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.
Highlights
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
We have recently reported that LCFA and their MEDICA analogs activate AMP-protein kinase (AMPK) through increase in intracellular AMP/ATP ratio by the free LCFA/ MEDICA acid, complemented by activation of liver kinase B1 (LKB1) phosphorylation of AMPK␣(Thr172) by the respective CoA monothioester [12]
Apart from dissecting the mode of action of M in suppressing agonist-induced lipolysis, the reported findings may indicate that synthetic LCFA may serve as insulin mimetics in the lipolysis context, while bypassing the insulin transduction pathway
Summary
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. Similar to M (Fig. 2) and in line with previous reports of suppression of lipolysis by activated AMPK [16,17,18], isoproterenol-induced lipolysis (Fig. 3B), P-HSL, and P-perilipin (Fig. 3C) were inhibited by AICAR, being abrogated by inhibition of the adenosine kinase by 5′amino-5′-deoxyadenosine (AMDA) [20, 21], implying ZMPactivated AMPK.
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