Suppression of adipose lipolysis by long-chain fatty acid analogs

Abstract

This article is available online at http://www.jlr.org lipoproteins. Agonist-induced lipolysis is mediated by consecutive activation of the adenylate cyclase (AC), resulting in cAMP production and protein kinase A (PKA) activation by cAMP, followed by PKA-induced phosphorylation of hormone-sensitive lipase (HSL) at three serine residues (563, 659, and 660), resulting in its activation and translocation from the cytosol to the lipid-droplet surface. Concomitant with HSL phosphorylation, the phosphorylation of perilipin by PKA at multiple sites (S81, S222, S276, and S517) results in a dynamic restructuring of the lipid-droplet surface, in facilitating the translocation of phosphorylated HSL to the lipid droplet, and in activating its hydrolyzing activity. Perilipin phosphorylation by PKA further results in releasing CGI-58 from the lipid droplet, in its association with adipose triacylglycerol lipase (ATGL), and in activating its lipolytic activity. Activated ATGL, HSL, and monoglyceride lipase may act now consecutively in hydrolyzing adipose triacyglycerols to diacylglycerol, monoacylglycerol, and fi nally to free glycerol and LCFA. Agonist-induced cAMP and lipolysis is restrained by insulin due to cAMP hydrolysis by insulin-activated phosphodiesterase3B (PDE3B) ( 2 ), combined with insulin-induced reesterifi cation of LCFA into adipose fat (reviewed in Ref.3 ). Indeed, increased adipose effl ux of free LCFA, due to increased adipose lipolysis and/or suppression of adipose LCFA reesterifi cation, is considered a cornerstone of diabetes. Agonist-induced lipolysis is further robustly inhibited by the LCFA generated during lipolysis ( 4, 5 ). In fact, agonist-induced lipolysis is made possible only by removing the free nonesterifi ed LCFA product through their binding to medium albumin or by frequent medium replacement Lipolysis of adipose fat stores results in the production of nonesterifi ed long-chain fatty acids (LCFA) in response to changes in energy requirements and availability (reviewed in Ref. 1 ). Fatty acids derived by adipose fat lipolysis may either be reesterifi ed into adipose fat, or serve as major source of oxidizable substrate for muscle activity and as precursor for the hepatic production of triacylglycerol-richFunded by Eurostars project E!5138.

The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation

“…1A,B). Of note, Prkar1a, Prkar2b, Ndrg1, Raf1, Lats2, Peg3, and Trib3, which appeared in our screen, were previously implicated in the regulation of lipolysis and different aspects of adipocytes function (Curley et al 2005;Qi et al 2006;Kalderon et al 2012;An et al 2013;Cai et al 2017;Torres-Quesada et al 2017). These confirm the accuracy of our screening strategy.…”

“…For example, our screen revealed that silencing of two regulatory subunits of multisubunit complex of PKA (Prkar1a and Prkar2b, which inhibits PKA activation) (Torres-Quesada et al 2017) enhances the lipolysis rate. On the other hand, silencing of Ndrg1, Raf1, Lats2, Peg3, and Trib3, which were previously shown to promote lipolysis or to regulate other aspects of adipocytes function (Curley et al 2005;Qi et al 2006;Kalderon et al 2012;An et al 2013;Cai et al 2017), resulted in inhibition of lipolysis. These results confirm the appropriate design and relevance of our screen.…”

Lack of Adipocyte AMPK Exacerbates Insulin Resistance and Hepatic Steatosis through Brown and Beige Adipose Tissue Function

“…Consistent with minimal effects of AMPK on the phosphorylation of these residues, we found no changes in adipose tissue lipolysis basally or following β-adrenergic stimulation. Interestingly, the non-specific pharmacological AMPK activator AICAR impaired lipolysis independent of AMPK—an effect that is likely related to observations that AICAR and biguanides can supress cAMP production in cells independent of AMPK (Kalderon et al, 2012; Miller et al, 2013). Collectively, these studies suggest that AMPK has a minimal role in regulating adipocyte lipolysis.…”

CD36 is important for adipocyte recruitment and affects lipolysis

“…Because CD36‐deficiency impairs FA uptake by adipocytes, less FA might be present intracellularly, which may lead to decreased product inhibition of HSL. Recently, it has been shown that long‐chain FA reduce production of cAMP, which results in a decreased phosphorylation of HSL . Moreover, it has been shown that A‐FABP null mice have decreased lipolysis, whereas E‐FABP transgenic mice have increased lipolysis .…”