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Journal of Lipid Research, Vol. 50, 704-715, April 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

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. Ceddia¹

School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada

This research was funded by the Natural Science and Engineering Research Council (NSERC), the Canadian Institute of Health Research (CIHR), and by the Canadian Diabetes Association through operating grants awarded to R.B.C. R.B.C. is also a recipient of the CIHR New Investigator Award. M.P.G. was supported by a CIHR Canadian graduate scholarship doctoral award. S.F. was supported by a doctoral NSERC post-graduate scholarship. Canadian graduate scholarships masters awards from CIHR and NSERC supported N.M.A. and M.S., respectively.

Published, JLR Papers in Press, December 2, 2008.

¹ To whom correspondence should be addressed. e-mail: 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 5'-aminoimidasole-4-carboxamide-1-β-D-ribofuranoside (AICAR;0.5 mM) for 15 h. Also, epididymal adipocytes were isolated 15 h after AICAR was injected (i.p. 0.7 g/kg body weight) in rats. Adipocytes were utilized for various metabolic assays and for determination of gene expression and protein content. Time-dependent in vivo plasma NEFA concentrations were determined. AICAR treatment significantly increased AMPK activation, inhibited lipogenesis, and increased FA oxidation. This was accompanied by upregulation of peroxisome proliferator-activated receptor (PPAR), PPAR, and PPAR-coactivator-1 (PGC-1) 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 (ATGL) content 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 upregulating 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.

Supplementary key words obesity • AMP-activated protein kinase • adipose triglyceride lipase • hormone-sensitive lipase • PGC-1 • FA oxidation

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