title: Suppression of adipose lipolysis by long-chain fatty acid analogs.
abstract: Agonist-induced lipolysis of adipose fat is robustly inhibited by insulin or by feedback inhibition by the long-chain fatty acids (LCFA) produced during lipolysis. However, the mode of action of LCFA in suppressing adipose lipolysis is not clear. β,β'-Tetramethyl hexadecanedioic acid (Mββ/ EDICA16) is a synthetic LCFA that is neither esterified into lipids nor β-oxidized, and therefore, it was exploited for suppressing agonist-induced lipolysis in analogy to natural LCFA. Mββ is shown here to suppress isoproterenol-induced lipolysis in the rat in vivo as well as in 3T3-L1 adipocytes. Inhibition of isoproterenol-induced lipolysis is due to decrease in isoproterenol-induced cAMP with concomitant inhibition of the phosphorylation of hormone-sensitive lipase and perilipin by protein kinase A. Suppression of cellular cAMP levels is accounted for by inhibition of the adenylate cyclase due to suppression of Raf1 expression by Mββ-activated AMPK. Suppression of Raf1 is further complemented by induction of components of the unfolded-protein-response by Mββ. Our findings imply genuine inhibition of agonist-induced adipose lipolysis by LCFA, independent of their β-oxidation or reesterification. Mββ suppression of agonist-induced lipolysis and cellular cAMP levels independent of the insulin transduction pathway may indicate that synthetic LCFA could serve as insulin mimetics in the lipolysis context under conditions of insulin resistance.
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120.
authors.forename: Bella
authors.initials: B
authors.lastname: Kalderon
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120.
authors.forename: Narmen
authors.initials: N
authors.lastname: Azazmeh
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120.
authors.forename: Nili
authors.initials: N
authors.lastname: Azulay
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120.
authors.forename: Noam
authors.initials: N
authors.lastname: Vissler
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120.
authors.forename: Michael
authors.initials: M
authors.lastname: Valitsky
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120. Electronic address: jacobb@ekmd.huji.ac.il.
authors.forename: Jacob
authors.initials: J
authors.lastname: Bar-Tana
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry* / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats; D017208:Rats, Wistar; D012263:Ribonucleosides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D000242:Cyclic AMP; D019908:Proto-Oncogene Proteins c-raf; C546782:Raf1 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D020930:MAP Kinase Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000262:Adenylyl Cyclases; D007545:Isoproterenol