Novel Pharmacological Probes Reveal ABHD5 as a Locus of Lipolysis Control in White and Brown Adipocytes.

Autor:	Rondini EA; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan (E.A.R., L.M.-L., J.G.G.); Department of Chemistry, Scripps Research Institute, Jupiter, Florida (W.R.R., G.T.H.); and Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (A.E.G.)., Mladenovic-Lucas L; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan (E.A.R., L.M.-L., J.G.G.); Department of Chemistry, Scripps Research Institute, Jupiter, Florida (W.R.R., G.T.H.); and Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (A.E.G.)., Roush WR; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan (E.A.R., L.M.-L., J.G.G.); Department of Chemistry, Scripps Research Institute, Jupiter, Florida (W.R.R., G.T.H.); and Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (A.E.G.)., Halvorsen GT; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan (E.A.R., L.M.-L., J.G.G.); Department of Chemistry, Scripps Research Institute, Jupiter, Florida (W.R.R., G.T.H.); and Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (A.E.G.)., Green AE; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan (E.A.R., L.M.-L., J.G.G.); Department of Chemistry, Scripps Research Institute, Jupiter, Florida (W.R.R., G.T.H.); and Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (A.E.G.)., Granneman JG; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan (E.A.R., L.M.-L., J.G.G.); Department of Chemistry, Scripps Research Institute, Jupiter, Florida (W.R.R., G.T.H.); and Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (A.E.G.) jgranne@med.wayne.edu.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2017 Dec; Vol. 363 (3), pp. 367-376. Date of Electronic Publication: 2017 Sep 19.
DOI:	10.1124/jpet.117.243253
Abstrakt:	Current knowledge regarding acute regulation of adipocyte lipolysis is largely based on receptor-mediated activation or inhibition of pathways that influence intracellular levels of cAMP, thereby affecting protein kinase A (PKA) activity. We recently identified synthetic ligands of α - β -hydrolase domain containing 5 (ABHD5) that directly activate adipose triglyceride lipase (ATGL) by dissociating ABHD5 from its inhibitory regulator, perilipin-1 (PLIN1). In the current study, we used these novel ligands to determine the direct contribution of ABHD5 to various aspects of lipolysis control in white (3T3-L1) and brown adipocytes. ABHD5 ligands stimulated adipocyte lipolysis without affecting PKA-dependent phosphorylation on consensus sites of PLIN1 or hormone-sensitive lipase (HSL). Cotreatment of adipocytes with synthetic ABHD5 ligands did not alter the potency or maximal lipolysis efficacy of the β -adrenergic receptor (ADRB) agonist isoproterenol (ISO), indicating that both target a common pool of ABHD5. Reducing ADRB/PKA signaling with insulin or desensitizing ADRB suppressed lipolysis responses to a subsequent challenge with ISO, but not to ABHD5 ligands. Lastly, despite strong treatment differences in PKA-dependent phosphorylation of HSL, we found that ligand-mediated activation of ABHD5 led to complete triglyceride hydrolysis, which predominantly involved ATGL, but also HSL. These results indicate that the overall pattern of lipolysis controlled by ABHD5 ligands is similar to that of isoproterenol, and that ABHD5 plays a central role in the regulation of adipocyte lipolysis. As lipolysis is critical for adaptive thermogenesis and in catabolic tissue remodeling, ABHD5 ligands may provide a means of activating these processes under conditions where receptor signaling is compromised. (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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