Activation of G Protein-Coupled Receptor 43 in Adipocytes Leads to Inhibition of Lipolysis and Suppression of Plasma Free Fatty Acids

Abstract

G protein-coupled receptor 43 (GPR43) has been identified as a receptor for short-chain fatty acids that include acetate and propionate. A potential involvement of GPR43 in immune and inflammatory response has been previously suggested because its expression is highly enriched in immune cells. GPR43 is also expressed in a number of other tissues including adipocytes; however, the functional consequences of GPR43 activation in these other tissues are not clear. In this report, we focus on the potential functions of GPR43 in adipocytes. We show that adipocytes treated with GPR43 natural ligands, acetate and propionate, exhibit a reduction in lipolytic activity. This inhibition of lipolysis is the result of GPR43 activation, because this effect is abolished in adipocytes isolated from GPR43 knockout animals. In a mouse in vivo model, we show that the activation of GPR43 by acetate results in the reduction in plasma free fatty acid levels without inducing the flushing side effect that has been observed by the activation of nicotinic acid receptor, GPR109A. These results suggest a potential role for GPR43 in regulating plasma lipid profiles and perhaps aspects of metabolic syndrome.

Fatty Acid Binding Receptors and Their Physiological Role in Type 2 Diabetes

“…The reduction in plasma FFA levels can control plasma lipid parameters, which, in turn, are linked to diabetes and obesity [62].…”

Effects of gut microbiota manipulation onex vivolipolysis in human abdominal subcutaneous adipocytes

“…Interestingly, SCFA and BA receptors (i.e. GPR43 and FXR) are expressed in adipose tissue, and both SCFA and BA have been able to modulate fasting and β-adrenoceptor-mediated lipolysis in murine and human adipocytes [15,26]. indicating a possible role for BA and SCFA signaling in catecholamine-induced lipolysis.…”

“…In line, human in vivo studies showed that plasma ANGPTL4 concentrations were positively associated with fasting levels of free fatty acids (FFA) and adipose tissue lipolysis [11]. Oral or rectal administration of SCFA, in particular acetate, significantly decreased plasma FFA concentrations in humans [12–14], and treatment of murine 3T3-L1 adipocytes with SCFA reduced fasting and catecholamine-mediated lipolysis, via activation of the G-protein-coupled receptor GPR43 [15]. Finally, also gut-derived bile acids (BA) [16,17], lipopolysaccharides and glucagon-like peptide 1 (GLP-1) [18], might affect adipose tissue lipid metabolism, but the underlying mechanisms are unknown.…”

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“…The administration of prebiotics also stimulates the production of SCFA which may modulate the secretion of gut peptides (Brown et al 2003;Ge et al 2008;Samuel et al 2008;Kimura et al 2011). Prebiotics may exert a satietogenic effect as demonstrated and confirmed in studies with mice in which the effects of acetate on production of appetite suppression were shown, even in absence of increased levels of GLP-1 and PYY (Frost et al 2014).…”