Russell D’Souza MD Jurnal Widya Medika Surabaya Vol.1 No.2 Oktober 2013

Obesity An overview of the complex biological effects of expanding adipose tissue

T.W. van Haeften*

Abstract

Obesity has a more complex biology than previously thought. Feeding behaviour is regulated via a integrative circuit of afferent input from the stomach, the pancreas and the intestines via hormonal influences and the vagal nerve, which affect hypothalamic nuclei. This will lead to satiety and inhibition of hunger combined with other effects such as energy expenditure and growth promoting effects. Moreover, upon sufficient caloric intake, triglycerides are taken up in adipocytes, which in their turn will produce more which inhibits hypothalamic nuclei and which will add to these hypothalamic effects. It has been suggested that more macrophages enter the adipose tissue which would alter adipocyte secretion. Adipocytes are now known to produce an array of with hormonal effects calledadipo(cyto)kines. In obesity, many of these adipokines are produced in substantially higher amounts with potentially deleterious effcets notably on the risk of atherosclerosis, type 2 diabetes and cancer.

______* Dept Internal Medicine F 02.126. UMC Utrecht PO Box 8085 NL 3508 GA Utrecht The Netherlands

INTRODUCTION and various forms of cancer (1).

Many countries now see a rapidly expanding Although the biology behind this is still a “pandemic” of obesity. matter of intense research, the complexity of this becomes gradually apparent. The unique While this started mainly in the Western position of visceral fat as to the portal vein world, since some 20 years virtually all circulation has led to intense research into the countries now see their populations literally relationship of visceral fat and liver function growing fatter. and more generally to the “endocrinological” role of visceral fat tissue. The causes for this are more complex than was initially thought. Fat tissue is now known not only to act as storage pool for calories in the form of A major concern has become the development triglyceride, but also to secrete a number of “visceral obesity” that is the phenomenon of proteins which act as cytokines at distal that adipose tissue has enlarged around the sites, known as adipocytokines or adipokines. “viscera” i.e. within the abdomen. Although obesity is a recent phenomenon, Visceral obesity may lead to larger risks for adipocytokines date back over many millions a number of diseases, notably cardiovascular of years and are present in all mammals and (atherosclerotic) disease, diabetes mellitus, even other species.

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BIOLOGY OF ADIPOCYTES to the situation of obesity, leptin’s major physiological effects are notable when Adipose tissue exists mainly of adipocytes, adipocytes are small. which are formed from precursor cells, so called pre-adipocytes . Adipocytes can rapidly Adipocytes are now known to produce an take up fatty acids (FA) and can store fat is array of adipocytokines with effects not only triglycerides. on appetite and energy expenditure (leptin) but also on the vasculature (, FA circulate in the plasma mainly in the form visfatin, , omentin, chemerin, ), of triglycerides,bound to Very Low Density the immune system (interleukin-6) or have Lipoproteins (VLDL) and chylomicrons. effects on inflammation (Tumor Necrosis Upon activation by , Lipoprotein Lipase Factor-alpha (TNF-alpha), adipsin) (4). Many (LPL) located in the vascular tissue will exert adipokines may have a role in cell division a lipolytic effect on VLDL-bound triglyceride, (leptin, interleukins). forming glycerol and three molecules of FA. FA’sare then taken up into the adipocyte by The roles of adiponectin and the effects of Fatty Acid Binding Proteins (FABP) which leptin for food intake will first be described, are located at the cell surface. followed by the influences of other organs on food intake. Within the adipocyte, FA’s and glycerol can form triglyceride,again under stimulation of Adiponectin insulin.Upon uptake of fat, adipocytes become Adiponectin is produced by adipose tissue larger , but obesity will not induce further and skeletal muscle. While larger adipocytes development of preadipocytes to adipocytes. will produce larger quantities of most Inversely, adipocyte triglyceride can rapidly adipocytokines, the production of adiponectin undergo lipolysis in which the FA’s and is lower in larger adipocytes. Adiponectin has glycerol are formed; FA’s can then leave the anti-inflammatory actions in macrophages via adipocyte. Lipolysis occurs by enzymatic inhibition of nuclear factor kappa-light chain effects of adipose triglyceride lipase enhancer of B cells (NF-kB) (5). A similar (ATGL), hormone sensitive lipase (HSL) and inhibition may also have an anti-atherogenic monoglyceride lipase (2). This process is under effect in endothelial cells. By virtue of its effect stimulatory influence of (nor-)epinephrine by on endothelial nitric oxide synthase (eNOS), virtue of the activation of hormone sensitive which regulates the production of nitric oxide lipase (HSL) (3); insulin is notable in that it (NO), adiponectin may diminish proliferation has a strong inhibitory effect on HSL and thus of vascular smooth muscle cells. Some on lipolysis. The latter inhibitory mechanism studies point also to a role for adiponectin underlines actually the weight losing effect of in myocardial remodeling protecting the a calorie-restricted diet:caloric restriction will myocardium from injury (6). lead to less insulin production ; thereby less Adiponectin may increase insulin sensitivity, inhibition of lipolysis ensues. fatty acid oxidation and inhibit hepatic Interestingly, a slight increase in size will gluconeogenesis. These protective effects induce adipocytes to produce larger quantities (anti-atherogenic, anti-diabetic, anti- of most of its proteins. In apparent contrast inflammatory) make adiponectin a” good”

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adipokine. It is of particular note that since HORMONAL RELATIONS BETWEEN adipocytes become larger in obesity, they OTHER ORGANS AND FOOD INTAKE produce less adiponectin possibly adding Stomach to the augmented risk of obese subjects for atherosclerosis and diabetes. GhrelinInterestingly, the effects of leptin are largely opposed by gastric production Leptin and food intake of ghrelin, a which is produced Leptin is exclusively produced from under circumstances of hunger. Ghrelin can adipocytes.Its production is regulated over stimulate the release of the course of weeks. Plentitude of food intake (GH), hence its name. Upon binding to will lead to increased production of leptin by specific receptors in the hypothalamus, the (enlarged) adipocytes. Ghrelin stimulates (NPY) release and induces food intake (9). It was Leptin acts on leptin receptors present in originally thought that the stomach would various tissues (7). Upon binding with leptin, secrete ghrelin simply because the stomach leptin receptors present in the hypothalamus was empty and therefore the person was will lead to activation of the melanocortin 4 hungry. The thus secreted ghrelin would then (MC4) which will decrease hunger stimulate the person via the hypothalamus to (with reduction of food intake) and at the go and eat. However, it now appears that in same time will lead to expenditure of energy. humans this relationship is more complex and Leptin will further diminish neuropeptide Y that the simple knowledge of a person that “it (NPY) in arcuate nucleus cells, which will is time to eat” may be sufficient for cerebral then suppress hunger. stimulation of the stomach to secrete more ghrelin, which indeed in turn will activate the In addition, leptin receptors in the hypothalamus to make the person feel hungry. hypothalamus are nicely situated to also Therefore, the clinical importance of ghrelin influence pituitary function (7,8). Leptin can is still under debate. stimulate gonadotrophin production which activates gonadal function. Upon continued Pancreas food intake , increasing levels of leptin will then enable the animals gonadal function Insulin secretion Insulin is secreted in low and ultimately its breeding. Similarly, leptin amounts during the fasting state by B cells appears to influence growth hormone and in the pancreas islets. Upon eating insulin is possibly also Thyrotropin Releasing Hormone secreted in larger amounts, both due to the (TRH) and thereby Thyroid Stimulating effects of swallowing and the stimulation of Hormone (TSH) levels and thyroidal food on the intestines and by the mere effect function. This constellation would lead to the of the rise in plasma glucose. Insulin will then proposition that feeding itself will activate lead to decreases in hepatic glucose production in the animal a complex hormonal interplay and uptake of glucose and formation of ultimately leading to growth and procreation. glycogen in muscle and adipose tissue. Interestingly, insulin is now known to have more effects: it has cell nucleus effects leading to changes in protein production and even mitosis in various tissues. Moreover, insulin

127 T.W. van Haeften Jurnal Widya Medika Surabaya Vol.1 No.2 Oktober 2013 has multiple effects on the hypothalamus In the lower intestines Peptide YY (PYY) is leading to enhancing satiety after a meal , and also released in response to food and , just as inhibition of hunger (10). Indeed , intranasal GLP1, notably in response to protein (14). insulin administration reduces body weight in men (but not in women) (11). Thus, Taken together the leptin pathways imply a insulin appears to have leptin-like actions useful feedback of adipocytes on appetite and on hypothalamic centers although its time food intake. Various hormonal and neuronal course is possibly more rapid. Indirectly, it effects from the gut further influence food may enhance energy expenditure possibly via intake. They also enable the animal to expand enhanced sympathetic tone. energy, and appear to fulfill roles in enabling the animal to grow and to breed under The gut circumstances with sufficient food. The presence of food in the intestines will ROLE OF INFLAMMATION IN lead to production of gastric inhibitory EXPANDING ADIPOSE TISSUE polypeptide also known as glucose- Normal fat tissue contains a low amount of independent insulinotropic polypeptide inflammatory cells, notably macrophages (GIP) and -like peptide 1 (GLP1) of the M2 type and eosinophils. In obesity, which will activate the B-cells via specific these cells are relatively scarce, while other cell receptors to produce and secrete insulin inflammatory cells predominate, notably M1- especially at times that plasma glucose levels macrophages, neutrophils , lymphocytes, are (slightly) elevated (12). mast cells and others (15). This apparently GLP1 and GIPGLP1 has multiple effects leads to augmented secretion of cytokines, presumably on cardiac tissue and especially among which Tumor Necrosis Factor –alpha on food intake. In rodents, GLP1 diminishes (TNF-α), Interleukin-6 (IL-6) and others, food intake by activation of specific which have been reported to impair insulin receptors on hypothalamic centers by effects signaling. reminiscent of leptin. However, in humans Visceral fat and subcutaneous tissue express GLP1 is metabolized to inactive metabolites a large number of in an identical within minutes by dipeptidyl peptidase 4 manner. However, subtle differences exist (1), (DPP4). In humans the effects of GLP1 on with preponderance of leptin production in food intake have been suggested to be indirect subcutaneous fat tissue, while no differences via stimulation of the autonomic nervous exist in TNF-alpha; complement factors, system especially the afferent branches of angiotensinogen and others are produced the vagal nerve (13). However, subcutaneous predominantly in visceral tissue. Many of administration of analogues of GLP-1, that the deleterious effects of obesity seem to are not readily metabolized by DPP4, are relate mainly to the development of visceral effective in reducing hunger and consequently adiposity. in reducing food intake presumably by direct hypothalamic effects. BIOLOGICAL IMPACT OF OBESITY

In rodents GIP has also an effects on the Obesity has a slowly evolving effect on hypothalamus leading to satiety and less alarge number of systems in mammals. It has hunger. gradually become clear that obesity increases

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the risk of atherosclerosis, type 2 diabetes Dyslipidemia Obesity is associated with mellitus (Type 2 DM) and of certain types of disturbances in plasma lipids, with a notable cancer.These three disorders will be described increase in Low Density Lipoprotein only briefly, since an elaborate review of these cholesterol (LDL-cholesterol) and plasma complex disorders is outside the scope of this triglycerides, and a decrease in High Density overview. Lipoprotein cholesterol (HDL-cholesterol) especially in insulin resistant subjects. Atherosclerosis Presumably, the underlying insulin resistance Epidemiological studies have concluded to leads to slightly elevated lipolysis with a augmented risk for atherosclerotic disease production of fatty acids in adipose tissue. for obese people (1). However, the largest Upon uptake in the liver, fatty acids will be risk seems to relate to visceral adiposity, bound to triglyceride. In the liver this is process that is the existence of adiposity around the is related to the production of cholesterol and “viscera” within the abdomen, as opposed its binding lipoprotein (Apo-B 100); this leads to subcutaneous fat. Atherosclerosis is a to Very-Low-Density-Lipoprotein (VLDL) complex disease with disturbances in the formation. VLDL is transported into the arteries among which in the intima media . blood, and it can release its cholesterol and A large number of mechanisms is involved, its triglycerides in the vessel wall, potentially including macrophage activation in the arterial leading to atherosclerosis. wall, enhanced inflammatory changes, pro- Hypertension .Angiotensinogen and leptin thrombotic changes etc. have been proposed to lead to hypertension. Adipokines have multiple effects which Indeed, although obesity itself clearly relates can augment the atherosclerotic process. to hypertension, leptin-deficient humans For example, leptin has an NO-dependent (who are very obese) are not hypertensive. vasodilatory effect but it can also upregulate Leptin can augment sympathetic tone and can endothelin-1 , a vasoconstrictor (16). It upregulate Na/K ATP-ase in the kidney. Large has also been proposed to lead to cellular adipocytes produce more angiotensinogen, changes in vascular cells. Resistin has been which would activate aldosterone and thereby proposed to activate endothelin (15), and to lead to hypertension. have multiple effects leading to endothelial Insulin resistance dysfunction and possibly proliferative effects on the vasculature (6). Adiponectin has been Insulin has a number of secondary effects: proposed to exert anti-atherosclerotic effects upon activation of the , via its inhibitory effects on TNF-alpha in autophosphorylation of the receptor activates the vascular wall. Unfortunately, in obesity, Insulin Receptor Substrate-1 (IRS-1), which less adiponectin is produced in adipocytes. in its turn will phosphorylate subsequent Visfatin is also produced less in obesity. molecules, Phospho- Inositol-3 phosphate Kinase (PI3-Kinase) leading to activation of In obesity, adipocytes grow larger and produce Akt, ultimately leading to transcription of larger amounts of most of the adipokines. other factors at the DNA level, which will It has been proposed that this is related to lead to production of various protein involved hypoxia within the adipose cell (16). in diverse cellular processes as glycogen formation, (inhibition of) gluconeogenesis,

129 T.W. van Haeften Jurnal Widya Medika Surabaya Vol.1 No.2 Oktober 2013 and to stimulation of glucose uptake. Insulin Type 2 Diabetes will also activate IRS-2. Via separate pathway of activating Mitogen Activating Protein Obesity is strongly associated with Type Kinase (MAPK), activation of the IRS-1 will 2 diabetes.Type 2 diabetes ensues as a also lead to processes involved in expression consequence of the combination of insulin of other genes notably involved in cellular resistance and pancreas beta cell failure growth and mitosis. (20). The above mentioned mechanisms for the development of insulin resistance are The activity of IRS1 is of major importance certainly of importance for the development for overall insulin signaling. IRS-1 activity of diabetes. During the development of type 2 can be decreased by serine phosphorylation by diabetes beta cell mass is probably diminished Protein Kinase C (PKC), C-JunKinase (JNK), in part by apoptosis (21). mammalian target of rapamycin (m-Tor), Suppressor of cytokine signaling-3 (Socs3)and It is now suspected that a number of adipokines others (17). This will decrease phosphorylation have deleterious effects in beta-cells. of PI-3K and activateproteasome dependent Leptin itself can augment insulin secretion. degradation. There is conflicting evidence regarding its Although the precise mechanisms of the potential to affect B cell apoptosis. On one side occurrence of insulin resistance is still a leptin has been shown to decrease uncoupling matter of intense research, Free Fatty Acids protein 2 (UCP2) in Bcells which would (FFA), interleukin -6 and TNF-alpha have decrease apoptosis, but othershave not found been proposed as causing insulin resistance an effect on apoptosis (22). However, leptin by inducing transcription of factors leading has multiple effects on transcription in to serine phosphorylation of IRS-1(and various cell types both via Janus Kinase / possibly IRS-2) at sites which will decrease Signal Transducer and Activator Transcription the activation of down-stream molecules. (JAK/STAT) and MAPK/extracellular signal- The (separate) pathway leading to activation regulated kinase (ERK) pathways which may of mitogen activated protein kinase (MAPK) have more subtle effects in apoptosis and/or and cellular growth is presumably less or not in B cell function. involved in the process of insulin resistance. Fatty acids, among which notably palmitate, This has led to the hypothesis that under states have been shown to be deleterious for B cells of insulin resistance the MAPK dependent and to be able to cause apoptosis. Adiponectin mechanisms have deleterious effects, for has been proposed to diminish the deleterious example in the myocardium (18). Similarly, it effects of palmitate . In its turn, palmitate has been proposed that vasoconstrictor effects appears to lower 2 of insulin is regulated by MAPK dependent mRNA. Adiponectin may also have effects signaling while nitric oxide (NO) dependent on gene transcription via ERK pathways (22). vasodilator effects are regulated via PI-3K. Others have proposed that adiponectin (and In states of insulin resistance the MAPK leptin) increase proliferation of B cells. effects would predominate possibly leading to endothelial dysfunction (19). TNF-alpha is able to induce apoptosis in B cells (22) either directly or possibly also via augmenting expression; amylin has

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been proposed to lead to accumulation of which is also augmented in obesity has also amyloid in islets. been hypothesized to relate to cancer by promoting tumour growth and/or by effects Although a possible role of visfatin is far on the vasculature such as adhesion and from clear, it now appears that visfatin may angiogenesis (22). Although more adipokines stimulate B cell proliferation; it may have have been named as potentially involved in additional effects possibly via gene regulation tumorigenesis, more research will be needed of PDX1 and the insulin gene (22). Visfatin before this would become clearer (22). is notable since its production is decreased in obesity and therefore its potential beneficial CONCLUSION effects on B cells might be of less importance Recent years have seen the exciting discovery in obesity. of the fundamental role of fat tissue hormonal Cancer regulation of food intake, satiety, and energy expenditure, as exemplified by the role of leptin. Obesity is associated with a markedly This has subsequently led to the discovery increased risk for a number of cancer types of several of hormones from other organs ,such as colon, esophageal, breast, uterine, , especially the gut , with important effects prostate and other cancers. In view of the in the regulation of food intake. Expanding marked hyperinsulinemia associated with adipose tissue, as is seen in obesity, has now insulin resistance, insulin is suspected to play been proposed to be under the influence of a major role. Indeed, insulin has proliferative inflammatory cells such as macrophages. and anti-apoptotic effects in various tissues. This leads presumably to production of Whether this effect is via the actual insulin deleterious substances such as TNF-alpha, receptor or via the Insulin-like Growth Factor interleukins and others. Several adipokines –I (IGF-1) receptor is so far less clear; insulin may be involved in the development of insulin can actually be bound to both receptor types resistance. Moreover, in obesity, adipocytes (23). The growth promoting properties of produce high amounts of deleterious IGF-1 are complex, since IGF-1 is bound to a adipokines that may have deleterious effects number of binding proteins, the levels of which on the risk of atherosclerosis, type 2 diabetes are partly dependent on plasma insulin. and cancer. Obese subjects are generally hyperinsulinemic in response to the prevailing A number of studies have looked into the insulin resistance. It has been suggested that potential role of leptin for breast cancer. insulin may have growth proliferative effects Leptinappears to augment production involved in tumour growth. Unfortunately, and expression , and it has a proliferative effect in obesity lower amounts of adiponectin are on breast tumour cells (23,24). By its MAPK produced; adiponectin may have protective and STAT signaling effects leptin is relevant effects both against the development of for cell proliferation and differentiation (23). atherosclerosis, and cancer and possibly type Adiponectin has been proposed to protect 2 diabetes. against carcinogenesis by its insulin sensitizing Legends effects (counteracting hyperinsulinemia), and by inactivating MAPK. Figure 1. A schematic representation of the effects of various hormones influencing Plasminogen activator inhibitor-1 (PAI-1)

131 T.W. van Haeften Jurnal Widya Medika Surabaya Vol.1 No.2 Oktober 2013 feeding behaviour. Ntaios G, Gatselis NK, Makaritsis K, Dalekos GN. Adipokines as mediators of endothelial Figure 2. Hypothalamic effects of leptin function and atherosclerosis. Atherosclerosis on feeding behaviour are associated with 2013; 227: 216-221 other effects notably on energy expenditure, and complex interactions with growth, and Tschop M, Smiley DL, Heiman ML. Ghrelin procreation. induces adiposity in rodents. Nature 2000: 407;908-913 Figure 3 .Insulin resistance: Effects of adipokines on insulin signaling Yu JH, Kim MS: Molecular mechanisms of appetite regulation. Diabetes Metab J 2012;36: Figure 4. Schematic representation of potential 391-398 effects of adipokines on atherosclerosis, cancer and type 2 diabetes mellitus Hallschmid M, Benedict C, Schultes B, Fehm HL, Born J, Kern W. Intranasal insulin reduces References body fat in men but not in women. Diabetes Hajer GR, Van Haeften TW, Visseren FLJ. 2004; 3024-3029 Adipose tissue dysfunction in obesity, diabetes Drucker DJ: Incretin action in the pancreas: and cardiovascular diseases. Eur Heart J potential promise, possible perils, and 2008;29: 2959-2971 pathological pitfalls. Diabetes 2013:6:3316- Van de Voorde J, Pauwels B, Boydens C, 3323 Decaluwe K. Adipocytokines in relation to Nishizawa M, Nakabayashi H, Uehara cardiovascular disease. Metabolism 2013; K, Nakagawa A, Uchida K, Koya D: 62:1513-1521 Intraportal GLP1 stimulates insulin secretion Arner P. Human fat cell lipolysis: biochemistry, predominantly through the hepatoportal- regulation and clinical role. Best Pract Res pancreatic vagal reflex pathways. Am J Clin Endocrinol Metab 2005:19:471-482 Physiol Endocrinol Metab 2013;305:E 376- 387 Mattu HS, Randeva HS: Role of adipokines in cardiovascular disease. J Endocrinol Van der Klaauw AA, Keogh JM, Henning E, 2013;216: T17-T36 Trowse VM, Dhillo WS, Ghatei MA, Farooqi IS: High protein intake stimulates postprandial Mattu HS, Randeva HS. Role of adipokines GLP1 and PYY release. Obesity 2013;21: in cardiovascular disease. J Endocrinol 1602-1607 2013;216:T17-T36 Feng B, Zhang T, Xu H. Human adipose Ouchi N, Shibata R, Walsh K. Cardioprotection dynamics and metabolic health. Ann N Y by adiponectin. Trends Cardiovasc Medicine Acad Sci 2013;1281: 160-177 2006; 16: 141-146 Van de Voorde J, Pauwels B, Boydens C, Yadav A, Kataria MA, Saini V, Yadav A. Role Decaluwe K. Adipocytokines in relation to of leptin and adiponectin in insulin resistance. cardiovascular disease. Metabolism 2013; ClinChim Acta 2013;417:80-84 62:1513-1521

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Aroor AR, McKarns S, Demarco VG, Jia Dunmore SJ, Brown JEP. The role of G, Sowers JR: Maladaptive immune and adipokines in B-cell failure of type 2 diabetes. inflammatory pathways lead to cardiovascular J Endocrinol 2013;216:T37-T45 insulin resistance. Metabolism 2013: 62:1543- 1552 De Pergola G, Silvestris F.Obesity as a major risk factor for cancer. J Obesity PMCID: Qi Y, Xu Z, Zhu Q, Thomas C, Kumar R, PMC3773450 ; Published online 2013 August Feng H, Dostal DE, White MF, Baker KM, 29. doi: 10.1155/2013/291546 Guo S:Myocardial loss of IRS-1 and IRS-2 causes heart failure and is controlled by p38a Vona-Davis L, Rose DP. Adipokines as MAPK during insulin resistance. Diabetes endocrine, paracrine, and autocrine factors in 2013; 3887-3900 breast cancer risk and progression. Endocrine- Related Cancer. 2007;14:189–206 Muniyappa R, Sowers JR: Role of insulin resistance in endothelial dysfunction. Rev Dieudonne M-N, Bussiere M, Dos Santos Endocr Metab Disord 2013; 14:5-12 E, Leneveu M-C, Giudicelli Y, Pecquery R. Adiponectin mediates antiproliferative and Stumvoll M, Goldstein BJ, Van Haeften TW: apoptotic responses in human MCF7 breast Type 2 diabetes – principles of pathogenesis cancer cells. Biochem Biophys Res Comm and therapy. Lancet 2005; 365: 1333-1346 2006;345:271–279

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Stomach Ghrelin

+ Hunger

Adipose tissue Leptin Hypothalamus - - Satiety Pancreas Insulin -

GLP1 - Gut PYY

Fig 1

Hunger - Hypothalamus Adipose tissue Leptin Satiety

GH

TRH LH

Energy Thyroid Procreation Growth Expenditure

Fig 2

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Insulin

Insulin Receptor

IL-6 P JNK IRS-1 Grb DNA P TNF- Socs-3 alpha

PI-3Kinase MAPK Akt

DNA- Glucose effect Fig 3

Resistin

Visfatin Atherosclerosis Adipo- nectin

PAI-1 Adipose Cancer Tissue IL-6

Leptin

Fatty Diabetes Acid TNF- alpha

Fig 4

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