TY - JOUR T1 - Novel pharmacological probes reveal ABHD5 as a locus of lipolysis control in white and brown adipocytes. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.117.243253 SP - jpet.117.243253 AU - Elizabeth A. Rondini AU - Ljiljana Mladenovic-Lucas AU - William R. Roush AU - Geoff Halvorsen AU - Alex E. Green AU - James G. Granneman Y1 - 2017/01/01 UR - http://jpet.aspetjournals.org/content/early/2017/09/19/jpet.117.243253.abstract N2 - Current knowledge regarding acute regulation of adipocyte lipolysis is largely based on receptor-mediated activation or inhibition of pathways that influence intracellular levels of cyclic AMP (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 HSL. Co-treatment of adipocytes with synthetic ABHD5 ligands did not alter the potency or maximal lipolysis efficacy of the β-adrenergic receptor (ADRB) agonist, isoproterenol, indicating 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 hormone sensitive lipase (HSL), we found that ligand-mediated activation of ABHD5 led to complete TG hydrolysis, which involved predominately 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. ER -