PAHSAs enhance hepatic and systemic insulin sensitivity through direct and indirect mechanisms
Peng Zhou, … , Dionicio Siegel, Barbara B. Kahn
Peng Zhou, … , Dionicio Siegel, Barbara B. Kahn
Published October 1, 2019; First published August 26, 2019
Citation Information: J Clin Invest. 2019;129(10):4138-4150. https://doi.org/10.1172/JCI127092.
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Research Article Endocrinology Metabolism

PAHSAs enhance hepatic and systemic insulin sensitivity through direct and indirect mechanisms

Abstract

Palmitic acid esters of hydroxy stearic acids (PAHSAs) are bioactive lipids with antiinflammatory and antidiabetic effects. PAHSAs reduce ambient glycemia and improve glucose tolerance and insulin sensitivity in insulin-resistant aged chow- and high-fat diet–fed (HFD-fed) mice. Here, we aimed to determine the mechanisms by which PAHSAs improve insulin sensitivity. Both acute and chronic PAHSA treatment enhanced the action of insulin to suppress endogenous glucose production (EGP) in chow- and HFD-fed mice. Moreover, chronic PAHSA treatment augmented insulin-stimulated glucose uptake in glycolytic muscle and heart in HFD-fed mice. The mechanisms by which PAHSAs enhanced hepatic insulin sensitivity included direct and indirect actions involving intertissue communication between adipose tissue and liver. PAHSAs inhibited lipolysis directly in WAT explants and enhanced the action of insulin to suppress lipolysis during the clamp in vivo. Preventing the reduction of free fatty acids during the clamp with Intralipid infusion reduced PAHSAs’ effects on EGP in HFD-fed mice but not in chow-fed mice. Direct hepatic actions of PAHSAs may also be important, as PAHSAs inhibited basal and glucagon-stimulated EGP directly in isolated hepatocytes through a cAMP-dependent pathway involving Gαi protein–coupled receptors. Thus, this study advances our understanding of PAHSA biology and the physiologic mechanisms by which PAHSAs exert beneficial metabolic effects.

Authors

Peng Zhou, Anna Santoro, Odile D. Peroni, Andrew T. Nelson, Alan Saghatelian, Dionicio Siegel, Barbara B. Kahn

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Figure 4

PAHSAs suppress lipolysis, and this partially accounts for the effects of PAHSAs to suppress EGP.

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PAHSAs suppress lipolysis, and this partially accounts for the effects o...
(A) Free fatty acid (FFA) levels at baseline and at the end of the clamp. Insulin dose: chow, 2.5 mU/kg/min (Figure 2, C–G); HFD, 4 mU/kg/min (Figure 3, E–H). n = 6–9/group. *P < 0.05 versus all other groups within the same diet. (B) FFA release from perigonadal WAT explants. n = 10–29/group. *P < 0.05 versus untreated control cells, †P < 0.05 versus isoproterenol-treated cells. (C–H) Hyperinsulinemic-euglycemic clamps were performed with infusion of Intralipid (5 mL/kg/h)/heparin (6 U/hour) or heparin (6 U/hour) alone. GIR and GIR at steady state (bar graph) (C), EGP and percent suppression of EGP by insulin (D), and C-peptide levels (E) during clamps (2.5 mU/min/kg insulin infusion rate) in vehicle- and PAHSA-treated (29 weeks) chow-fed mice. n = 6–8/group. For C–E, *P < 0.05 versus vehicle and vehicle + Intralipid, #P = 0.09 versus PAHSA group, †P < 0.05 versus all other groups except PAHSA + Intralipid, ‡P < 0.05 versus basal. GIR and GIR at steady state (bar graph) (F), insulin at the end of clamp (G), and EGP and percent suppression of EGP by insulin (H) during clamps (4 mU/min/kg insulin infusion rate) in vehicle- and PAHSA-treated (19 weeks) HFD-fed mice. n = 4/group. Statistical significance for C and F was evaluated by 2-way repeated-measures ANOVA; for all others, 2-way ANOVA with Tukey’s post hoc test or unpaired 2-tailed Student’s t test. Data are mean ± SEM.