ADIPOSE

Introduction to Adipose Tissue
Adipose tissue is not merely an organ designed to passively store excess carbon in
the form of fatty acids esterified to glycerol (triglycerides). Mature adipocytes
synthesize and secrete numerous enzymes, growth factors, cytokines and hormones
that are involved in overall energy homeostasis. Many of the factors that influence
adipogenesis are also involved in diverse processes in the body including lipid
homeostasis and modulation of inflammatory responses. In addition, a number of
proteins secreted by adipocytes play important roles in these same processes. In
fact recent evidence has demonstrated that many factors secreted from adipocytes
are pro-inflammatory mediators and these proteins have been termed
adipocytokines or adipokines. There are currently over 50 different adipokines
recognized as being secreted from adipose tissue. These adipokines are implicated
in the modulation of a range of physiological responses that globally includes
appetite control and energy balance. Specific metabolic processes regulated by
adipose tissue include lipid metabolism, glucose homeostasis, inflammation,
angiogenesis, hemostasis (regulation of blood coagulation), and blood pressure.
The major form of adipose tissue in mammals (commonly referred to as "fat") is
white adipose tissue, WAT. Specialized adipose tissue that is primarily tasked with
thermogenesis, especially in the neonate, is brown adipose tissue, BAT. BAT is socalled because it is darkly pigmented due to the high density of mitochondria rich in
cytochromes. BAT specializes in the production of heat (adaptive thermogenesis)
and lipid oxidation.
Histological section of adipose tissue demonstrating distinctive morphology
of WAT and BAT. White adipocytes occupy the left side of the image and brown
adipocytes the right side. As described below white adipocytes are generally
rounded with over 90% of the cell volume taken up by a single fat droplet. The few
small mitochondria and the nucleus are compressed to the very edge of the white
adipocyte. The brown adipocytes are smaller in overall size, polygonal in shape,
contain several small lipid droplets and high numbers of large mitochondria which
imparts the brown color to these cells. Image from Junqueira’s Basic Histology, 12th
ed. by Anthony L. Mescher, McGraw-Hill Professional Division, reproduced with
permission.
WAT is composed of adipocytes held together by a loose connective tissue that is
highly vascularized and innervated. White adipocytes are rounded cells that contain
a single large fat droplet that occupies over 90% of the cell volume. The
mitochondria within white adipocytes are small and few in number. The mitochondria
and nucleus of the white adipocyte is squeezed into the remaining cell volume.
Molecular characteristics of white adipocytes include expression of leptin but no
expression of uncoupling protein 1, UCP1 (designated UCP1–, leptin+). Brown
adipocytes are smaller in overall size compared to white adipocytes. Brown
adipocytes are polygonal in shape and contain numerous large mitochondria packed
with cristae. Whereas, white adipocytes contain a single large fat droplet, brown
adipocytes contain several small lipid droplets. Brown adipocytes are molecularly

UCP1+ and leptin–. BAT is primarily visceral with highest concentrations around the
aorta. BAT is highly vascularized and contains a very high density of noradrenergic
nerve fibers.

In addition to adipocytes, WAT contains macrophages, leukocytes, fibroblasts,
adipocyte progenitor cells, and endothelial cells. The presence of the fibroblasts,
macrophages, and other leukocytes along with adipocytes, accounts for the vast
array of proteins that are secreted from WAT under varying conditions. The highest
accumulations of WAT are found in the subcutaneous regions of the body and
surrounding the viscera (internal organs of the chest and abdomen).

Although WAT can be found associated with numerous organs its functions are more
than just insulation of the organ and a ready reservoir of fat for energy production.
Depending on its location WAT serves specialized functions. The WAT associated
with abdominal and thoracic organs (excluding the heart), the so-called visceral fat,
secretes several inflammatory cytokines and is thus involved in local and systemic
inflammatory processes. WAT associated with skeletal muscle secretes free fatty
acids, interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) and as a consequence
plays a significant role in the development of insulin resistance. Cardiac tissue
associated WAT secretes numerous cytokines resulting in local inflammatory events
and chemotaxis that can result in the development of atherosclerosis and systolic
hypertension. Kidney associated WAT plays a role in sodium reabsorption and
therefore can affect intravascular volume and hypertension.

The major focus of this discussion will be on the biological activities associated with
WAT, however, discussion of BAT is included at the end of this page. WAT serves
many functions including insulating the viscera, storing excess carbon energy in the
form of triglycerides and mediating glucose homeostasis. WAT also plays important
roles as an endocrine/immune organ by secreting adipokines that includes
inflammatory cytokines, complement-like factors, chemokines, and acute phase
proteins. The endocrine functions of WAT regulate appetite, energy metabolism,
glucose and lipid metabolism, inflammatory processes, angiogenesis, and
reproductive functions.
REGULATION OF ADIPOGENESIS
The process of adipocyte differentiation from a precursor preadipocyte to a fully
mature adipocyte follows a precisely ordered and temporally regulated series of
events. Adipocyte precursor cells emerge from mesenchymal stem cells (MSCs) that
are themselves derived from the mesodermal layer of the embryo. The pluripotent
MSCs receive extracellular cues that lead to the commitment to the preadipocyte
lineage. Pre-adipocytes cannot be morphologically distinguished from their precursor
MSCs but they have lost the ability to differentiate into other cell types. This initial
step in adipocyte differentiation is referred to as determination and leads to

proliferating pre-adipocytes undergoing a growth arrest. This initial growth arrest
occurs coincident with the expression of two key transcription factors,
CCAAT/enhancer binding protein alpha (C/EBPα) and peroxisome proliferatoractivated receptor gamma (PPARγ). Following the induction of these two critical
transcription factors there is a permanent period of growth arrest followed by
expression of the fully differentiated adipocyte phenotype. This latter phase of
adipogenesis is referred to as terminal differentiation.

Although PPARγ and C/EBPα are the most important factors regulating adipogenesis
additional transcription factors are known to influence this process. These additional
factors include sterol-regulated element binding protein 1c (SREBP1c, also known
as ADD1 for adipocyte differentiation-1), signal transducers and activators of
transcription 5 (STAT5), AP-1 and members of the Krüppel-like factor (KLF4, KLF5,
and KLF15) family as well as C/EBP beta (β) and C/EBP delta (δ). More information
about the roles of PPARγ and SREBP in metabolic homeostasis can be found in the
PPAR page as well as the Cholesterol Metabolism page. Although these numerous
transcription factors have been shown to influence overall adipogenesis, either
positively or negatively, PPARγ is the only one that is necessary for adipogenesis to
take place. In fact, in the absence of PPARγ, adipocyte differentiation fails to occur
and as yet no factor has been identified that can rescue adipogenesis in the absence
of PPARγ. In spite of this fact, expression of PPARγ does not commence during the
initial activation of adipocyte differentiation but only after the responses elicited by
STAT5, KLF4, KLF5, AP-1, SREBP1c, and C/EBPβ and C/EBPδ are exerted.

PPARγ was originally identified as being expressed in differentiating adipocytes and
as indicated above it is now recognized as a master regulator of adipogenesis.
PPARγ was identified as the target of the thiazolidinedione (TZD) class of insulinsensitizing drugs. The mechanism of action of the TZDs is a function of the activation
of PPARγ and the consequent induction of genes necessary for differentiation of
adipocytes. The human PPARγ gene (symbol PPARG) is located on chromosome
3p25 spanning over 100kb and composed of 9 exons encoding two biologically
active isoforms as a consequence of alternative mRNAs and translational start
codon usage. The principal protein products of the PPARG gene are identified as
PPARγ1 and PPARγ2. PPARγ1 is encoded for by exons A1 and A2 then common
exons 1 through 6. PPARγ2 is encoded by exon B and common exons 1 through 6.
PPARγ2 is almost exclusively expressed in adipocytes. Like all nuclear receptors the
PPARγ proteins contain a DNA-binding domain (DBD) and a ligand-binding domain
(LBD). In addition, like PPARα, the PPARγ proteins contain a ligand-dependent
activation function domain (identified as AF-2) and a ligand-independent activation
function domain (identified as AF-1). The AF-2 domain resides in the LBD and the
AF-1 domain is in the N-terminal region of the PPARγ proteins. PPARγ2 protein
contains an additional 30 N-terminal amino acids relative to PPARγ1 and these
additional amino acids confer a 5–6-fold increase in the transcription-stimulating
activity of AF-1 when compared to the same domain in the PPARγ1 protein.

several phospholipase A (PLA) genes. zinc-finger protein 423 (Zfp423). in part. The C/EBP family of transcription factors were among the first to be shown to play a role in overall adipocyte differentiation. for example whole body disruption of C/EBPα expression results in death shortly after birth due to liver defects. PPARγ2 is expressed near exclusively in white adipose tissue (WAT) where it is involved in lipid storage and in BAT where it is involved in energy dissipation. the gluconeogenic enzyme PEPCK.Expression of PPARγ1 is nearly ubiquitous. Additional genes regulated by PPARγ that are involved in lipid metabolism or glucose homeostasis include lipoprotein lipase (LPL). These genes include aP2 which is required for transport of free fatty acids (FFAs) and perilipin which is a protein covering the surface of mature lipid droplets in adipocytes. This fact explains the necessity for SREBP expression to precede that of PPARγ. generate PPARγ ligands. levels of SREBP-2 are increased in these animals indicating that this may be a compensatory mechanism. adiponectin. One of the major effects of the expression of C/EBPα in adipocytes is enhanced insulin sensitivity of adipose tissue. several acyl-CoA synthases (FATP1 and FATP2). SREBP-1c. PPARγ also functions in macrophage lipid metabolism by inducing the expression of the macrophage scavenger receptor. This later fact . regulated by the actions of C/EBPβ and C/EBPδ. Using knockout mice it has been determined that the roles of C/EBPβ and C/EBPδ are exerted early in the process of adiopcyte differentiation whereas those of C/EBPα are required later. as part of their activities. In the process of adipocyte differentiation PPARγ activates nearly all of the genes required for this process. and glycerol-3-phosphate dehydrogenase (GPD1). CD36. and early B-cell factor 1 (EBF1). KLF15. The role of SREBP-1c in activation of adipocyte differentiation is thought to be the result of this transcription factor initiating the expression of genes that. ectopic overexpression of SREBP-1c does enhance the adipogenic activity of PPARγ. In fact. The importance of these factors in adipogenesis has been demonstrated in knockout mouse models. As indicated above. The expression of both C/EBPα and PPARγ is. expression of C/EBPα is induced late in adipogenesis and is most abundant in mature adipocytes. In spite of this fact it has been shown that mice lacking SREBP-1 do not display significant reductions in the amount of WAT. However. KLF5. during adipocyte differentiation several upstream genes are required for the activation of the PPARG gene. Although loss of SREBP-1 expression does not result in a significant deficit in adipose tissue development. and failure of WAT or BAT accumulation. hypoglycemia. These include C/EBPβ and C/EBPδ. acetyl-CoA acetyltransferase 1 (ACAT1). C/EBPβ and C/EBPδ) are highly conserved basic-leucine zipper containing transcription factors. The three members of the family (C/EBPα. The CD36 receptor is also known as fatty acid translocase (FAT) and it is one of the receptors responsible for the cellular uptake of fatty acids.

These latter two factors in turn activate the expression of SREPB-1 and KLF15 which leads to the activation of PPARγ and C/EBPα. KLF2 and KLF3. There is also a balance exerted at the level of transcription factor-mediated inhibition of adipogenesis. These changes in chromatin dynamics involve both histone protein methylation and DNA methylation events. where CREB is cAMP- . it is necessary that adipocyte differentiation genes such as PPARγ and C/EBPα be silenced if the induced pathway is to bone or muscle. When MSCs are induced down the bone lineage the histone 3 proteins in the PPARγ promoter region are methylated on lysine 9 (identified as H3K9) by a co-repressor complex that includes the histone methyltransferase SETDB1 and the associated proteins NLK (Nemo-like kinase) and CHD7 (chromodomain helicase DNA binding protein-7). Lineage-specific genes are demethylated whereas pluripotency genes are methylated resulting in transcriptional activation and silencing. Some of the factors that are anti-adipogeneic include members of the Krüppel-like factor family. Associated with transcriptional silencing are protein complexes termed co-repressors and associated with transcriptional activation are complexes termed co-activators. The changes in the pattern of expression of transcription factors that control the overall process of adipogenesis is associated with changes in chromatin dynamics. GATA2 and GATA3 also exert anti-adipogenic activity.is demonstrated by the fact that C/EBPα knockout does not abolish adipogenesis but the WAT is not sensitive to the actions of insulin. the activity of the PPARγ protein on its target genes is also restricted by association with co-repressor complexes. The chromatin in pluripotent cells displays a highly dynamic nature with a high level of decondensed DNA. and KLF5 are activated early and result in the transactivation of C/EBPβ and C/EBPδ. KLF4. The general model of transcription factor activation of adipogenesis indicates that AP-1. As the process of adipocyte differentiation proceeds the genes encoding PPARγ and C/EBPα are observed to be repositioned into the interior of the nucleus coincident with their increased rates of transcription. STAT5. This in turn results in the recruitment of histone acetyltransferases (HATs) and the coactivator protein CBP/p300 (CBP is CREB binding protein. In preadipocytes PPARγ activity is repressed by association with pRB and HDAC3 (histone deacetylase 3). It is important to keep in perspective that it is not only transcription factor activation of adipocyte precursors that controls adipogenesis. as well as adipocyte. Since MSCs can be induced to differentiate into bone and muscle. In addition to silencing of the PPARγ promoter. The induction of differentiation results in the phosphorylation of pRB which leads to its release from the repressive complex. Two of the interferon regulatory factor family of transcription factors. GATA factors are so-called because they bind DNA elements that contain a core GATA sequence. IRF3 and IRF4. respectively. Once differentiation is induced there is a change in the overall pattern of methylated genes. oppose the process of adipogenesis as well.

also DAG). These histone modifying complexes include HATs. and pathophysiology. when HSL-null mice were generated it was discovered that the process involves additional adipocyte HSL-independent TG lipase activities. diglycerides (DG. When assayed in vitro the activity of HSL is at least 10-fold higher against DG than TG. The pool of TG is in a constant state of flux that is regulated by food intake and fasting and the consequences of those dietary states on the levels of pancreatic and adrenal hormones. results from studies in these mice indicate that HSL-mediated lipolysis is a significant contributor to overall fatty acid liberation from adipocytes. and histone demethylases (HDMs). However. Numerous experiments have begun to define the large array of histone modifications that regulate the expression of genes involved in overall adipogenesis particularly the expression of PPARγ. Conversely. Subsequent research has led to the identification of at least five adipose tissue TAG lipases in addition to HSL. In addition. The overall biochemistry of TG metabolism is covered in the Lipid Synthesis page and the Fatty Acid Oxidation page. HSL was believed to be the principle enzyme involved in adipocyte TG and DG hydrolysis as well as the primary neutral cholesteryl ester hydrolase (NCEH1) activity. HDACs. The general consequences of activation of HATs and HMTs is the activation of PPARγ expression and/or enhancement of PPARγ activity at its target gene promoters.response element-binding protein) to the PPARγ complex resulting in activation of PPARγ target gene transcription. HDAC activation results in inhibited PPARγ activity at its target gene promoters. In mice lacking HSL there is a reduced level of circulating free fatty acids and TGs as well as reduced hepatic storage of TG. When acting on TG or DG the activity of HSL is greatest against fatty acids that are in the sn-1 or sn-3 position of the glycerol backbone. Although HSL-null mice still exhibit TG hydrolase activity. inflammatory processes. histone methyltransferases (HMTs). It was originally believed that the liberation of fatty acids from adipose tissue TAG stores was triggered exclusively via hormonal activation of hormone-sensitive lipase (HSL). These results indicate that in the absence of HSL there is insufficient adipose tissue lipolysis to support the normal cellular demands for energy from fatty acids nor for . Until recent experiments in knock-out mice demonstrated otherwise. adipose tissue fat pools change as a result of other hormonal fluctuations. Regulation of Lipid Metabolism in Adipocytes The triglycerides (TG or TAG) found in WAT represent the major energy reserves of the body. HSL has demonstrated activity with a wide variety of substrates that includes TG. and cholesterol esters (CEs). The aim of this section is to discuss in more detail the enzyme activities that regulate overall adipose tissue TG homeostasis as well as the physiological and hormonal regulation of these processes. as expected.

to 30-times that the rate of release from TG. desnutrin/ATGL has limited activity against DG since in these and similar in vitro experiments there is a significant accumulation of DG compared to the same types of experiments carried out with HSL. Subsequent to the identification of desnutrin another lipase was characterized and called adipose triglyceride lipase (ATGL). also MAG). The desnutrin/ATGL gene is expressed predominantly in adipose tissue but also at much lower levels in cardiac and skeletal muscle and the testes. To date the only DG lipase identified in adipose tissue is HSL. In addition. Further understanding of the role of HSL in overall adipose tissue lipolysis came from the identification of an additional TG lipase that was originally termed desnutrin. The intracellular location of desnutrin/ATGL is the cytosol as well as in tight association with lipid droplets. in HSL-null mice there is an accumulation of DGs indicating that the critical role for HSL is in the liberation of fatty acid from DG which in turn generates monoacylglycerides (MG. Results of studies on the role of HSL in overall adipose tissue lipolysis demonstrate that it is not strictly required for the initiation of TAG hydrolysis as originally thought. Desnutrin and ATGL are the same protein so it is often designated desnutrin/ATGL. The rate of fatty acid release from DGs is on the order of 10. However.adequate VLDL synthesis in the liver. The overall structure of desnutrin indicates that it contains typical domains found in many other lipases. The activity of desnutrin/ATGL is specific for TG as evidenced in cell culture experiments where over-expression of the gene results in increased free fatty acid release with no effect on phospholipid stores. .

Activated PKA phosphorylates both perilipin-1 and HSL. ABHD5 (also known as CGI-58). which counter the effects of epinephrine or glucagon. HSL then hydrolyzes DAG to a free fatty acid (FFA) and MAG. PKA. to induce fat storage. to some extent. AQP7. are primarily the result of the activation of PKB which then phosphorylates and activates phosphodiesterase (PDE) leading to a reduced level of cAMP and consequent reduced activity of PKA. whereas insulin action is to counter the responses to these two hormones. .Hormone-mediated regulation of adipocyte lipolysis: Epinephrine (as well as norepinephrine) and glucagon stimulate fatty acid release from triglycerides stored in adipocyte fat droplets. and conversely. The actions of insulin. The phosphorylation of perilipin-1 leads to the release of the ATGL co-activator. The glycerol released through the action of monoacylglycerol lipase (MGL) is transported across the plasma membrane via the action of aquaporin 7. The activity of PKA is. regulated via the lipid droplet protein caveolin. thereby providing more DAG substrates for PKA-activated HSL. Free fatty acids are transported to the plasma membrane bound to adipocyte fatty acid-binding protein (aP2: also known as FABP4) which are then transported across the plasma membrane into the circulation by one of several fatty acid transport proteins. ABHD5 then increases the activity of ATGL. Epinephrine and glucagon binding to their respective receptors triggers activation of adenylate cylcase (AC) and subsequently.

The adipose tissue regulation of TGH expression is effected. When experiments are performed that artificially reduce the level of desnutrin/ATGL RNA or protein there is a significant drop in the level of free fatt acid release. skeletal muscle. In addition to HSL and desnutrin/ATGL. It appears that although this enzyme is a member of the lipase family of enzymes it plays an anabolic rather than a catabolic role in adipocyte lipid metabolism. when it is over-expressed in cells it has no effect on TG hydrolysis. Adipose tissue microsomes contain a non-HSL TG lipase that is identified as triacylglycerol hydrolase (TGH. Numerous other proteins in addition to the lipases are involved in overall TG homeostasis in adipose . In fasting animals the level of desnutrin/ATGL increases and then declines following refeeding. in part. In addition. adiponutrin expression exhibits the opposite pattern. whereas desnutrin/ATGL (as well as most other lipases) expression is increased in the fasting state and decreased following re-feeding. Demonstrating a synergy between HSL and desnutrin/ATGL activity. This enzyme possesses no catalytic activity towards TGs or DGs nor cholesteryl esters. and testes. This protein is called adiponutrin. TGH does not hydrolyze phospholipids . Whereas. and short-chain TAGs as well as neutral cholesteryl esters. medium-. There is another interesting protein expressed predominantly in adipose tissue with a significant degree of homology to desnutrin/ATGL. TGH expression is also seen in adipocytes and the level of its expression increases dramatically when preadipocytes differentiate into mature adipocytes.Expression of desnutrin/ATGL is under the influence of dietary status. However. The final step in the complete hydrolysis of TGs occurs when glycerol and the last fatty acid are released from MGs by MAG lipase. a hypothesis supported by the fact that in genetically obese mice (ob/ob and db/db) the level of desnutrin/ATGL expression is reduced. A critical role for desnutrin/ATGL in TG hydrolysis in tissues other than adipose tissue was shown by results of desnutrin/ATGL knockout in mice. adipose tissue expresses a number of other TG hydrolases. via the action of C/EBPα. These data point to a critical role for desnutrin/ATGL in TG hydrolysis and fatty acid release not only from adipose tissue but also from tissues such as the heart. In fasted animals adiponutrin mRNA is essentially undetectable and its levels increase dramatically in the re-fed state. also called carboxylesterase 3). Expression of TGH is seen predominantly in the liver where its primary functions are to mobilize intracellular TAG stores and participate in the synthesis of TG-rich VLDLs. In addition. total lipase activities in several tissues in addition to WAT and BAT were altered in the desnutrin/ATGL-null mice. identified as TGH-2. These animals died at around 12-weeks of age due to increased ectopic fat stores particularly in the heart. This dietary regulation of desnutrin/ATGL suggests that it may play a contributory role in the development of obesity. A related protein. has also been found predominantly expressed in the liver but is also present in adipose tissue and kidney. TGH contains typical lipase motifs and displays catalytic activity against long-. adiponutrin shows TG lipase activity when assayed in vitro. in cells where both enzymes are reduced there is an additive level of reduction in free fatty acid release.

The activity of HSL is also affected via phosphorylation by AMPK. The role of lipotransin is believed to be in shuttling HSL from the cytosol to the lipid droplet upon stimulation of adipocytes. These mice release free fatty acids upon stimulation of adipose tissue with catecholamines but no glycerol is released. The principle cAMP-independent mechanism for insulinmediated reduction in TG lipolysis is due to the stimulation of protein phosphatase-1 which removes the phosphate from HSL rendering it much less active. adipose fatty acid-binding protein (aP2. In turn the cAMP activates PKA which then phosphorylates and activates HSL. In brief. also called FABP4 and aFABP). The cAMP-dependent changes that occur in response to insulin binding are effected by activation of phosphodiesterase 3B which hydrolyzes cAMP rendering PKA much less active. catecholamines such as epinephrine and norepinephrine. The perilipins play a role in restricting access of TG lipases to substrates in order to prevent unrestrained hydrolysis in the un-stimulated state. The primary change in adipose tissue TG lipolysis following feeding is exerted via the actions of insulin. The primary mechanism for the stimulation of adipose tissue TG hydrolysis is discussed in the fatty acid oxidation page.tissue. as well as the pancreatic hormone glucagon. Inhibition of HSL by AMPK may seem paradoxical since the release of fatty acids stored in TGs would seem necessary to promote the production of ATP via fatty acid oxidation and the major function of AMPK is to shift cells to ATP production from ATP consumption. The role of aP2 is to carry free fatty acids from the fat droplet to the plasma membrane where they can be released to the plasma. The glycerol that is released from TGs is exported via the action of aquaporin 7 as shown by experiments in mice lacking expression of this gene. Several of these other proteins are associated with the lipid droplets inside the cell such as the perilipins. Of significance is the fact that activation of PKA in HSL-null mice also results in enhanced TG hydrolysis albeit at a level much lower than in the presence of active HSL. In this case the phosphorylation inhibits the enzyme. and caveolin-1. This paradigm can be explained if one considers that if the fatty acids that are released from TGs are not consumed they will be recycled back into TGs at the expense of ATP consumption. Thus. Additional proteins important in overall TG metabolism include aquaporin 7 (a water and glycerol transport protein) and lipotransin. This indicates that there are PKA-mediated events in adipose tissue TG lipolysis that are distinct from the classic HSL-mediated process. it has been proposed that inhibition of HSL by AMPK mediated-phosphorylation is a mechanism to ensure that the rate of fatty acid release does not exceed the rate at which they are utilized either by export or oxidation. Table of Adipose Tissue Hormones and Cytokines . The activation of phosphodiesterase 3B occurs via PKB/Akt-mediated phosphorylation which itself is activated following insulin binding its receptor. hormonal and physiological status of the organism. Whether adipose tissue stores fatty acids as TGs or releases them for energy production by other tissues is dependent upon the dietary. bind to their cognate receptors on adipocytes triggering activation of adenylate cyclase resulting in increased levels of cAMP.

IL-4. androgens. resistin. For example. IL-18. thyroid hormone. IL-6. normally T cell expressed and secreted (RANTES) Metabolic processes: adipocyte fatty acid binding protein (FABP4. glucagon. chemokines. III. vitamin D. lysyl oxidase Acute phase proteins: C-reactive protein (CRP). vascular endothelial cell growth factor (VEGF). gastrin. and angiotensin-II. nitric oxide synthase pathway. visfatin. and VI. transforming growth factor-β (TGFβ). IL-10. retinol binding protein 4 (RBP4). MMP7. vascular cell adhesion molecule-1 (VCAM-1). growth hormone. renin-angiotensin system. . adiponectin. MMP10. increases in visceral WAT. macrophage migration inhibitory factor (MIF) Complement-like factors: adipsin. Growth and angiogenic factors: fibroblast growth factors (FGFs). angiopoietin-1. leptin Other processes: COX pathway products PGE 2 and PGI2 (prostacyclin). Nuclear receptors include peroxisome proliferator-activated receptor-γ (PPARγ). ASP) Adhesion molecules and ECM components: α2-macroglobulin. carry a greater metabolic risk for insulin resistance and diabetes and cardiovascular disease. MMP11. regulated upon activation. tissue inhibitors of metalloproteinases (TIMPs) In addition to these secreted factors adipose tissue produces several plasma membrane and nuclear receptors that can trigger changes in adipose tissue function. insulin-like growth factor-1 (IGF-1). MMP15. apolipoprotein E (apoE). MMP14. collagen types I. haptoglobin Chemokines: chemerin. omentin. complement-like factors. This is most significant when considering the clinical risks associated with increased adipose tissue mass. monocyte chemotactic protein-1 (MCP-1). adiponectin. complement factor 3 (active form is C3adesArg and is commonly known as acylation stimulating protein. tissue factor (TF. macrophage inhibitory protein-1 alpha (MIP-1α). MMP9. serum amyloid A3 (SAA3). adiponectin. Plasma membrane receptors include those for insulin. plasminogen activator inhibitor-1 (PAI-1). fibronectin. and adhesion molecules. acute phase proteins. angiopoietin-2. even when subcutaneous fat depots are not increased. IV. The Table below describes several of the adipocyte proteins in more detail with leptin. apelin. progesterone. also known as aP2). and glucocorticoids. tumor necrosis factor-alpha (TNFα). matrix metalloproteinase 1 (MMP1). hepatocyte growth factor (HGF). estrogens. The proteins of the various signaling processes are listed below. IL-8.Adipose tissue produces and releases a vast array of protein signals including growth factors. intercellular adhesion molecule-1 (ICAM-1). cytokines. coagulation factor 3) Cytokines: Interleukin-1beta (IL-1β). Not all WAT secretes the same adipokines as is evident from studies of differences in adipose tissue function in various anatomical regions of the body as described above. vaspin. and resistin discussed in greater detail in the following sections. nerve growth factor (NGF).

Factor Principal Source Major Action adiponectin also called adipocyte adipocytes complement factor 1q-related protein (ACRP30). hemodynamic effects.g. modulates expression of adipocyte genes involved in glucose and lipid homeostasis adipocytes. CMKLR1). liver such as GLUT4 and fatty acid synthase (FAS).g. the CMKLR1 protein is also known as ChemR23 C-reactive protein (CRP) hepatocytes. UCP1. and selectins. exerts positive adipocytes. VCAM-1. induces MCP-1 expression in endothelium. and adipoQ adipsin (also complement factor D) called see below adipocytes. rate limiting enzyme monocytes. increase expression and activity of . enhances phagocytosis by macrophages. attenuates NO production by downregulating NOS expression. levels of expression regulated by circulating IL-6. adipocytes is a member of the pentraxin family of calcium-dependent ligand binding proteins. liver. complement activation macrophages in apelin levels increase with increased insulin. may vascular stromal regulate insulin resistance by cells. heart facilitating expression of BAT uncoupling proteins (e. potent antiinflammatory effects on macrophages expressing the chemerin receptor (chemokine-like receptor-1. modulates endothelial cell functions by inducing expression of various cell adhesion molecules. thermogenin) chemerin also known as retinoic acid receptor responder protein 2 (RARRES2) and as such chemerin is encoded by the RARRES2 gene. assists complement interaction with foreign and damaged cells. ICAM-1. e.

1 (MCP-1) adipocytes is a chemokine defined as CCL2 (C-C motif. hepatocytes. monocytes. intestinal intelectin-1 exhibits enterocytes galactofuranose. . see below spleen. endometrium resistin see the Blood Coagulation page for more details adipocytes. mammary see below gland. bone marrow. placenta monocyte chemotactic protein. galactose. the activity identified as omentin is also known as intestinal lactoferrin receptor. tissue. ligand 2). placenta. platelets. lung.PAI-1 IL-6 adipocytes. B cell activated Th2 proliferation. T cells. and dendritic cells to sites of infection and tissue injury omentin (intelectin-1) the omentum is one of the peritoneal folds that connects the stomach to other abdominal tissues. intelectins are vascular cells of members of the lectin family of omental adipose carbohydrate-binding proteins. the protein is encoded by the intelectin-1 visceral stromal (ITLN1) gene. and Nacetylgalactosamine (GalNAc) binding. protein also enhances insulin-stimulated glucose transport.leukocytes. monocytes. kidney. acute phase response. muscle. thrombopoiesis. levels in the blood inversely correlated with obesity and insulin resistance plasminogen-activator inhibitor-1 (PAI-1) adipocytes. intestine. macrophages. and synergistic with IL-1 and TNF on T antigencells presenting cells (APCs) leptin predominantly adipocytes. recruits monocytes. cells.

(NAMPT) changes in NAMPT activity occur during fasting and positively regulate the activity of the NAD+dependent deacetylase.3 and is composed of 3 exons that encode a 167 amino acid precursor protein. and bone mass. increase with adipose tissue obesity and impaired insulin sensitivity. conflicting results relative identical to the enzyme expression in to insulin receptor binding but nicotinamide visceral white blocking insulin receptor signaling phosphoribosyltransferase adipose tissue interferes with effects of eNAMPT. . the intracellular version of NAMPT (sometimes referred to as iNAMPT) has nicotinamide visfatin. However. and immune system balance. these two expressed with (eNAMPT) exhibits cytokine-like independent activities are highest levels of activity. colony-enhancing factor ubiquitously the extracellular version (PBEF). SIRT1. leading to alterations in gene expression Leptin Leptin is 16kDa peptide whose central function is the regulation of overall body weight by limiting food intake and increasing energy expenditure. hormonal. levels decrease with subcutaneous worsening diabetes. The LEP gene is located on chromosome 7q31. also called pre-B cell phosphoribosyltransferase activity. The human leptin gene (symbol: LEP) is the homolog of the mouse "obese" gene (symbol: OB) that was originally identified in mice harboring a mutation resulting in a severely obese phenotype. encoded by the SERPINA12 gene was originally reported to have insulin mimetic effects but that paper was subsequently retracted. Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice exhibit numerous disruption in energy. blood pressure. increases cellular responsiveness to growth factors and induces signaling pathways that lead to proliferation TNFα primarily activated macrophages.placenta induces expression of other autocrine growth factors. adipocytes vaspin (serpinA12) is a serine protease inhibitor of the serpin peptidase inhibitor clade A visceral and family. inflammatory responses. These mice are obese. leptin is also involved in the regulation of the neuroendocrine axis.

The leptin receptor mRNA is alternatively spliced resulting in six different products. have defects in thermoregulation. The role of leptin in the activation of mTOR function is an important factor in the ability of leptin to activate macrophages. OB-Rc. Ob-Rd. while simultaneously inhibiting AMPK activity. acetyl-CoA carboxylase. kidney. liver. and vascular endothelium. The resulting increased ACC activity leads to increased production of malonyl-CoA which is a potent modulator of hypothalamic inhibition of feeding behavior. Adipose Tissue: Not Just Fat Introduction Regulation Regulation to of Adipose Lipid Tissue: of Metabolism WAT in and BAT Adipogenesis Adipocytes . Leptin and its receptors possess structural similarities to the IL-6 family of cytokines and the class I cytokine receptor family. OB-Rb. Activation of the receptor leads to increased phosphatidylinositol-3-kinase (PI3K) activity. Levels of leptin increase in the serum in obese individuals and drop during weight loss.display hormonal imbalances. Decreased hypothalamic AMPK activity results in reduced inhibition of the rate limiting enzyme of fatty acid synthesis. ACC. the inhibition of AMPK activity is a major contributor to the anorexigenic actions of leptin. Leptin binding its receptor also results in the activation of mTOR both in the hypothalamus and in peripheral tissues. adrenal glands. have hematopoietic defects and are infertile. The role of mTOR in the regulation of protein synthesis is covered in both the Protein Synthesis page as well as in the Insulin Functions page. Leptin activates the anorexigenic axis (appetite suppression) in the arcuate nucleus (ARC) of the hypothalamus by increasing the frequency of action potentials in the hypothalamic POMC neurons by depolarization through a nonspecific cation channel and by reduced inhibition by local orexigenic neuropeptide-Y (NPY) neurons. and Ob-Rf. it is not surprising that there is a direct correlation between leptin levels and the development of atherosclerosis. Given that leptin levels rise in the serum of obese individuals and that leptin interaction with macrophages leads to increased macrophage inflammatory processes. One effect of the activation of the Jak/STAT pathway is activation of suppressor of cytokine signaling 3 (SOCS3) which then inhibits leptin signaling in a negative feedback loop. Leptin functions by binding to its receptor which is a member of the cytokine receptor family. The other receptor subtypes are expressed in numerous tissues including muscle. There is a direct correlation between the amount of body fat an individual carries and the circulating levels of leptin. The leptin receptors are named Ob-R. Ob-Re. An interesting aspect of the role of leptin in mTOR function is that within mature adipocytes leptin synthesis itself is dependent on mTOR activation. Within the hypothalamus. via activation of the Jak/STAT signaling pathway. The OB-Rb mRNA encodes the long form of the leptin receptor (also called LEPR-B) and is expressed primarily in the hypothalamus but is also expressed in cells of the innate and adaptive immune systems as well as in macrophages. leukocytes.

The major form of adipose tissue in mammals (commonly referred to as "fat") is white adipose tissue. hemostasis (regulation of blood coagulation). Specialized adipose tissue that is primarily tasked with thermogenesis. In fact recent evidence has demonstrated that many factors secreted from adipocytes are pro-inflammatory mediators and these proteins have been termed adipocytokines or adipokines. BAT specializes in the production of heat (adaptive thermogenesis) and lipid oxidation. and blood pressure. . In addition. These adipokines are implicated in the modulation of a range of physiological responses that globally includes appetite control and energy balance. a number of proteins secreted by adipocytes play important roles in these same processes. glucose homeostasis. There are currently over 50 different adipokines recognized as being secreted from adipose tissue. BAT index sitemap and Cytokines Adipose Tissue advanced site search by freefind Return to The Medical Biochemistry Page © 1996–2016 themedicalbiochemistrypage.org LLC | info @ Introduction to Adipose Tissue Adipose tissue is not merely an organ designed to passively store excess carbon in the form of fatty acids esterified to glycerol (triglycerides). cytokines and hormones that are involved in overall energy homeostasis. Many of the factors that influence adipogenesis are also involved in diverse processes in the body including lipid homeostasis and modulation of inflammatory responses. BAT is socalled because it is darkly pigmented due to the high density of mitochondria rich in cytochromes.Table of Adipose Tissue Hormones Leptin Adiponectin Resistin Inflammatory Functions of Metabolic Functions of Brown Adipose Tissue. growth factors. Mature adipocytes synthesize and secrete numerous enzymes. BAT. angiogenesis. is brown adipose tissue. inflammation. WAT.org. Specific metabolic processes regulated by adipose tissue include lipid metabolism. especially in the neonate. themedicalbiochemistrypage.

Mescher. adipocyte progenitor cells. reproduced with permission.Histological section of adipose tissue demonstrating distinctive morphology of WAT and BAT. Whereas. Brown adipocytes are molecularly UCP1+ and leptin–. McGraw-Hill Professional Division. UCP1 (designated UCP1 –. BAT is highly vascularized and contains a very high density of noradrenergic nerve fibers. White adipocytes are rounded cells that contain a single large fat droplet that occupies over 90% of the cell volume. polygonal in shape. contain several small lipid droplets and high numbers of large mitochondria which imparts the brown color to these cells. leukocytes. In addition to adipocytes. leptin+). The brown adipocytes are smaller in overall size. fibroblasts. WAT is composed of adipocytes held together by a loose connective tissue that is highly vascularized and innervated. Molecular characteristics of white adipocytes include expression of leptin but no expression of uncoupling protein 1. white adipocytes contain a single large fat droplet. Brown adipocytes are polygonal in shape and contain numerous large mitochondria packed with cristae. BAT is primarily visceral with highest concentrations around the aorta. As described below white adipocytes are generally rounded with over 90% of the cell volume taken up by a single fat droplet. WAT contains macrophages. 12th ed. The mitochondria within white adipocytes are small and few in number. . Brown adipocytes are smaller in overall size compared to white adipocytes. by Anthony L. brown adipocytes contain several small lipid droplets. The presence of the fibroblasts. White adipocytes occupy the left side of the image and brown adipocytes the right side. Image from Junqueira’s Basic Histology. and endothelial cells. The few small mitochondria and the nucleus are compressed to the very edge of the white adipocyte. The mitochondria and nucleus of the white adipocyte is squeezed into the remaining cell volume.

The highest accumulations of WAT are found in the subcutaneous regions of the body and surrounding the viscera (internal organs of the chest and abdomen). This initial step in adipocyte differentiation is referred to as determination and leads to proliferating pre-adipocytes undergoing a growth arrest.macrophages. energy metabolism. The endocrine functions of WAT regulate appetite. Although WAT can be found associated with numerous organs its functions are more than just insulation of the organ and a ready reservoir of fat for energy production. Cardiac tissue associated WAT secretes numerous cytokines resulting in local inflammatory events and chemotaxis that can result in the development of atherosclerosis and systolic hypertension. This initial growth arrest occurs coincident with the expression of two key transcription factors. complement-like factors. discussion of BAT is included at the end of this page. inflammatory processes. secretes several inflammatory cytokines and is thus involved in local and systemic inflammatory processes. CCAAT/enhancer binding protein alpha (C/EBPα) and peroxisome proliferatoractivated receptor gamma (PPARγ). the so-called visceral fat. accounts for the vast array of proteins that are secreted from WAT under varying conditions. Depending on its location WAT serves specialized functions. The major focus of this discussion will be on the biological activities associated with WAT. Pre-adipocytes cannot be morphologically distinguished from their precursor MSCs but they have lost the ability to differentiate into other cell types. Following the induction of these two critical transcription factors there is a permanent period of growth arrest followed by expression of the fully differentiated adipocyte phenotype. interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) and as a consequence plays a significant role in the development of insulin resistance. WAT serves many functions including insulating the viscera. WAT associated with skeletal muscle secretes free fatty acids. . WAT also plays important roles as an endocrine/immune organ by secreting adipokines that includes inflammatory cytokines. and reproductive functions. storing excess carbon energy in the form of triglycerides and mediating glucose homeostasis. and acute phase proteins. Adipocyte precursor cells emerge from mesenchymal stem cells (MSCs) that are themselves derived from the mesodermal layer of the embryo. The WAT associated with abdominal and thoracic organs (excluding the heart). The pluripotent MSCs receive extracellular cues that lead to the commitment to the preadipocyte lineage. glucose and lipid metabolism. and other leukocytes along with adipocytes. however. This latter phase of adipogenesis is referred to as terminal differentiation. angiogenesis. chemokines. Kidney associated WAT plays a role in sodium reabsorption and therefore can affect intravascular volume and hypertension. Regulation of Adipogenesis The process of adipocyte differentiation from a precursor preadipocyte to a fully mature adipocyte follows a precisely ordered and temporally regulated series of events.

More information about the roles of PPARγ and SREBP in metabolic homeostasis can be found in the PPAR page as well as the Cholesterol Metabolism page. These include C/EBPβ and C/EBPδ. PPARγ2 is encoded by exon B and common exons 1 through 6. In addition. KLF4. KLF15. PPARγ was identified as the target of the thiazolidinedione (TZD) class of insulinsensitizing drugs. These additional factors include sterol-regulated element binding protein 1c (SREBP1c. The human PPARγ gene (symbol PPARG) is located on chromosome 3p25 spanning over 100kb and composed of 9 exons encoding two biologically active isoforms as a consequence of alternative mRNAs and translational start codon usage. the PPARγ proteins contain a ligand-dependent activation function domain (identified as AF-2) and a ligand-independent activation function domain (identified as AF-1).Although PPARγ and C/EBPα are the most important factors regulating adipogenesis additional transcription factors are known to influence this process. Additional genes regulated by PPARγ . like PPARα. The principal protein products of the PPARG gene are identified as PPARγ1 and PPARγ2. The AF-2 domain resides in the LBD and the AF-1 domain is in the N-terminal region of the PPARγ proteins. also known as ADD1 for adipocyte differentiation-1). PPARγ2 is almost exclusively expressed in adipocytes. Although these numerous transcription factors have been shown to influence overall adipogenesis. Expression of PPARγ1 is nearly ubiquitous. These genes include aP2 which is required for transport of free fatty acids (FFAs) and perilipin which is a protein covering the surface of mature lipid droplets in adipocytes. PPARγ1 is encoded for by exons A1 and A2 then common exons 1 through 6. AP-1 and members of the Krüppel-like factor (KLF4. PPARγ2 protein contains an additional 30 N-terminal amino acids relative to PPARγ1 and these additional amino acids confer a 5–6-fold increase in the transcription-stimulating activity of AF-1 when compared to the same domain in the PPARγ1 protein. and C/EBPβ and C/EBPδ are exerted. KLF5. in the absence of PPARγ. KLF5. In spite of this fact. zinc-finger protein 423 (Zfp423). In fact. adipocyte differentiation fails to occur and as yet no factor has been identified that can rescue adipogenesis in the absence of PPARγ. and KLF15) family as well as C/EBP beta (β) and C/EBP delta (δ). In the process of adipocyte differentiation PPARγ activates nearly all of the genes required for this process. PPARγ2 is expressed near exclusively in white adipose tissue (WAT) where it is involved in lipid storage and in BAT where it is involved in energy dissipation. expression of PPARγ does not commence during the initial activation of adipocyte differentiation but only after the responses elicited by STAT5. and early B-cell factor 1 (EBF1). AP-1. The mechanism of action of the TZDs is a function of the activation of PPARγ and the consequent induction of genes necessary for differentiation of adipocytes. SREBP1c. PPARγ was originally identified as being expressed in differentiating adipocytes and as indicated above it is now recognized as a master regulator of adipogenesis. PPARγ is the only one that is necessary for adipogenesis to take place. during adipocyte differentiation several upstream genes are required for the activation of the PPARG gene. KLF5. As indicated above. SREBP-1c. signal transducers and activators of transcription 5 (STAT5). Like all nuclear receptors the PPARγ proteins contain a DNA-binding domain (DBD) and a ligand-binding domain (LBD). either positively or negatively.

In fact. Using knockout mice it has been determined that the roles of C/EBPβ and C/EBPδ are exerted early in the process of adiopcyte differentiation whereas those of C/EBPα are required later. KLF2 and KLF3. several acyl-CoA synthases (FATP1 and FATP2). However. STAT5. . The CD36 receptor is also known as fatty acid translocase (FAT) and it is one of the receptors responsible for the cellular uptake of fatty acids. adiponectin. This later fact is demonstrated by the fact that C/EBPα knockout does not abolish adipogenesis but the WAT is not sensitive to the actions of insulin. Although loss of SREBP-1 expression does not result in a significant deficit in adipose tissue development. These latter two factors in turn activate the expression of SREPB-1 and KLF15 which leads to the activation of PPARγ and C/EBPα. several phospholipase A (PLA) genes. The general model of transcription factor activation of adipogenesis indicates that AP-1. It is important to keep in perspective that it is not only transcription factor activation of adipocyte precursors that controls adipogenesis. in part. CD36. GATA factors are so-called because they bind DNA elements that contain a core GATA sequence. ectopic overexpression of SREBP-1c does enhance the adipogenic activity of PPARγ. There is also a balance exerted at the level of transcription factor-mediated inhibition of adipogenesis. The expression of both C/EBPα and PPARγ is. expression of C/EBPα is induced late in adipogenesis and is most abundant in mature adipocytes. and failure of WAT or BAT accumulation. The role of SREBP-1c in activation of adipocyte differentiation is thought to be the result of this transcription factor initiating the expression of genes that. This fact explains the necessity for SREBP expression to precede that of PPARγ. Some of the factors that are anti-adipogeneic include members of the Krüppel-like factor family. PPARγ also functions in macrophage lipid metabolism by inducing the expression of the macrophage scavenger receptor. The C/EBP family of transcription factors were among the first to be shown to play a role in overall adipocyte differentiation. as part of their activities. for example whole body disruption of C/EBPα expression results in death shortly after birth due to liver defects. levels of SREBP-2 are increased in these animals indicating that this may be a compensatory mechanism. and glycerol-3-phosphate dehydrogenase (GPD1). C/EBPβ and C/EBPδ) are highly conserved basic-leucine zipper containing transcription factors. IRF3 and IRF4. the gluconeogenic enzyme PEPCK. GATA2 and GATA3 also exert anti-adipogenic activity. Two of the interferon regulatory factor family of transcription factors. regulated by the actions of C/EBPβ and C/EBPδ. acetyl-CoA acetyltransferase 1 (ACAT1). KLF4. The importance of these factors in adipogenesis has been demonstrated in knockout mouse models. One of the major effects of the expression of C/EBPα in adipocytes is enhanced insulin sensitivity of adipose tissue. The three members of the family (C/EBPα. In spite of this fact it has been shown that mice lacking SREBP-1 do not display significant reductions in the amount of WAT. and KLF5 are activated early and result in the transactivation of C/EBPβ and C/EBPδ.that are involved in lipid metabolism or glucose homeostasis include lipoprotein lipase (LPL). generate PPARγ ligands. oppose the process of adipogenesis as well. hypoglycemia.

The pool of TG is in a constant state of flux that is regulated by food intake and fasting and the consequences of those dietary states on the levels of pancreatic and adrenal hormones. as well as adipocyte. adipose tissue fat pools change as a result of other hormonal fluctuations. Numerous experiments have begun to define the large array of histone modifications that regulate the expression of genes involved in overall adipogenesis particularly the expression of PPARγ. and histone demethylases (HDMs). The overall biochemistry of TG metabolism is covered in the Lipid Synthesis page and . the activity of the PPARγ protein on its target genes is also restricted by association with co-repressor complexes. The induction of differentiation results in the phosphorylation of pRB which leads to its release from the repressive complex. Regulation of Lipid Metabolism in Adipocytes The triglycerides (TG or TAG) found in WAT represent the major energy reserves of the body. Once differentiation is induced there is a change in the overall pattern of methylated genes.The changes in the pattern of expression of transcription factors that control the overall process of adipogenesis is associated with changes in chromatin dynamics. respectively. As the process of adipocyte differentiation proceeds the genes encoding PPARγ and C/EBPα are observed to be repositioned into the interior of the nucleus coincident with their increased rates of transcription. it is necessary that adipocyte differentiation genes such as PPARγ and C/EBPα be silenced if the induced pathway is to bone or muscle. Since MSCs can be induced to differentiate into bone and muscle. where CREB is cAMPresponse element-binding protein) to the PPARγ complex resulting in activation of PPARγ target gene transcription. The general consequences of activation of HATs and HMTs is the activation of PPARγ expression and/or enhancement of PPARγ activity at its target gene promoters. The chromatin in pluripotent cells displays a highly dynamic nature with a high level of decondensed DNA. HDACs. In addition. These histone modifying complexes include HATs. This in turn results in the recruitment of histone acetyltransferases (HATs) and the coactivator protein CBP/p300 (CBP is CREB binding protein. In addition to silencing of the PPARγ promoter. Associated with transcriptional silencing are protein complexes termed co-repressors and associated with transcriptional activation are complexes termed co-activators. In preadipocytes PPARγ activity is repressed by association with pRB and HDAC3 (histone deacetylase 3). inflammatory processes. Conversely. Lineage-specific genes are demethylated whereas pluripotency genes are methylated resulting in transcriptional activation and silencing. histone methyltransferases (HMTs). HDAC activation results in inhibited PPARγ activity at its target gene promoters. as expected. and pathophysiology. These changes in chromatin dynamics involve both histone protein methylation and DNA methylation events. When MSCs are induced down the bone lineage the histone 3 proteins in the PPARγ promoter region are methylated on lysine 9 (identified as H3K9) by a co-repressor complex that includes the histone methyltransferase SETDB1 and the associated proteins NLK (Nemo-like kinase) and CHD7 (chromodomain helicase DNA binding protein-7).

. When assayed in vitro the activity of HSL is at least 10-fold higher against DG than TG. HSL has demonstrated activity with a wide variety of substrates that includes TG. The aim of this section is to discuss in more detail the enzyme activities that regulate overall adipose tissue TG homeostasis as well as the physiological and hormonal regulation of these processes. Subsequent to the identification of desnutrin another lipase was characterized and called adipose triglyceride lipase (ATGL). when HSL-null mice were generated it was discovered that the process involves additional adipocyte HSL-independent TG lipase activities. It was originally believed that the liberation of fatty acids from adipose tissue TAG stores was triggered exclusively via hormonal activation of hormone-sensitive lipase (HSL). To date the only DG lipase identified in adipose tissue is HSL. The desnutrin/ATGL gene is expressed predominantly in adipose tissue but also at much lower levels in cardiac and skeletal muscle and the testes. In mice lacking HSL there is a reduced level of circulating free fatty acids and TGs as well as reduced hepatic storage of TG. The activity of desnutrin/ATGL is specific for TG as evidenced in cell culture experiments where over-expression of the gene results in increased free fatty acid release with no effect on phospholipid stores. Desnutrin and ATGL are the same protein so it is often designated desnutrin/ATGL.to 30-times that the rate of release from TG. The overall structure of desnutrin indicates that it contains typical domains found in many other lipases. results from studies in these mice indicate that HSL-mediated lipolysis is a significant contributor to overall fatty acid liberation from adipocytes.the Fatty Acid Oxidation page. These results indicate that in the absence of HSL there is insufficient adipose tissue lipolysis to support the normal cellular demands for energy from fatty acids nor for adequate VLDL synthesis in the liver. In addition. Although HSL-null mice still exhibit TG hydrolase activity. However. HSL was believed to be the principle enzyme involved in adipocyte TG and DG hydrolysis as well as the primary neutral cholesteryl ester hydrolase (NCEH1) activity. When acting on TG or DG the activity of HSL is greatest against fatty acids that are in the sn-1 or sn-3 position of the glycerol backbone. Subsequent research has led to the identification of at least five adipose tissue TAG lipases in addition to HSL. Further understanding of the role of HSL in overall adipose tissue lipolysis came from the identification of an additional TG lipase that was originally termed desnutrin. desnutrin/ATGL has limited activity against DG since in these and similar in vitro experiments there is a significant accumulation of DG compared to the same types of experiments carried out with HSL. and cholesterol esters (CEs). The intracellular location of desnutrin/ATGL is the cytosol as well as in tight association with lipid droplets. also DAG). The rate of fatty acid release from DGs is on the order of 10. However. in HSL-null mice there is an accumulation of DGs indicating that the critical role for HSL is in the liberation of fatty acid from DG which in turn generates monoacylglycerides (MG. also MAG). Results of studies on the role of HSL in overall adipose tissue lipolysis demonstrate that it is not strictly required for the initiation of TAG hydrolysis as originally thought. Until recent experiments in knock-out mice demonstrated otherwise. diglycerides (DG.

Free fatty acids are transported to the plasma membrane bound to adipocyte fatty acid-binding protein (aP2: also known as FABP4) which are then transported across the plasma membrane into the circulation by one of several fatty acid transport proteins. Epinephrine and glucagon binding to their respective receptors triggers activation of adenylate cylcase (AC) and subsequently. HSL then hydrolyzes DAG to a free fatty acid (FFA) and MAG. and conversely. This dietary regulation of desnutrin/ATGL suggests that it may play a . regulated via the lipid droplet protein caveolin. whereas insulin action is to counter the responses to these two hormones. are primarily the result of the activation of PKB which then phosphorylates and activates phosphodiesterase (PDE) leading to a reduced level of cAMP and consequent reduced activity of PKA. The phosphorylation of perilipin-1 leads to the release of the ATGL co-activator. which counter the effects of epinephrine or glucagon. The actions of insulin. In fasting animals the level of desnutrin/ATGL increases and then declines following refeeding. The activity of PKA is. to some extent. AQP7. ABHD5 then increases the activity of ATGL.Hormone-mediated regulation of adipocyte lipolysis: Epinephrine (as well as norepinephrine) and glucagon stimulate fatty acid release from triglycerides stored in adipocyte fat droplets. Activated PKA phosphorylates both perilipin-1 and HSL. thereby providing more DAG substrates for PKA-activated HSL. to induce fat storage. PKA. ABHD5 (also known as CGI-58). The glycerol released through the action of monoacylglycerol lipase (MGL) is transported across the plasma membrane via the action of aquaporin 7. Expression of desnutrin/ATGL is under the influence of dietary status.

when it is over-expressed in cells it has no effect on TG hydrolysis.contributory role in the development of obesity. adiponutrin shows TG lipase activity when assayed in vitro. in cells where both enzymes are reduced there is an additive level of reduction in free fatty acid release. total lipase activities in several tissues in addition to WAT and BAT were altered in the desnutrin/ATGL-null mice. adipose tissue expresses a number of other TG hydrolases. It appears that although this enzyme is a member of the lipase family of enzymes it plays an anabolic rather than a catabolic role in adipocyte lipid metabolism. in part. and short-chain TAGs as well as neutral cholesteryl esters. In addition. also called FABP4 and aFABP). adiponutrin expression exhibits the opposite pattern. There is another interesting protein expressed predominantly in adipose tissue with a significant degree of homology to desnutrin/ATGL. Several of these other proteins are associated with the lipid droplets inside the cell such as the perilipins. also called carboxylesterase 3). via the action of C/EBPα. In addition. Demonstrating a synergy between HSL and desnutrin/ATGL activity. TGH expression is also seen in adipocytes and the level of its expression increases dramatically when preadipocytes differentiate into mature adipocytes. Adipose tissue microsomes contain a non-HSL TG lipase that is identified as triacylglycerol hydrolase (TGH. Expression of TGH is seen predominantly in the liver where its primary functions are to mobilize intracellular TAG stores and participate in the synthesis of TG-rich VLDLs. Additional proteins important in overall TG . In addition to HSL and desnutrin/ATGL. and testes. medium-. Whereas. has also been found predominantly expressed in the liver but is also present in adipose tissue and kidney. These animals died at around 12-weeks of age due to increased ectopic fat stores particularly in the heart. whereas desnutrin/ATGL (as well as most other lipases) expression is increased in the fasting state and decreased following re-feeding. identified as TGH-2. Numerous other proteins in addition to the lipases are involved in overall TG homeostasis in adipose tissue. adipose fatty acid-binding protein (aP2. These data point to a critical role for desnutrin/ATGL in TG hydrolysis and fatty acid release not only from adipose tissue but also from tissues such as the heart. skeletal muscle. The final step in the complete hydrolysis of TGs occurs when glycerol and the last fatty acid are released from MGs by MAG lipase. This protein is called adiponutrin. This enzyme possesses no catalytic activity towards TGs or DGs nor cholesteryl esters. In fasted animals adiponutrin mRNA is essentially undetectable and its levels increase dramatically in the re-fed state. and caveolin-1. A critical role for desnutrin/ATGL in TG hydrolysis in tissues other than adipose tissue was shown by results of desnutrin/ATGL knockout in mice. However. The adipose tissue regulation of TGH expression is effected. TGH contains typical lipase motifs and displays catalytic activity against long-. When experiments are performed that artificially reduce the level of desnutrin/ATGL RNA or protein there is a significant drop in the level of free fatt acid release. A related protein. TGH does not hydrolyze phospholipids . a hypothesis supported by the fact that in genetically obese mice (ob/ob and db/db) the level of desnutrin/ATGL expression is reduced.

These mice release free fatty acids upon stimulation of adipose tissue with catecholamines but no glycerol is released. The activity of HSL is also affected via phosphorylation by AMPK. Thus. The role of lipotransin is believed to be in shuttling HSL from the cytosol to the lipid droplet upon stimulation of adipocytes.metabolism include aquaporin 7 (a water and glycerol transport protein) and lipotransin. The cAMP-dependent changes that occur in response to insulin binding are effected by activation of phosphodiesterase 3B which hydrolyzes cAMP rendering PKA much less active. Table of Adipose Tissue Hormones and Cytokines Adipose tissue produces and releases a vast array of protein signals including growth factors. In this case the phosphorylation inhibits the enzyme. This paradigm can be explained if one considers that if the fatty acids that are released from TGs are not consumed they will be recycled back into TGs at the expense of ATP consumption. The primary change in adipose tissue TG lipolysis following feeding is exerted via the actions of insulin. as well as the pancreatic hormone glucagon. The glycerol that is released from TGs is exported via the action of aquaporin 7 as shown by experiments in mice lacking expression of this gene. Inhibition of HSL by AMPK may seem paradoxical since the release of fatty acids stored in TGs would seem necessary to promote the production of ATP via fatty acid oxidation and the major function of AMPK is to shift cells to ATP production from ATP consumption. Of significance is the fact that activation of PKA in HSL-null mice also results in enhanced TG hydrolysis albeit at a level much lower than in the presence of active HSL. complement-like . cytokines. bind to their cognate receptors on adipocytes triggering activation of adenylate cyclase resulting in increased levels of cAMP. The activation of phosphodiesterase 3B occurs via PKB/Akt-mediated phosphorylation which itself is activated following insulin binding its receptor. catecholamines such as epinephrine and norepinephrine. In turn the cAMP activates PKA which then phosphorylates and activates HSL. it has been proposed that inhibition of HSL by AMPK mediated-phosphorylation is a mechanism to ensure that the rate of fatty acid release does not exceed the rate at which they are utilized either by export or oxidation. In brief. The role of aP2 is to carry free fatty acids from the fat droplet to the plasma membrane where they can be released to the plasma. This indicates that there are PKA-mediated events in adipose tissue TG lipolysis that are distinct from the classic HSL-mediated process. hormonal and physiological status of the organism. chemokines. The primary mechanism for the stimulation of adipose tissue TG hydrolysis is discussed in the fatty acid oxidation page. The perilipins play a role in restricting access of TG lipases to substrates in order to prevent unrestrained hydrolysis in the un-stimulated state. acute phase proteins. The principle cAMP-independent mechanism for insulinmediated reduction in TG lipolysis is due to the stimulation of protein phosphatase-1 which removes the phosphate from HSL rendering it much less active. Whether adipose tissue stores fatty acids as TGs or releases them for energy production by other tissues is dependent upon the dietary.

MMP10. IL-8. MMP11. Growth and angiogenic factors: fibroblast growth factors (FGFs). and VI. complement factor 3 (active form is C3adesArg and is commonly known as acylation stimulating protein. lysyl oxidase Acute phase proteins: C-reactive protein (CRP). and glucocorticoids.factors. thyroid hormone. matrix metalloproteinase 1 (MMP1). MMP15. also known as aP2). adiponectin. normally T cell expressed and secreted (RANTES) Metabolic processes: adipocyte fatty acid binding protein (FABP4. The proteins of the various signaling processes are listed below. For example. III. nitric oxide synthase pathway. gastrin. tumor necrosis factor-alpha (TNFα). carry a greater metabolic risk for insulin resistance and diabetes and cardiovascular disease. serum amyloid A3 (SAA3). increases in visceral WAT. Nuclear receptors include peroxisome proliferator-activated receptor-γ (PPARγ). tissue factor (TF. plasminogen activator inhibitor-1 (PAI-1). and angiotensin-II. monocyte chemotactic protein-1 (MCP-1). nerve growth factor (NGF). progesterone. Not all WAT secretes the same adipokines as is evident from studies of differences in adipose tissue function in various anatomical regions of the body as described above. growth hormone. IL-10. haptoglobin Chemokines: chemerin. vascular endothelial cell growth factor (VEGF). adiponectin. vascular cell adhesion molecule-1 (VCAM-1). The Table below describes several of the adipocyte proteins in more detail with leptin. fibronectin. vitamin D. MMP9. This is most significant when considering the clinical risks associated with increased adipose tissue mass. macrophage inhibitory protein-1 alpha (MIP-1α). IV. Plasma membrane receptors include those for insulin. renin-angiotensin system. resistin. insulin-like growth factor-1 (IGF-1). IL-4. regulated upon activation. angiopoietin-2. hepatocyte growth factor (HGF). collagen types I. retinol binding protein 4 (RBP4). ASP) Adhesion molecules and ECM components: α2-macroglobulin. leptin Other processes: COX pathway products PGE 2 and PGI2 (prostacyclin). transforming growth factor-β (TGFβ). vaspin. and adhesion molecules. androgens. intercellular adhesion molecule-1 (ICAM-1). IL-6. angiopoietin-1. macrophage migration inhibitory factor (MIF) Complement-like factors: adipsin. adiponectin. apelin. . even when subcutaneous fat depots are not increased. omentin. glucagon. tissue inhibitors of metalloproteinases (TIMPs) In addition to these secreted factors adipose tissue produces several plasma membrane and nuclear receptors that can trigger changes in adipose tissue function. IL-18. coagulation factor 3) Cytokines: Interleukin-1beta (IL-1β). apolipoprotein E (apoE). MMP14. and resistin discussed in greater detail in the following sections. MMP7. estrogens. visfatin.

potent antiinflammatory effects on macrophages expressing the chemerin receptor (chemokine-like receptor-1. enhances phagocytosis by macrophages. the CMKLR1 protein is also known as ChemR23 C-reactive protein (CRP) hepatocytes. hemodynamic effects. adipocytes is a member of the pentraxin family of calcium-dependent ligand binding proteins.g. complement activation macrophages in apelin levels increase with increased insulin. may vascular stromal regulate insulin resistance by cells. liver such as GLUT4 and fatty acid synthase (FAS). thermogenin) chemerin also known as retinoic acid receptor responder protein 2 (RARRES2) and as such chemerin is encoded by the RARRES2 gene. UCP1. assists complement interaction with foreign and damaged cells. and adipoQ adipsin (also complement factor D) called see below adipocytes. modulates expression of adipocyte genes involved in glucose and lipid homeostasis adipocytes. . levels of expression regulated by circulating IL-6. exerts positive adipocytes. liver. heart facilitating expression of BAT uncoupling proteins (e. modulates endothelial cell functions by inducing expression of various cell adhesion molecules. rate limiting enzyme monocytes. CMKLR1).Factor Principal Source Major Action adiponectin also called adipocyte adipocytes complement factor 1q-related protein (ACRP30).

mammary see below gland. cells. intestinal tissues. attenuates NO production by downregulating NOS expression. the protein is encoded by the intelectin-1 (ITLN1) gene. acute phase response. and Nacetylgalactosamine (GalNAc) binding.leukocytes. intelectin-1 exhibits galactofuranose. protein also enhances insulin-stimulated glucose transport. increase expression and activity of PAI-1 IL-6 adipocytes. induces MCP-1 expression in endothelium.g. 1 (MCP-1) adipocytes omentin (intelectin-1) is a chemokine defined as CCL2 (C-C motif. recruits monocytes. T cells. and dendritic cells to sites of infection and tissue injury visceral stromal the omentum is one of the vascular cells of peritoneal folds that connects the omental adipose stomach to other abdominal tissue. ICAM-1. and synergistic with IL-1 and TNF on T antigencells presenting cells (APCs) leptin predominantly adipocytes. ligand 2). VCAM-1. placenta monocyte chemotactic protein. intestine. levels in the blood inversely correlated with obesity . intelectins are members of the lectin family of carbohydrate-binding proteins. and selectins. galactose. the activity identified as enterocytes omentin is also known as intestinal lactoferrin receptor. hepatocytes. B cell activated Th2 proliferation. thrombopoiesis. muscle.e.

bone marrow. placenta. spleen. platelets. levels decrease with subcutaneous worsening diabetes. increases cellular responsiveness to growth factors and induces signaling pathways that lead to proliferation visfatin. also called pre-B cell ubiquitously was originally reported to have colony-enhancing factor expressed with insulin mimetic effects but that (PBEF). independent activities are expression in the intracellular version of NAMPT identical to the enzyme visceral white (sometimes referred to as nicotinamide adipose tissue iNAMPT) has nicotinamide phosphoribosyltransferase phosphoribosyltransferase activity. placenta TNFα primarily activated macrophages. macrophages. see below lung. endometrium resistin adipocytes. SIRT1. adipocytes vaspin (serpinA12) is a serine protease inhibitor of the serpin peptidase inhibitor clade A visceral and family. increase with adipose tissue obesity and impaired insulin sensitivity. (NAMPT) the extracellular version (eNAMPT) exhibits cytokine-like activity. monocytes. kidney. changes in NAMPT activity occur during fasting and positively regulate the activity of the NAD+dependent deacetylase. these two highest levels of paper was subsequently retracted.and insulin resistance plasminogen-activator inhibitor-1 (PAI-1) adipocytes. . encoded by the SERPINA12 gene see the Blood Coagulation page for more details induces expression of other autocrine growth factors. monocytes. conflicting results relative to insulin receptor binding but blocking insulin receptor signaling interferes with effects of eNAMPT.

The leptin receptors are named Ob-R. The leptin receptor mRNA is alternatively spliced resulting in six different products.3 and is composed of 3 exons that encode a 167 amino acid precursor protein. and vascular endothelium. These mice are obese. The human leptin gene (symbol: LEP) is the homolog of the mouse "obese" gene (symbol: OB) that was originally identified in mice harboring a mutation resulting in a severely obese phenotype. via activation of the Jak/STAT signaling pathway. Leptin functions by binding to its receptor which is a member of the cytokine receptor family. and immune system balance. Ob-Rd. hormonal. the inhibition of AMPK activity is a major contributor to the anorexigenic actions of leptin. Leptin and its receptors possess structural similarities to the IL-6 family of cytokines and the class I cytokine receptor family. Ob-Re. and Ob-Rf. have defects in thermoregulation. and bone mass. inflammatory responses. acetyl-CoA carboxylase. leptin is also involved in the regulation of the neuroendocrine axis. Levels of leptin increase in the serum in obese individuals and drop during weight loss. blood pressure. The other receptor subtypes are expressed in numerous tissues including muscle. while simultaneously inhibiting AMPK activity. OB-Rc. There is a direct correlation between the amount of body fat an individual carries and the circulating levels of leptin. leukocytes. OB-Rb.leading to alterations in gene expression Leptin Leptin is 16kDa peptide whose central function is the regulation of overall body weight by limiting food intake and increasing energy expenditure. The OB-Rb mRNA encodes the long form of the leptin receptor (also called LEPR-B) and is expressed primarily in the hypothalamus but is also expressed in cells of the innate and adaptive immune systems as well as in macrophages. The resulting increased ACC activity leads to increased production of malonyl-CoA which is a potent modulator of hypothalamic inhibition of feeding behavior. have hematopoietic defects and are infertile. display hormonal imbalances. The LEP gene is located on chromosome 7q31. Activation of the receptor leads to increased phosphatidylinositol-3-kinase (PI3K) activity. Within the hypothalamus. kidney. liver. One effect of the activation of the Jak/STAT pathway is activation of suppressor of cytokine signaling 3 (SOCS3) which then inhibits leptin signaling in a negative feed- . However. ACC. Decreased hypothalamic AMPK activity results in reduced inhibition of the rate limiting enzyme of fatty acid synthesis. Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice exhibit numerous disruption in energy. adrenal glands. Leptin activates the anorexigenic axis (appetite suppression) in the arcuate nucleus (ARC) of the hypothalamus by increasing the frequency of action potentials in the hypothalamic POMC neurons by depolarization through a nonspecific cation channel and by reduced inhibition by local orexigenic neuropeptide-Y (NPY) neurons.

The gene that encodes SHP2 is identified as PTPN11. Leptin receptor-mediated signal transduction. The role of mTOR in the regulation of protein synthesis is covered in both the Protein Synthesis page as well as in the Insulin Functions page. 1077. Leptin binding its receptor also results in the activation of mTOR both in the hypothalamus and in peripheral tissues. Activated Jak2 will autophosphrylate itself as well as phosphorylate the tyrosine (Y) residues in LEPR-B at positions 985. and 1138.back loop. it is not surprising that there is a direct correlation between leptin levels and the development of atherosclerosis. Phosphorylated Y-1077 serves as a docking site for STAT5 (signal transduction and activation of transcription 5). Given that leptin levels rise in the serum of obese individuals and that leptin interaction with macrophages leads to increased macrophage inflammatory processes. An interesting aspect of the role of leptin in mTOR function is that within mature adipocytes leptin synthesis itself is dependent on mTOR activation. The role of leptin in the activation of mTOR function is an important factor in the ability of leptin to activate macrophages. When leptin binds to its receptor (LEPR-B) the receptor undergoes a conformational change that activates the receptor-associated Jak2 tyrosine kinase. also called PTP1D). Phosphorylated Y-985 serves as a docking site for SHP2 (SH2 domain containing protein tyrosine phosphatase. Phosphorylated Y-1138 .

In addition to effects on appetite exerted via central nervous system functions. Although resistin is expressed in adipocytes. Leptin expression is under complex control and a number of transcription factor binding sites have been identified in the promoter region of the leptin gene. and toxins released during acute infection. In mice resistin expression increases during adipocyte differentiation and levels of resistin increase in diet-induced obesity. This effect of catecholamines has been shown to be due to activation of β-adrenergic receptor signaling. What is known is that overexpression of . When SHP2. in humans it appears that macrophages may be the most important source of the protein. Activated STAT3 in turn activates the transcription of SOCS3 (suppressor of cytokine signaling 3). leptin is also known to exert effects on inflammatory processes. Whether these same responses to resitin are evident in human is still under investigation. too much leptin is not beneficial as high concentrations can result in an abnormally strong immune response which predisposes an individual to autoimmune phenomena. IL-6. also referred to as FIZZ3. However. whereas. Leptin levels are higher in age and weight-matched females compared with males. Resistin Resistin is a 12 kDa protein that was originally identified in mice in a screen for genes suppressed by an agonist of the peroxisome proliferator-activated receptor-γ (PPARγ). The sympathetic nervous system triggers a reduction in circulating leptin levels via the release of catecholamines. cytokines. elevation in resistin levels is associated with increased hepatic glucose production and glucose intolerance. Resistin is thus. In addition leptin reduces thymocyte apoptosis and increases thymic cellularity. and STAT3 bind to phosphorylated LEPR-B they themselves are activated by Jak2-mediated phosphorylation. Leptin modulates peripheral T cell function leading to increased levels of T helper cell type 1 cytokines. These result correlate well with observations demonstrating a reduced capacity for immunologic defense when leptin levels are low. Reduction in resistin levels is associated with increased AMPK activity in the liver which leads to decreased expression of gluconeogenic enzymes and consequent reduction in hepatic glucose production. STAT5. chronic stimulation by IL-1. The name resistin derives from the original observation that this protein induced insulin resistance in mice. Resistin belongs to a family of four proteins referred to as FIZZ proteins for "found in inflammatory zone". SOCS3 will then interact with Y-985 and attenuate signaling from SHP2 as well as interact with Jak2 and attenuate its tyrosine kinase activity resulting in a negative feed-back loop. Conversely. Activated SHP2 in turn activates the ERK1/2 (extracellularregulated kinase 1/2) signal pathway that results in increased transcription of the EGR-1 gene.serves as a docking site for STAT3. This is partially due to the inhibition of leptin expression by androgens and the stimulation of expression by estrogens. Acute stimulation with pro-inflammatory cytokines results in increased serum levels of leptin. or TNFα leads to reduced levels of serum leptin. Leptin expression has been shown to be increased by sex steroids. glucocorticoids.

There is a growing body of evidence that demonstrates a direct link between the changes in adipose tissue function in obesity and the development of type 2 diabetes and the metabolic syndrome. Unphosphorylated GSK3β would normally phosphorylate and inhibit glycogen synthase activity. TNF-α (as well as IL-6) trigger the release of pro-inflammatory cytokines such as JUN Nterminal kinase (JNK) and nuclear factor kappa B (NFκB). Resistin modulates endothelial cell function by enhancing expression of the cell adhesion molecule VCAM-1 and the chemoattractant MCP-1. This effect of TNF-α is the result of increased insulin receptor serine phosphorylation. As indicated above adiponectin plays an important anti-inflammatory role by suppressing the production of both TNF-α and IL-6. Activation of JNK leads to the insulin receptor serine phosphorylation as well as insulin receptor substrate (IRS) serine phosphorylation. As WAT density increases there is an associated increase in IL-6 secretion which is correlated to an increase in the circulating levels of acute-phase proteins such as CRP. Macrophages are a primary source of proinflammatory cytokines secreted by adipose tissue. The PI3K-activated signal pathway leads to the phosphorylation and inhibition of glycogen synthase kinase 3β (GSK3β). Loss of this pathway then leads to a higher rate of glycogen synthase inhibition by GSK3β-mediated phosphorylation. Both of these TNF-α-mediated serine phosphorylations lead . Resistin also exerts effects on the immune system and the vasculature. Part of the mechanism for impaired glycogen synthesis is that resistin decreases the expression of one of the insulin receptor substrates (IRS-2) which is involved in the activation of PI3K. Adipose tissue-derived IL-6 accounts for approximately 30% of the circulating level of this pro-inflammatory cytokine.resistin in human heptocytes impairs insulin-stimulated glucose uptake and glycogen synthesis. In addition to the effects of TNF-α on adiponectin production the cytokine also directly affects insulin sensitivity by inhibiting insulin receptor signaling. Visceral WAT has been shown to secrete a higher percentage of the circulating IL-6 than subcutaneous WAT and this fact correlates with the negative effects of a pro-inflammatory status (as is the case with obesity) on the organs. One key change in adipose tissue during obesity is an increase in the percentage of macrophages resident within the tissue. As the level of macrophages increases in adipose tissue the level of proinflammatory cytokine secretion by the tissue increases. Resistin has also been shown to exert a pro-inflammatory effect on smooth muscle cells. However. as the level of macrophage infiltration increases in obesity the increased secretion of TNF-α results in suppression of adiponectin production and secretion. Inflammatory Functions of Adipose Tissue The significance of inflammatory responses elicited via secretion of adipose tissuederived (WAT) cytokines relates to the fact that their production and secretion is increased in obese individuals. The primary adipokine responsible for this infiltration is monocyte chemotactic protein-1 (MCP-1). Circulating levels of both TNF-α and IL-6 increase as adipose tissue expands in obesity and these changes are directly correlated with insulin resistance and the development of type 2 diabetes.

JNK and NFκB activate pro-inflammatory genes which results in a self-perpetuating cycle of increased inflammatory cytokine release. Metabolic Functions of Brown Adipose Tissue. the β 3 subtype is the most significant. Although lymphocytes (T-cells and B-cells) are not constituents of adipose tissue they are physically associated within the lymph nodes. Leptin effects on the vascular endothelium are also pro-inflammatory. Leptin has also been shown to modulate T-cell function. One important interaction between lymph tissue and WAT involves leptin. However. Proinflammatory cytokine production and release from T-cells is increased as a result of leptin action. Leptin induces a number of signal transduction pathways in immune and endothelial cells as outlined above. This leads increased oxidative stress. α2. The responses of the cell to the increased oxidative stress is further increases in NFkB releases and thus. BAT It was originally thought that BAT was present in humans only during the neonatal period. This close association allows for 2-way paracrine interactions between the lymph and adipose tissues. leptin plays a major role in the regulation of appetite and energy balance and the circulating levels of leptin increases as adipose tissue mass increases. However. Expression of adhesion molecules is increased by leptin binding its receptor on endothelial cells. recent evidence has demonstrated that adults retain some metabolically active BAT deposits that respond to cold and sympathetic nervous system activation. accumulation of reactive oxygen species (ROS). increased inflammatory processes. Within BAT. norepinephrine interacts with all three types of adrenergic receptors (α 1. and β) each of which activates distinct signaling pathways in the brown adipocyte. β 1 receptors are expressed in brown preadipocytes but not mature adipocytes and β 2 receptors are expressed in BAT but not brown adipocytes themselves. The effects of adipocytederived TNF-α and IL-6 demonstrates a clear correlation between obesity and a proinflammatory role for adipocytes. Indeed. The most studied regulator of the action of BAT is norepinephrine. and increased endoplasmic reticulum stress. As indicated above. TNF-α also decreases endothelial nitric oxide synthase (eNOS) resulting in decreased levels of NO as well as decreased expression of mitochondrial oxidative phosphorylation genes. Lymph tissue is surrounded by pericapsular adipose tissue which increases in density with increasing obesity. this effect is . With respect to the β-adrenoreceptors. This results in an increased ability of neutrophils and other leukocytes to adhere to the endothelium leading to increased local inflammatory processes. However. thus demonstrating a pro-inflammatory role for leptin. Of significance to the role of BAT in thermogenesis and the major role of β 3adrenoreceptors is the fact that these receptors are not subject to desensitization as are the β1 and β2 receptors.to impaired insulin receptor signaling. Leptin protects T-cells from apoptosis and enhances the switching of T-cells to a Th1 response. this is not to say that continuous adrenergic stimulation has no negative effect in BAT. the level of β 3 receptor expression is downregulated during continuous adrenergic stimulation.

also known as thermogenin).transient and the mRNA rapidly re-accumulates after termination of the stimulatory signal. and regulates the expression of the UCP1 gene. Uncoupling the proton gradient releases the energy of that gradient as heat. Activation of HSL leads to release of free fatty acids which are taken up by the mitochondria similarly as they would be for purposes of oxidation. In addition to stimulating heat production in BAT. For more information on the types of G-proteins visit the Signal Transduction page. The thermogenic function of BAT is outlined in the Figure below. in BAT they interact with and activate the proton gradient uncoupling activity of uncoupling protein 1 (UCP1. Signal transduction events triggered by adrenergic stimulation of BAT are effected via the activation of Gs type G-proteins. Active adenylate cyclase generates cAMP which in turn activates PKA leading to phosphorylation and activation of HSL. Hormonal generation of heat in brown fat: In response to cold norepinephrine binds to β3-adrenergic receptors on browen adipocytes resulting in the activation of adenylate cyclase. however. Some of the fatty acids are oxidized and . inhibits apoptosis of brown adipocytes. Active HSL then accelerates fatty acid release from stored triglycerides. Gs proteins couple to the activation of adenylate cyclase resulting in increased cAMP production and activation of PKA. promotes the differentiation of mature brown adipocytes. norepinephrine promotes the proliferation of brown preadipocytes.

Acute and chronic cold exposure results in increased FGF2 expression in BAT as does norepinephrine.a few molecules of fat activate UCP1 which uncouples the proton gradient in the mitochondria releasing the energy as heat. Within brown adipocytes the . insulin-like growth factor-1 (IGF-1). norepinephrine stimulation of α2-adrenergic receptors on BAT has the opposite effect to β3 receptor activation. The FGF receptor 1 (FGFR1) gene is also expressed in BAT and the result of FGF2 activation of the receptor is increased brown adipocyte cell density. Several proteins produced from BAT serve autocrine functions such as adipsin. FLK-1 and FLK-4. ASP stimulates TAG synthesis and glucose uptake in WAT. This is due to the fact that the α 2 receptors are coupled to Gi type G-proteins whose activation results in inhibition of adenylate cyclase. and adenosine. eNOS expression is seen in brown adipocytes. In addition to its expression in the endothelial cells of BAT. Expression of VEGF is high in proliferating and mature brown adipocytes and the VEGF receptors. Similarly. Both inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) are expressed in BAT. results in increase NO production. Interestingly. The level of C3 expression is much higher in WAT than in BAT and ASP has not been found in BAT so the precise function of adipsin in BAT is not clear although it could be functional when BAT is in a thermogenically inactive state and is functioning in an anabolic state to store TAGs. during cold exposure the levels of IGF-1 mRNA increase and IGF1 receptors are highly expressed on brown adipocytes. and NO. BAT balances the thermogenic stimulatory actions of β 3 receptors with the inhibitory actions of α2 receptors but it may allow the cells to modulate their responses to norepinephrine under varying physiological conditions. Paracrine factors synthesized by BAT include nerve growth factor (NGF). prostaglandins. are expressed in BAT. Similar to the endocrine role of WAT. or when. The precise physiological significance of this parallel response of BAT to norepinephrine is as yet not fully appreciated. However. C3a is inactivated to C3desArg which is more commonly referred to as acylation-stimulating protein (ASP). Norepinephrine stimulation and cold stress both result in increased levels of VEGF expression in BAT. This is not to say that BAT doesn't have a potential endocrine role it is just not as well established as the endocrine role of WAT. vascular endothelial cell growth factor (VEGF). as well as brown adipocytes in culture. angiotensinogen. BAT also synthesizes and secretes numerous factors. It is unclear how. The secretion of NGF occurs primarily from proliferating brown preadipocytes and in this capacity is believed to promote sympathetic innervation of the tissue which in turn permits increased norepinephrine stimulation of the cells in BAT. Norepinephrine stimulation of BAT. fibroblast growth factor 2 (FGF2). IGF-1 action can prevent TNF-α-induced apoptosis in brown fat. Adipsin (also known as complement factor D) cleaves the complement protein C3 into C3a and C3b. The expression of VEGF in BAT may promote and maintain the high level of vascularization in this tissue. due to the relatively small overall size of brown fat compared to white fat the role of factors secreted from BAT serve many autocrine and paracrine roles.

production of NO may lead to inhibition of mitochondrial oxidation. . Within BAT the production of NO likely promotes rapid increases in blood flow.