Metformin reduces lipolysis in primary rat adipocytes stimulated by tumor necrosis factor-α or isoproterenol

Abstract

In patients with type 2 non-insulin-dependent diabetes mellitus (NIDDM), the biguanide, metformin, exerts its antihyperglycemic effect by improving insulin sensitivity, which is associated with decreased level of circulating free fatty acids (FFA). The flux of FFA and glycerol from adipose tissue to the blood stream primarily depends on the lipolysis of triacylglycerols in the adipocytes. Adipocyte lipolysis is physiologically stimulated by catecholamine hormones. Tumor necrosis factor-a (TNF-a), a cytokine largely expressed in adipose tissue, stimulates chronic lipolysis, which may be associated with increased systemic FFA and insulin resistance in obesity and NIDDM. In this study, we examined the role of metformin in inhibiting lipolytic action upon various lipolytic stimulations in primary rat adipocytes. Treatment with metformin attenuated TNF-a-mediated lipolysis by suppressing phosphorylation of extracellular signal-related kinase 1/2 and reversing the downregulation of perilipin protein in TNF-a-stimulated adipocytes. The acute lipolytic response to adrenergic stimulation of isoproterenol was also restricted by metformin. A high concentration of glucose in the adipocyte culture promoted the basal rate of glycerol release and significantly enhanced the lipolytic action stimulated by either TNF-a or isoproterenol. Metformin not only inhibits the basal lipolysis simulated by high glucose, but also suppresses the high glucose-enhanced lipolysis response to TNF-a or isoproterenol. The antilipolytic action in adipocytes could be the mechanism by which cellular action by metformin reduces systemic FFA concentration and thus improves insulin sensitivity in obese patients and the hyperglycemic conditions of NIDDM.

A short bout of HFD promotes long-lasting hepatic lipid accumulation

“…8 In addition, TNFa stimulates lipolysis in adipocytes. 16 Hence, increased TNFa expression in mesenteric WAT may have promoted FFA release in HFD RF mice. Such effect may be limited to the mesenteric fat depot since short-term HFD did not affect lipolytic function of systemically drained epididymal WAT.…”

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

“…The positive influence of different drugs, such as metformin, thiazolidinediones, and salicylates, on NAFLD has been related, at least in part, to their modulation of peripheral lipolysis (Ren et al, 2006). In particular, thiazolidinediones and salicylates are thought to reduce TNF-␣-induced lipolysis, the latter of which potentially involves a mechanism that prevents reduction of perilipin A (Souza et al, 1998;Zu et al, 2008).…”

TNF‐α, a potent lipid metabolism regulator

“…47 Treatment of adipocytes with metformin could attenuate TNF-a-mediated lipolysis by suppressing phosphorylation of ERK1/2 and reverse the down-regulation of perilipin protein. 48 Another study indicated that TNF-ainduced lipolysis by blunting endogenous inhibition of lipolysis and Gi protein down-regulation might also be involved. 49 However, results from subcutaneous administration of a polyclonal goat anti-rat TNF antibody to Zucker rats revealed that anti-TNF treatment could not alter lipid metabolism in the obese animals.…”