Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), bioactive lipids with anti-inflammatory and antidiabetic effects, improve systemic and hepatic insulin sensitivity in insulin-resistant mice. PAHSAs augment insulin action on endogenous glucose production (EGP) through direct and indirect actions involving inter-tissue communication between liver and adipose tissue. The direct effect of PAHSAs to inhibit EGP is mediated through a cAMP dependent pathway involving Gα/i protein-coupled receptors. Here, we investigated which receptor mediates PAHSA effects on EGP. We found that 9-PAHSA activates GPR43 in a Ca+2 flux assay. 4-CMTB (0.4μM), a selective agonist-allosteric modulator of GPR43, reduced basal EGP by 23% and glucagon-stimulated EGP by 20% in primary hepatocytes ex vivo. Acute 9-PAHSA treatment (40μM) inhibited basal EGP to the same extent as 4-CMTB. 9-PAHSA suppression of basal EGP was abolished in primary hepatocytes from whole body GPR43 KO mice. Intravenous infusion of 9-PAHSA (9μg/hr) for 3 hrs decreased ambient EGP in chow-fed mice studied 5 hours after food removal (WT: vehicle= 24.2±1.9 vs. PAHSA= 17.2±0.7 mg/kg/min p<0.05). This effect was absent in GPR43 KO mice (KO: vehicle= 25.3±4.2 vs. PAHSA= 23.4±2.7 mg/kg/min). We also examined whether GPR43 activation is required for the direct effect of 9-PAHSA on WAT lipolysis. Treatment with the β-adrenergic agonist isoproterenol increased FFA release from WAT explants by 3.8-fold, and 9-PAHSA inhibited isoproterenol-induced lipolysis by 21% which was similar to the effects of insulin and 4-CMTB. In WAT explants from GPR43 KO mice, 9-PAHSA suppression of isoproterenol-induced FFA release was abolished while insulin still suppressed lipolysis.
Sum: 9-PAHSA activates GPR43, which is involved in its direct effects to reduce hepatic glucose production and WAT lipolysis.
Conclusion: We have identified a new receptor that mediates some of the beneficial metabolic effects of PAHSAs.
A. Santoro: None. P. Zhou: None. Y. Zhu: None. O.D. Peroni: None. A.T. Nelson: None. D. Siegel: None. B. Kahn: Advisory Panel; Self; Harrington Discovery Institute, Janssen Pharmaceuticals, Inc., National Institute of Diabetes and Digestive and Kidney Diseases.
American Diabetes Association (1-18-PDF-134 to P.Z.); National Institutes of Health (DK43051, DK57521, DK106210, DK112622); JPB Foundation; American Heart Association