Abstract
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-beta-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)alpha, PPARdelta, and PPARgamma-coactivator-1alpha (PGC-1alpha) 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.
Highlights
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)
We demonstrate the novel finding that chronic AMPK activation remodels adipocyte metabolism by preventing TAG storage and by activating pathways that promote energy dissipation within the adipocyte
We found that the activity of glycerol kinase (GyK) was not affected in isolated adipocytes treated with AICAR, whereas the incorporation of glycerol into lipids was reduced by ?35%
Summary
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). This article is available online at http://www.jlr.org regulation of gene expression [5] Support for this comes from correlative in vivo studies reporting that chronic AMPK activation in hyperleptinemic rats is associated with increased expression of PGC-1a, higher mitochondrial content, upregulation of uncoupling proteins (UCPs), elevated expression of enzymes involved in b-oxidation, such as carnitine palmitoyl transferase 1 and acetyl-CoA oxidase, and decreased expression of lipogenic enzymes (acetyl-CoA carboxylase and fatty acid synthase) in WAT [6, 7]. Our data indicate that through chronic AMPK activation, WAT metabolism can be remodeled toward energy dissipation, and this may be of great relevance for the treatment of obesity and its related metabolic disorders
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