Elsevier

Cytokine

Volume 45, Issue 1, January 2009, Pages 12-19
Cytokine

The adipose triglyceride lipase, adiponectin and visfatin are downregulated by tumor necrosis factor-α (TNF-α) in vivo

https://doi.org/10.1016/j.cyto.2008.10.006Get rights and content

Abstract

Inflammatory cytokines have been linked to obesity-related insulin resistance. To investigate the effect of TNF-α, an inflammatory cytokine, on insulin action, C57BL/6J mice were treated with TNF-α for 7 days after which we examined the in vivo effects of TNF-α on glucose tolerance and insulin sensitivity with IV glucose tolerance tests and hyperinsulinemic-euglycemic clamps. In addition, we analyzed the in vivo effect of TNF-α on several metabolism-related genes and adipocytokines implicated in the development of insulin resistance. TNF-α treatment resulted in markedly increased fasting blood glucose, insulin and free fatty acids (FFA) levels and reduced glucose tolerance. During the clamps, the rates insulin-stimulated whole body (GRd) and skeletal muscle glucose uptake (MGU) and insulin’s ability to suppress hepatic glucose production (HGP) were decreased in TNF-α treated animals, indicating insulin resistance. In addition, both PPARγ and ATGL mRNA expression in adipose tissues as well as ATGL protein levels in plasma were downregulated. Moreover, adipose mRNA expression and plasma protein levels of adiponectin and visfatin were significantly down-regulated. We conclude that the alterations of PPARγ, ATGL, adiponectin and visfatin may contribute to the development of insulin resistance mediated by TNF-α.

Introduction

Insulin resistance (IR) is a common feature of several disorders such as obesity, dyslipidemias, type 2 diabetes (T2DM), and hypertension, all of which are risk factors for cardiovascular diseases [1], [2]. The precise cause of insulin resistance is yet to be determined in any of these disorders but many studies have suggested that inflammatory cytokines may play a critical role [3], [4], [5]. For example, TNF-α, a proinflammatory cytokine, is highly expressed in adipose tissues of obese animals and obese humans with T2DM [6], [7], and obese mice lacking either TNF-α or TNF-α receptors are protected from developing insulin resistance [3], [8]. At the cellular level, it has been shown that 3–5 days exposure of 3T3-L1 or 3T3-F442A adipocytes to TNF-α reduces insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation in response to a maximal dose of insulin [9], [10]. Furthermore, TNF-α may induce insulin resistance by inhibiting GLUT4 gene expression in brown adipocytes [11] and by elevating plasma free fatty acids via stimulation of adipose tissue lipolysis [12]. Nevertheless, the molecular mechanism of TNF-α induced insulin resistance is still not completely understood.

Although there are several studies showing effects of TNF-α on adipokines including adiponectin [13], [14], we are not aware of studies examining the effects of TNF-α on PPARγ, adipose triglyceride lipase (ATGL) and visfatin in vivo. In the present study, we, therefore, have examined the hypothesis that TNF-α may contribute to the development of IR by modifying PPARγ and ATGL activities.

Section snippets

Animals pretreatment

Twenty three male C57BL/6J mice weighing between 26 and 32 g were purchased from the Experimental Animal Center of Chongqing University of Medical Sciences (Chongqing, China). The mice were housed in individual cages and subjected to an environmentally controlled room with a 12-h light/dark cycle, where they had free access to standard rat chow and water for 7 d. Mice were randomly assigned to one of four groups. The first group (H group, n = 21) were injected intraperitoneally with recombinant

Basal metabolic parameters

There were no significant differences in body weight among the four groups. Interestingly, plasma FFA, insulin and fasting blood glucose levels were significantly higher in the H group than in the NC group (P < 0.05 and P < 0.01). Plasma triglyceride and total cholesterol were slightly increased in H group. However, this increase did not reach statistical significance (Table 2).

Effect of TNF-α on IV glucose tolerance testing

The peak glucose levels achieved over the first 10 min of the IVGTT were significantly higher in the H group than in the L

Discussion

In addition to its antitumor and proinflammatory actions, TNF-α also modulates adipocyte biology and affects systemic glucose and lipid metabolism. These metabolic functions include regulation of lipogenesis and lipolysis and blocking the action of insulin [3], [8]. Although a substantial amount of data demonstrate a role of TNF-α in inducing insulin resistance via inhibition of insulin signaling [7], [20], the in vivo effects of this cytokine on other adipokines are less well established. In

Acknowledgments

This work was supported by research Grants from the National Natural Science Foundation of China (30771037, 30871199), Chongqing Municipal Education Commission (JK 050304), Chongqing medical university (XBZD200704) and the National Institutes of Health (R01-DK 58895 to G.B.).

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