Role of hormone-sensitive lipase in beta-adrenergic remodeling of white adipose tissue.
Free fatty acids (FFA) are important extracellular and intracellular signaling molecules and are thought to be involved in beta-adrenergic-induced remodeling of adipose tissue, which involves a transient inflammatory response followed by mitochondrial biogenesis and increased oxidative capacity. This work examined the role of hormone-sensitive lipase (HSL), a key enzyme of acylglycerol metabolism, in white adipose tissue (WAT) remodeling using genetic inactivation or pharmacological inhibition. Acute treatment with the beta(3)-adrenergic agonist CL-316,243 (CL) induced expression of inflammatory markers and caused extravasation of myeloid cells in WAT of wild-type (WT) mice. HSL-knockout (KO) mice had elevated inflammatory gene expression in the absence of stimulation, and acute injection of CL did not further recruit myeloid cells, nor did it further elevate inflammatory gene expression. Acute pharmacological inhibition of HSL with BAY 59-9435 (BAY) had no effect on inflammatory gene expression in WAT or in cultured 3T3-L1 adipocytes. However, BAY prevented induction of inflammatory cytokines by beta-adrenergic stimulation in WAT in vivo and in cultured 3T3-L1 adipocytes. Chronic CL treatment stimulated mitochondrial biogenesis, expanded oxidative capacity, and increased lipid droplet fragmentation in WT mice, and these effects were significantly impaired in HSL-KO mice. In contrast to HSL-KO mice, mice with defective signaling of Toll-like receptor 4, a putative FFA receptor, showed normal beta-adrenergic-induced remodeling of adipose tissue. Overall, results reveal the importance of HSL activity in WAT metabolic plasticity and inflammation.
Mottillo
Emilio P
EP
Center for Integrative Metabolic and Endocrine Research, Department of Psychiatry and Behavioral Neuroscience, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Shen
Xiang Jun
XJ
Granneman
James G
JG
D041721:3T3-L1 Cells; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000096:biosynthesis / Q000235:genetics; D052436:Adipose Tissue, White / Q000187:drug effects / Q000201:enzymology*; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D004149:Dioxoles / Q000494:pharmacology*; D003576:Electron Transport Complex IV / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006651:Histocytochemistry; D008066:Lipolysis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D047493:PPAR alpha / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D002787:Sterol Esterase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D004149:Dioxoles; D004791:Enzyme Inhibitors; D047493:PPAR alpha; D012333:RNA, Messenger; D022702:Receptors, Adrenergic, beta-3; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D003576:Electron Transport Complex IV; D002787:Sterol Esterase