capacity is belie/ed to promote sympat#etic inner/ation of t#e tissue !#ic# in turn permits increased norepinep#rine stimulation of t#e cells in BAT, F0pression of OF= is #ig# in proliferating and mature bro!n adipocytes and t#e OF= receptors" LD4% and LD4I" are e0pressed in BAT, T#e e0pression of OF= in BAT may promote and maintain t#e #ig# le/el of /asculari3ation in t#is tissue, Corepinep#rine stimulation and cold stress bot# result in increased le/els of OF= e0pression in BAT, Bot# inducible nitric o0ide synt#ase 1iCM62 and endot#elial CM6 1eCM62 are e0pressed in BAT, In addition to its e0pression in t#e endot#elial cells of BAT" eCM6 e0pression is seen in bro!n adipocytes, Corepinep#rine stimulation of BAT" as !ell as bro!n adipocytes in culture" results in increase CM production, Wit#in bro!n adipocytes t#e production of CM may lead to in#ibition of mitoc#ondrial o0idation, Wit#in BAT t#e production of CM likely promotes rapid increases in blood flo!, back to t#e top Return to T#e Medical Bioc#emistry >age
Mic#ael W Ding" >#? - $ %&&'()*%+ t#emedicalbioc#emistrypage,org" LLC - info . t#emedicalbioc#emistrypage,org

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