Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance

Hotamışlıgil, Gökhan S.; Shargill, Narinder S.; Spiegelman, Bruce M.

doi:10.1126/science.7678183

Cited by 6,744 publications

(5,020 citation statements)

References 66 publications

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“…Infiltration of adipose tissue by immune cells such as macrophages has recently been described in obese mice and humans 67,68 . Chronic inflammation is characterized by abnormal cytokine production 69 , and tumour necrosis factor-(TNF ) has been found to be overexpressed in the adipose tissue of obese mice 70 . TNF is a pro-inflammatory cytokine that activates various signal transduction cascades, including many of the pathways that are discussed below as crucial inhibitors of insulin action.…”

Section: Nature Reviews | Molecular Cell Biologymentioning

confidence: 99%

Lipid signalling in disease

Wymann

Schneiter

2008

Nat Rev Mol Cell Biol

1,101

877

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Section: Nature Reviews | Molecular Cell Biologymentioning

confidence: 99%

Lipid signalling in disease

Wymann

Schneiter

2008

Nat Rev Mol Cell Biol

1,101

877

View full text Add to dashboard Cite

“…6 Several findings have converged to indicate that adipocytes share certain properties with immune cells, such as complement activation 7 and proinflammatory cytokine production. 8 Fat cell precursors also share features with macrophages. Numerous genes that code for transcription factors, cytokines, inflammatory signaling molecules, and fatty acid transporters are essential for adipocyte biology and are also expressed and functional in macrophages.…”

Section: Introductionmentioning

confidence: 99%

Leptin in immuno-rheumatological diseases

et al. 2011

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Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic actions. One of these functions is the relationship between nutritional status and immune competence. It structurally resembles proinflammatory cytokines, such as IL-6 and IL-12. The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. The role of leptin in regulating immune responses has been assessed in vitro as well as in clinical studies. It has been shown that disease conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with the increased secretion of leptin and the production of proinflammatory pathogenic cytokines. In this paper, we review the most recent advances of the role of leptin in immune-rheumatological diseases, and we discuss whether strategies aimed at modifying leptin levels could represent innovative and therapeutic tools for autoimmune disorders. Keywords: adipokines; autoimmune diseases; leptin; rheumatic diseases INTRODUCTIONThe existence of a factor secreted by white adipose tissue (WAT), which acts to control feeding, weight and WAT mass, was first proposed by Kennedy 1 and is supported by monogenic mutations resulting in obesity. [2][3][4] WAT is composed of adipocytes filled mainly with triacylglycerol and embedded in loose connective tissue containing adipocyte precursors, fibroblasts, immune and other cells. Obesity, the condition that originally motivated the research on WAT, is characterized by low-grade systemic inflammation. It is thought that excess WAT can contribute to the maintenance of obesity through inflammation-inducing lipotoxicity by secreting factors that stimulate the synthesis of inflammatory agents in other organs and by secreting inflammatory agents itself. 5 The current view of WAT states that it is an active contributor to body homeostasis by sending out and responding to signals that modulate appetite, energy expenditure, insulin sensitivity, the endocrine and reproductive systems, bone metabolism, inflammation and immunity. 6 Several findings have converged to indicate that adipocytes share certain properties with immune cells, such as complement activation 7 and proinflammatory cytokine production. 8 Fat cell precursors also share features with macrophages. Numerous genes that code for transcription factors, cytokines, inflammatory signaling molecules, and fatty acid transporters are essential for adipocyte biology and are also expressed and functional in macrophages. 9 Adipose tissue secrets a variety of factors: the term 'adipokine' is generally given to any protein that can be synthesized and secreted by adipocytes. Among these factors, only leptin and adiponectin (and possibly resistin, adipsi...

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“…Adipose tissue is now recognized as an endocrine organ that secretes many cytokines and growth factors. 4,5 For example, several reports have demonstrated that adipocytes secrete tumor necrosis factor alpha, 6 resistin, 7 plasminogen activator inhibitor-1 (PAI-1), 8 leptin 9 and angiotensinogen. 10,11 Vascular endothelial growth factor (VEGF) is an angiogenetic growth factor, which is secreted by rat adipose tissue ex vivo.…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte growth factor secreted by cultured adipocytes promotes tube formation of vascular endothelial cells in vitro

et al. 2006

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Objective: Adipose tissue is closely associated with angiogenesis, but the mechanisms are not fully understood. Some of the adipocyte-derived cytokines are hypothesized to play an important role in angiogenesis. We evaluated tube formation of human umbilical vascular endothelial cells (HUVECs) cultured in type I collagen gel when overlaid with the supernatant of 3T3-L1 cell culture, and expression of tube-forming factor(s) in 3T3-L1 cells with or without pioglitazone. We also studied plasma growth factor levels in patients with type 2 diabetes mellitus treated with pioglitazone. Results and methods: The supernatant of 3T3-L1 cells increased tube formation of HUVECs by 9.03-fold of control. Reverse transcription-polymerase chain reaction showed that hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) mRNA were expressed in 3T3-L1 cells. Western blot analysis also demonstrated HGF and VEGF protein expression. When 3T3-L1 cells were treated with 100 nM small interfering RNAs (siRNAs) for HGF, the HGF mRNA and protein were suppressed. The VEGF mRNA and protein in the cells were also suppressed by siRNA for VEGF. The supernatant of 3T3-L1 cells treated with HGF siRNA suppressed tube formation of HUVECs by 61% compared with the supernatant of cells treated with control siRNA. Addition of VEGF siRNA resulted in no significant changes. The supernatant conditioned with pioglitazone further promoted the tube formation. Pioglitazone enhanced HGF mRNA expression in 3T3-L1 cells. After 12 weeks of pioglitazone treatment, the changes of plasma HGF levels in patients treated with pioglitazone were significantly higher than those in control. Conclusion: These results suggest that HGF secreted from 3T3-L1 cells may be the major factor regulating the tube formation, and agents that enhance the differentiation of adipocytes may promote tube formation of HUVECs mediated by HGF secreted by adipocytes.

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Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance

Cited by 6,744 publications

References 66 publications

Lipid signalling in disease

Lipid signalling in disease

Leptin in immuno-rheumatological diseases

Hepatocyte growth factor secreted by cultured adipocytes promotes tube formation of vascular endothelial cells in vitro

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