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 1

Acute PAHSA treatment decreases glucose production in vivo through inhibition of cAMP signaling.

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Acute PAHSA treatment decreases glucose production in vivo through inhib...
Five hours after food removal, [3-3H]glucose (0.05 μCi/min) was infused through the jugular vein together with vehicle (Veh) (0.5% BSA, 3 μL/h) or 9-PAHSA (chow: 9 μg/h; HFD: 18 μg/h, preconjugated with 0.5% BSA) for 3 hours in 16-week-old mice on a chow or HFD for 11 weeks. Endogenous glucose production (EGP) (A), glycemia (B), glucose clearance (C), and insulin levels (D) at the end of infusion. n = 7–9/group. (E) Representative Western blots for total and phosphorylated CREB proteins in liver lysates from chow-fed mice at the end of infusion. n = 8–9/group. Bar graph represents fold change relative to vehicle. This Western blot is representative of 4 Western blots using the same samples. (F) Hepatic glucose-6-phosphatase catalytic unit (G6pc1) and phosphoenolpyruvate carboxykinase 1 (Pck1) mRNA expression in chow- and HFD-fed mice at the end of the infusion. G6pc1 and Pck1 mRNA are expressed as a ratio to GAPDH, which was used as the housekeeping gene. Graphs represent fold change relative to vehicle. n = 8–10/group. (A–F) *P < 0.05 versus vehicle, #P = 0.08 versus chow vehicle, †P < 0.05 versus chow diet. (G) Hepatic glucose-6-phosphatase (G6pase) activity (Vmax and Km) at the end of the infusion. n = 8–11/group. *P < 0.05 versus vehicle-treated mice on a chow diet, †P < 0.05 versus vehicle-treated HFD-fed mice. Statistical significance for all panels was evaluated by 2-way ANOVA, followed by Tukey’s post hoc test or unpaired 2-tailed Student’s t test. Data are mean ± SEM.