Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 47, Pages 40477-40485Publisher
ELSEVIER
DOI: 10.1074/jbc.M111.257923
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Funding
- National Institutes of Health [DK089178]
- American Diabetes Association
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TNF-alpha 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 beta-adrenergic stimulation. Here, we sought to determine their functional roles in TNF-alpha-induced lipolysis. Silencing of ATGL expression in adipocytes almost completely abolished basal and TNF-alpha-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-alpha treatment caused a rapid abrogation of the ATGL inhibitory protein G0S2. TNF-alpha 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-alpha-stimulated lipolysis mediated by overexpressed ATGL or CGI-58. We propose that the early reduction in G0S2 content is permissive for TNF-alpha-induced lipolysis.
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