Abstract 14473: Apelin Inhibits Lipolysis in a Gq-, Gi-, and AMPK-Dependent Manner
Background: The release of free fatty acids (FFA) from adipocytes (i.e. lipolysis) is known to play a major role in the development of insulin resistance and cardiovascular disease. A recently identified adipokine, apelin, is up-regulated in states of insulin resistance. Although apelin is secreted by adipocytes, its biological functions in these cells remain largely unknown.
Methods: FFA and glycerol levels were measured at baseline and after reintroduction of exogenous apelin in apelin-null (APKO) mice. To examine the mechanism of apelin's effects in vitro, isoproterenol-induced FFA/glycerol release and hormone-sensitive lipase (HSL) and acetyl CoA carboxylase (ACC) phosphorylation were investigated in differentiated 3T3L1 adipocytes. Involvement of Gi, Gq, and AMP-activated protein kinase (AMPK) was confirmed by incubating isoproterenol/apelin-treated cells with pertussis toxin (PTX), glycoprotein antagonist-2A (Gp2A), and compound C (CC), respectively. To independently document apelin-mediated Gi and Gq activation in 3T3L1 cells, cAMP and inositol triphosphate accumulation was measured using fluorometric kits.
Results: Serum FFA and glycerol concentrations were significantly increased in APKO mice compared to wild type animals; these levels were reduced in response to a 2 week apelin infusion. Apelin also decreased isoproterenol-induced FFA release in adipocytes isolated from wild type mice, but not in mice with generalized deletion of the apelin receptor APJ. In 3T3L1 adipocytes, apelin significantly attenuated isoproterenol-induced FFA/glycerol release. Apelin's inhibitory effect on lipolysis was reversed by PTX, Gp2A, and CC. Apelin increased HSL phosphorylation at the Ser-565 residue, and also abrogated isoproterenol-induced HSL phosphorylation at Ser−563. Notably, Gi and Gq were activated in response to apelin. Apelin also increased ACC phosphorylation, supporting AMPK involvement.
Conclusions: Apelin inhibits lipolysis by modulating HSL phosphorylation. Its actions may be carried out through multiple pathways involving Gq, Gi, and AMPK. Modulating lipolysis through apelin/APJ pathway thus represents a novel potential strategy for preventing and managing complications of insulin resistance.
- © 2010 by American Heart Association, Inc.