Prolonged aicar-induced amp-kinase activation promotes energy dissipation in white adipocytes: Novel mechanisms integrating HSL and ATGL

Mandeep P. Gaidhu, Sergiu Fediuc, Nicole M. Anthony, Mandy So, Mani Mirpourian, Robert L. S. Perry, and Rolando B. Ceddia

Kinesiology and Health Science, York University, Toronto, ON M3J 1P3

Corresponding Author: roceddia{at}yorku.ca

This study was designed to investigate the effects of prolonged activation of AMP-activated protein kinase (AMPK) on lipid partitioning and the potential molecular mechanisms involved in these processes in white adipose tissue (WAT). Rat epididymal adipocytes were incubated with AICAR (0.5mM) for 15h. Also, epididymal adipocytes were isolated 15h after AICAR was injected (i.p. 0.7g/kg b.w.) in rats. Adipocytes were utilized for various metabolic assays and for determination of gene expression and protein content. Time-dependent in vivo plasma non-esterified fatty acid (FA) concentrations were determined. AICAR treatment significantly increased AMPK activation, inhibited lipogenesis, and increased FA oxidation. This was accompanied by up-regulation of peroxisome proliferator-activated receptor (PPAR)a, PPARd, and PPAR-coactivator-1a (PGC-1a) mRNA levels. Lipolysis was first suppressed, but then increased both in vitro and in vivo with prolonged AICAR treatment. Exposure to AICAR increased adipose triglyceride lipase content (ATGL) and FA release, despite inhibition of basal and epinephrine-stimulated hormone sensitive lipase (HSL) activity. Here, we provide evidence that prolonged AICAR-induced AMPK activation can remodel adipocyte metabolism by up-regulating pathways that favor energy dissipation versus lipid storage in WAT. Additionally, we show novel time-dependent effects of AICAR-induced AMPK activation on lipolysis, which involves antagonistic modulation of HSL and ATGL.

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