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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Categories: 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 2

Chronic PAHSA treatment increases systemic insulin sensitivity in chow-fed mice.

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Chronic PAHSA treatment increases systemic insulin sensitivity in chow-f...
(A) Body weight of C57BL/6 male mice treated with 5-PAHSA (0.1 mg/d) and 9-PAHSA (0.4 mg/d) delivered by subcutaneous osmotic minipumps. PAHSA treatment was started with the initiation of HFD feeding at 12 weeks of age. Chow: n = 10/group; HFD: n = 20/group. *P < 0.05 for both HFD groups versus both chow-fed mice. (B) Serum 5-PAHSA (left) and 9-PAHSA (right) levels at 2 months of PAHSA treatment. n = 3–5/group (each sample represents a pool of serum from 3–4 mice). *P < 0.05 versus vehicle-treated mice, #P = 0.08 versus vehicle-treated mice on a chow diet, †P < 0.05 versus PAHSA-treated mice on a chow diet. (C–G) Hyperinsulinemic-euglycemic clamp studies were performed with a 2.5-mU/min/kg insulin infusion rate after 5-hour food removal in chow mice treated with PAHSAs or vehicle for 13 weeks: glycemia (C), Glucose infusion rate (GIR) and GIR at steady state (bar graph) (D), basal glucose clearance (E), EGP and percent suppression of EGP by insulin (F), and disappearance rate (Rd) (G). n = 6–7/group. (H–K) 2-[1-14C]-deoxy-d-glucose (2-DOG) incorporation into liver glycogen (H), levels of liver glycogen (I), hepatic GSK3β signaling (representative of 3 Westerns blots using same samples) (J), and liver triglyceride (TG) levels (K) at the end of the clamp. n = 6–7/group. For C–K, *P < 0.05 versus vehicle-treated chow mice, #P = 0.06 versus vehicle, †P < 0.05 versus vehicle-treated chow mice at baseline, ‡P < 0.05 versus all other groups. Statistical significance for A, C, and D was evaluated by 2-way repeated-measures ANOVA; for all others, 1- or 2-way ANOVA followed by Tukey’s post hoc test or unpaired 2-tailed Student’s t test. Data are mean ± SEM.