Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL

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-b-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. Timedependent 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)a, PPARd, and PPARgcoactivator-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 (ATGL) content and FA release, despite inhibition of basal and epinephrine-stimulated hormonesensitive 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.

GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1

“…Here, we found that exenatide (exendin-4) reduced adiposity by activating SIRT1 and consequently upregulating ATGL. In addition, AMPK, another SIRT1-interacting factor with a vital role in the regulation of hydrolysis and energy dissipation [27,28], was activated by exenatide in WAT. Our findings indicate that exenatide induces the phosphorylation of AMPK which, in turn, activates SIRT1 by regulating NAD + concentration [29], triggering a lipolytic cycle.…”

Apelin stimulates glucose uptake but not lipolysis in human adipose tissue ex vivo

“…AMPK activation is thus viewed as a consequence of ongoing re-esterification of fatty acids that consume energy (Gauthier et al 2008, Djouder et al 2010 and in fine AMPK activation restrains hydrolysis of triglycerides (lipolysis). Acute treatment (1 h) with AICAR has been shown to decrease both NEFA and glycerol release in rat adipocytes (Gaidhu et al 2009). In this study, AICAR decreased both NEFA and glycerol release in agreement with the results reported by Gaidhu et al (2009).…”

“…Isoprenaline (a b-adrenergic agonist) was used at 1 mM as a control of maximal lipolytic activation and AICAR was used at 2 mM as an activator of AMPK (Gaidhu et al 2009). Isoprenaline stimulated the basal release of glycerol and NEFA from AT explants whereas AICAR decreased basal lipolysis (Fig.…”

AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

“…Numerous studies using cell culture and rodent models have shown that AICAR treatment increases the phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase (ACC) (Guigas et al, 2007;Gaidhu et al, 2009;Hasenour et al, 2014;O'Neill et al, 2014;Kjøbsted et al, 2015;Monaco et al, 2015). In order to confirm whether AICAR treatment leads to activation of AMPK in our hands, mice were injected with AICAR or an equivalent volume of saline, and the phosphorylation of AMPK and ACC were measured.…”