Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), bioactive lipids with anti-inflammatory and antidiabetic effects, improve glucose tolerance and insulin sensitivity in insulin-resistant mice. We found that PAHSA treatment enhances insulin action to suppress endogenous glucose production (EGP) in chow and HFD mice and promotes glucose uptake in glycolytic muscle and heart in HFD-fed mice. We aimed to determine the mechanisms by which PAHSAs enhance hepatic insulin sensitivity. We examined both direct effects in hepatocytes and indirect effects resulting from augmentation of insulin-mediated suppression of WAT lipolysis. Here, we show that PAHSAs inhibit lipolysis in WAT explants to the same extent as insulin. PAHSAs also enhance the anti-lipolytic effect of insulin in vivo, as indicated by a 30% reduction in FFAs during the clamp in PAHSA-treated mice under conditions with no suppression in Vehicle treated mice. To determine whether lowering FFAs is necessary for PAHSA effects on insulin sensitivity, we infused intralipid during a hyperinsulinemic-euglycemic clamp. In chow-fed mice infused with intralipid, PAHSAs still have a partial effect to lower EGP (Intralipid: vehicle 12±0.8 vs. PAHSA 7±1.7 mg/kg/minute), whereas in HFD-fed mice, preventing PAHSA-induced FFA reduction blocks PAHSA effects on hepatic insulin sensitivity (EGP Intralipid: vehicle 13±0.6 vs. PAHSA 12±1.7 mg/kg/minute). Our mechanistic studies show that PAHSAs inhibit basal EGP and reduce glucagon stimulated EGP directly in isolated hepatocytes. This is mediated by a cAMP-dependent pathway involving Gα/i protein-coupled receptors. Hepatic phospho-CREB is also reduced by PAHSAs in vivo. Sum: PAHSAs enhance hepatic insulin sensitivity through direct and indirect actions involving inter-tissue communication between adipose tissue and liver. These data reveal new mechanisms underlying the beneficial effects of PAHSAs, which will clarify their roles in healthy and disease states.
P. Zhou: None. A. Santoro: None. O.D. Peroni: None. A.T. Nelson: None. A. Saghatelian: None. D. Siegel: None. B. Kahn: Advisory Panel; Self; Alterna Therapeutics, Inc., American Diabetes Association, Harrington Discovery Institute, Janssen Research & Development. Consultant; Self; Ironwood Pharmaceuticals, Inc. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases.
American Diabetes Association (1-18-PDF-134 to P.Z.); National Institutes of Health (R01DK43051 to B.K.), (R01DK106210 to B.K., A.S.); JPB Foundation (to B.K.); American Heart Association (to A.T.N.)