Tumor Necrosis Factor α Stimulates Lipolysis in Adipocytes by Decreasing Gi Protein Concentrations

Abstract

Prolonged treatment (12-24 h) of adipocytes with tumor necrosis factor ␣ (TNF␣) stimulates lipolysis. We have investigated the hypothesis that TNF␣ stimulates lipolysis by blocking the action of endogenous adenosine. Adipocytes were incubated for 48 h with TNF␣, and lipolysis was measured in the absence or presence of adenosine deaminase. Without adenosine deaminase, the rate of glycerol release was 2-3-fold higher in the TNF␣-treated cells, but with adenosine deaminase lipolysis increased in the controls to approximately that in the TNF␣-treated cells. This suggests that TNF␣ blocks adenosine release or prevents its antilipolytic effect. Both N 6 -phenylisopropyl adenosine and nicotinic acid were less potent and efficacious inhibitors of lipolysis in treated cells. A decrease in the concentration of ␣-subunits of all three G i subtypes was detected by Western blotting without a change in G s proteins or ␤-subunits. G i2 ␣ was about 50% of control, whereas G i1 ␣ and G i3 ␣ were about 20 and 40% of control values, respectively. The time course of G i down-regulation correlated with the stimulation of lipolysis. Furthermore, down-regulation of G i by an alternative approach (prolonged incubation with N 6 -phenylisopropyl adenosine) stimulated lipolysis. These findings indicate that TNF␣ stimulates lipolysis by blunting endogenous inhibition of lipolysis. The mechanism appears to be a G i protein down-regulation.TNF␣ 1 is a multifunctional cytokine important in many pathological and physiological states (1). A series of recent reports has demonstrated that adipose tissue expresses TNF␣ mRNA and protein. Furthermore, adipose tissue from obese animals and humans expresses considerably more TNF␣ than does tissue from their lean counterparts (2, 3). This excess expression of TNF␣ in adipose tissue may form a link between obesity and development of insulin resistance, which often leads to type 2 diabetes in obese subjects (4). However, TNF␣ is not measurable in the circulation of obese subjects and is therefore considered an autocrine or paracrine regulator of adipose tissue metabolism.TNF␣ has several effects on adipocytes that may be related to the development of type 2 diabetes in obese subjects. It has been reported that TNF␣ induces insulin resistance possibly by inducing serine phosphorylation of insulin receptor substrate-1 and converting it to an inhibitor of the insulin receptor tyrosine kinase (5). In addition, TNF␣ causes a net depletion of the adipose tissue triglyceride. Initially, this was thought to be largely because of a decrease in the activity of lipoprotein lipase (6). However, we and others have reported that TNF␣ also stimulates lipolysis both in rat adipocytes maintained in primary culture (7) and in 3T3-L1 adipocytes (8 -10). We found that TNF␣-induced stimulation of lipolysis in primary adipocytes is chronic in nature, taking approximately 6 -12 h before a measurable effect is observed (7). Furthermore, neither the rate of isoproterenol-stimulated lipolysis nor the concentration of hormone-sens...

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Mapping of Early Signaling Events in Tumor Necrosis Factor-α-mediated Lipolysis in Human Fat Cells

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