Relative Contribution of Adipose Triglyceride Lipase and Hormone-sensitive Lipase to Tumor Necrosis Factor-α (TNF-α)-induced Lipolysis in Adipocytes

Abstract

TNF-␣ potently stimulates basal lipolysis in adipocytes, which may contribute to hyperlipidemia and peripheral insulin resistance in obesity. Recent studies show that adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) act sequentially in catalyzing the first two steps of adipose lipolysis in response to ␤-adrenergic stimulation. Here, we sought to determine their functional roles in TNF-␣-induced lipolysis. Silencing of ATGL expression in adipocytes almost completely abolished basal and TNF-␣-induced glycerol release. In comparison, the glycerol release under the same conditions was only partially decreased upon reduction in expression of either HSL or the ATGL coactivator CGI-58. Interestingly, overexpression of ATGL restored the lipolytic rates in cells with silenced HSL or CGI-58, indicating a predominant role for ATGL. While expression of ATGL, HSL and CGI-58 remains mostly unaffected, TNF-␣ treatment caused a rapid abrogation of the ATGL inhibitory protein G0S2. TNF-␣ drastically decreased the level of G0S2 mRNA, and the level of G0S2 protein could be maintained by inhibiting proteasomal protein degradation using MG-132. Furthermore, coexpression of G0S2 was able to significantly decrease TNF-␣-stimulated lipolysis mediated by overexpressed ATGL or CGI-58. We propose that the early reduction in G0S2 content is permissive for TNF-␣-induced lipolysis.During extended starvation and exercise, catecholamines stimulate the hydrolysis of triacylglycerol (TAG) 2 stores within the lipid droplets (LDs) in adipocytes. The so-called lipolysis makes available surplus fuel in the form of free fatty acids (FFAs) and glycerol for use by other organs and tissues. During the instances of nutritional overload such as obesity, elevated basal adipose lipolysis contributes to the increase of systemic FFA levels, thereby exacerbating peripheral lipotoxicity and insulin resistance (1-4). Considering the importance of TAG turnover at both physiological and pathological levels, it is not surprising that enzymes governing lipolysis have attracted immense research interest over the years. Among many intracellular lipases identified thus far that possess in vitro capacity to hydrolyze TAG, hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) are the most characterized functionally (5, 6). A body of evidence has emerged recently, suggesting that ATGL and HSL act sequentially in mediating adipocyte lipolysis in response to ␤-adrenergic stimulation (7-12). In this newly established model, ATGL initiates lipolysis by specifically removing the first FA from TAGs to produce DAG substrates, which are then hydrolyzed by HSL to generate an additional FA and MAG substrates. MAGs are converted into FA and glycerol by MAG lipase in the final step of lipolysis.HSL was discovered nearly half a century ago due to its induction during fasting and by catabolic hormones (13,14). It has broad substrate specificity toward acylglycerols, including TAG, DAG, and MAG, as well as cholesteryl, retinyl, and lipoidal esters....

Dietary fat modifies lipid metabolism in the adipose tissue of metabolic syndrome patients

“…This is consistent with in vitro data in adipocytes, showing that TNF-a induces lipolysis (Yang et al 2011) and reinforces the association between inflammation and increased lipolysis, as has previously been shown (Langin et al 2005). Taken together, these data together with ours suggest that the increase in lipolysis after the consumption of saturated fat may be a consequence of a decrease in insulin sensitivity caused by the inflammatory status, which has indeed been shown to be made worse by saturated fat (Peairs et al 2011;van Dijk et al 2009).…”

G0/G1 switch gene-2 regulates human adipocyte lipolysis by affecting activity and localization of adipose triglyceride lipase

“…The expression of both proteins was strongly dependent on the presence of the PPAR-␥ agonist rosiglitazone, confi rming previous reports identifying ATGL and G0S2 as PPAR-␥ targets ( 13,19,35,36 ). In contrast, expression levels of CGI-58 remained unaffected by rosiglitazone treatment.…”

“…G0S2 expression is downregulated in response to fasting and increased upon refeeding in humans and chickens ( 17,18 ). Accordingly, the antilipolytic hormone insulin increases G0S2 expression in murine 3T3 cells, whereas stimulation of lipolysis by ␤ -adrenergic agonists and tumor necrosis factor-␣ has the opposite effect ( 13,19 ). Importantly, a recent report demonstrated that G0S2 mRNA and protein expression is reduced in adipose tissue of type 2 diabetic humans, indicating that enhanced ATGL activity contributes to elevated lipolysis and plasma fatty acid (FA) levels in type 2 diabetes ( 20 ).…”

Medium-chain Fatty Acid-sensing Receptor, GPR84, Is a Proinflammatory Receptor

“…Therefore, MCFAs and hydroxy-MCFAs are still just potential ligands but not the bona fide "endogenous ligands." However, it might be possible that MCFAs including the hydroxylated forms are liberated from tissues that are especially rich in fat because FFAs are released from adipocytes by TNF␣-induced lipolysis (35). Considering that all other FFAsensing receptors and hydroxy-carboxylic acid receptors work to regulate metabolic and/or inflammatory conditions (36 -38), it is likely that the MCFAs-GPR84 system can be a new player for chronic low grade inflammation in adipose tissue, affecting this metabolic disorder.…”