Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications. To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob). We found that the expression of 1,304 transcripts correlated significantly with body mass. Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass. Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass. Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68. Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1op/op) mice suggest that these F4/80+ cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages. Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-alpha expression and significant amounts of iNOS and IL-6 expression. Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.

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Obesity is associated with macrophage accumulation in adipose tissue

Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.

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Inflammation and metabolic disorders

Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance However, the underlying molecular pathways are largely unknown In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO) The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue

/pdf/chronic-inflammation-in-fat-plays-a-crucial-role-in-the-1sc0uiuvmi.pdf

Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.

Adipose tissue is a complex, essential, and highly active metabolic and endocrine organ. Besides adipocytes, adipose tissue contains connective tissue matrix, nerve tissue, stromovascular cells, and immune cells. Together these components function as an integrated unit. Adipose tissue not only responds to afferent signals from traditional hormone systems and the central nervous system but also expresses and secretes factors with important endocrine functions. These factors include leptin, other cytokines, adiponectin, complement components, plasminogen activator inhibitor-1, proteins of the renin-angiotensin system, and resistin. Adipose tissue is also a major site for metabolism of sex steroids and glucocorticoids. The important endocrine function of adipose tissue is emphasized by the adverse metabolic consequences of both adipose tissue excess and deficiency. A better understanding of the endocrine function of adipose tissue will likely lead to more rational therapy for these increasingly prevalent disorders. This review presents an overview of the endocrine functions of adipose tissue.

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Adipose Tissue as an Endocrine Organ

Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue i...

Brown Adipose Tissue: Function and Physiological Significance

Obesity is highly associated with insulin resistance and is the biggest risk factor for non-insulin-dependent diabetes mellitus. The molecular basis of this common syndrome, however, is poorly understood. It has been suggested that tumour necrosis factor (TNF)-alpha is a candidate mediator of insulin resistance in obesity, as it is overexpressed in the adipose tissues of rodents and humans and it blocks the action of insulin in cultured cells and whole animals. To investigate the role of TNF-alpha in obesity and insulin resistance, we have generated obese mice with a targeted null mutation in the gene encoding TNF-alpha and those encoding the two receptors for TNF-alpha. The absence of TNF-alpha resulted in significantly improved insulin sensitivity in both diet-induced obesity and that resulting for the ob/ob model of obesity. The TNFalpha-deficient obese mice had lower levels of circulating free fatty acids, and were protected from the obesity-related reduction in the insulin receptor signalling in muscle and fat tissues. These results indicate that TNF-alpha is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.

Protection from obesity-induced insulin resistance in mice lacking TNF-|[alpha]| function

Cytokines, in particular tumor necrosis factor-alpha (TNF-alpha), have significant effects on energy metabolism and appetite although their mechanisms of action are largely unknown. Here, we examined whether TNF-alpha modulates the production of leptin, the recently identified fat-specific energy balance hormone, in cultured adipocytes and in mice. TNF-alpha treatment of 3T3-L1 adipocytes resulted in rapid stimulation of leptin accumulation in the media, with a maximum effect at 6 h. This stimulation was insensitive to cycloheximide, a protein synthesis inhibitor, but was completely inhibited by the secretion inhibitor brefeldin A, indicating a posttranslational effect. Treatment of mice with TNF-alpha also caused a similar increase in plasma leptin levels. Finally, in obese TNF-alpha-deficient mice, circulating leptin levels were significantly lower, whereas adipose tissue leptin was higher compared with obese wild-type animals. These data provide evidence that TNF-alpha can act directly on adipocytes to regulate the release of a preformed pool of leptin. Furthermore, they suggest that the elevated adipose tissue expression of TNF-alpha that occurs in obesity may contribute to obesity-related hyperleptinemia.

/pdf/tumor-necrosis-factor-alpha-contributes-to-obesity-related-1wq107xwxu.pdf

Tumor necrosis factor-alpha contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes.

Adipocyte fatty acid-binding protein, aP2, is a member of the intracellular fatty acid binding protein family. Previously, studies have shown increased insulin sensitivity in aP2-deficient mice with dietary obesity. Here, we asked whether aP2-related alterations in lipolytic response and insulin production are features of obesity-induced insulin resistance and investigated the effects of aP2-deficiency on glucose homeostasis and lipid metabolism in ob/ob mice, a model of extreme obesity. ob/ob mice homozygous for the aP2 null allele (ob/ ob-aP2 2/2 ) became more obese than ob/ob mice as indicated by significantly increased body weight and fat pad size but unaltered body length. However, despite their extreme adiposity, ob/ob-aP2 2/2 animals were more insulin-sensitive compared with ob/ob controls, as demonstrated by significantly lower plasma glucose and insulin levels and better performance in both insulin and glucose tolerance tests. These animals also showed improvements in dyslipidemia and had lower plasma triglyceride and cholesterol levels. Lipolytic response to b-adrenergic stimulation and lipolysis-associated insulin secretion was significantly reduced in ob/ob-aP2 2/2 mice. Interestingly, glucose-stimulated insulin secretion, while virtually abolished in ob/ob controls, was significantly improved in ob/ob-aP2 2/2 animals. There were no apparent morphological differences in the structure or size of the pancreatic islets between genotypes. Taken together, the data indicate that in obesity, aP2-deficiency not only improves peripheral insulin resistance but also preserves pancreatic b cell function and has beneficial effects on lipid metabolism. (Endocrinology 141: 3388 ‐ 3396, 2000)

/pdf/improved-glucose-and-lipid-metabolism-in-genetically-obese-3refm68t1t.pdf

Improved Glucose and Lipid Metabolism in Genetically Obese Mice Lacking aP2

Although obesity has become the most common metabolic disorder in the developed world and is highly associated with insulin resistance and noninsulin-dependent diabetes mellitus, the molecular mechanisms underlying these disorders are not clearly understood. Tumor necrosis factor-alpha (TNF-alpha) is overexpressed in obesity and is a candidate mediator of obesity-induced insulin resistance. Complete lack of TNF-alpha function through targeted mutations in TNF-alpha gene or both of its receptors results in significant improvement of insulin sensitivity in dietary, chemical, or genetic models of rodent obesity. In this study, we have analyzed the in vivo role of TNF signaling from p55 [TNF receptor (TNFR) 1] and p75 (TNFR 2) TNFR in the development of insulin resistance by generating genetically obese mice (ob/ob) lacking p55 or p75 TNFRs. In the ob/ob mice, the absence of p55 caused a significant improvement in insulin sensitivity. p75 deficiency alone did not affect insulin sensitivity but might potentiate the effects of p55 deficiency in animals lacking both TNFRs. These results indicate that TNF-alpha is a component of insulin resistance in the ob/ob model of murine obesity and p55 TNFR is the predominant receptor mediating its actions.

/pdf/functional-analysis-of-tumor-necrosis-factor-tnf-receptors-2dzzlglfez.pdf

Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity.

Obesity is associated with a cluster of abnormalities, including hypertension, insulin resistance, hyperinsulinemia, and elevated levels of both plasminogen activator inhibitor 1 (PAI-1) and transforming growth factor β (TGF-β). Although these changes may increase the risk for accelerated atherosclerosis and fatal myocardial infarction, the underlying molecular mechanisms remain to be defined. Although tumor necrosis factor α (TNF-α) has been implicated in the insulin resistance associated with obesity, its role in other disorders of obesity is largely unknown. In this report, we show that in obese (ob/ob) mice, neutralization of TNF-α or deletion of both TNF receptors (TNFRs) results in significantly reduced levels of plasma PAI-1 antigen, plasma insulin, and adipose tissue PAI-1 and TGF-β mRNAs. Studies in which exogenous TNF-α was infused into lean mice lacking individual TNFRs indicate that TNF-α signaling of PAI-1 in adipose tissue can be mediated by either the p55 or the p75 TNFR. However, TNF-α signaling of TGF-β mRNA expression in adipose tissue is mediated exclusively via the p55 TNFR. Our results suggest that TNF-α is a common link between the insulin resistance and elevated PAI-1 and TGF-β in obesity. The chronic elevation of TNF-α in obesity thus may directly promote the development of the complex cardiovascular risk profile associated with this condition.

https://www.pnas.org/content/pnas/96/12/6902.full.pdf

S M Wiesbrock

Papers

Protection from obesity-induced insulin resistance in mice lacking TNF-|[alpha]| function

Tumor necrosis factor-alpha contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes.

Improved Glucose and Lipid Metabolism in Genetically Obese Mice Lacking aP2

Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity.

Tumor necrosis factor α is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1