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. 2021 Feb 22;6(4):e139946.
doi: 10.1172/jci.insight.139946.

Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol/PKCε/insulin receptor Thr1160 phosphorylation

Kun Lyu  1   2 , Dongyan Zhang  1 , Joongyu Song  1 , Xiruo Li  1   2 , Rachel J Perry  1   2 , Varman T Samuel  1   3 , Gerald I Shulman  1   2
Affiliations

Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol/PKCε/insulin receptor Thr1160 phosphorylation

Kun Lyu et al. JCI Insight. .

Abstract

White adipose tissue (WAT) insulin action has critical anabolic function and is dysregulated in overnutrition. However, the mechanism of short-term high-fat diet-induced (HFD-induced) WAT insulin resistance (IR) is poorly understood. Based on recent evidences, we hypothesize that a short-term HFD causes WAT IR through plasma membrane (PM) sn-1,2-diacylglycerol (sn-1,2-DAG) accumulation, which promotes protein kinase C-ε (PKCε) activation to impair insulin signaling by phosphorylating insulin receptor (Insr) Thr1160. To test this hypothesis, we assessed WAT insulin action in 7-day HFD-fed versus regular chow diet-fed rats during a hyperinsulinemic-euglycemic clamp. HFD feeding caused WAT IR, reflected by impaired insulin-mediated WAT glucose uptake and lipolysis suppression. These changes were specifically associated with PM sn-1,2-DAG accumulation, higher PKCε activation, and impaired insulin-stimulated Insr Tyr1162 phosphorylation. In order to examine the role of Insr Thr1160 phosphorylation in mediating lipid-induced WAT IR, we examined these same parameters in InsrT1150A mice (mouse homolog for human Thr1160) and found that HFD feeding induced WAT IR in WT control mice but not in InsrT1150A mice. Taken together, these data demonstrate the importance of the PM sn-1,2-DAG/PKCε/Insr Thr1160 phosphorylation pathway in mediating lipid-induced WAT IR and represent a potential therapeutic target to improve WAT insulin sensitivity.

Keywords: Adipose tissue; Endocrinology; Glucose metabolism; Insulin signaling; Metabolism.

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Conflict of interest statement

Conflict of interest: GIS serves on the scientific advisory boards for Merck, AstraZeneca, Esperion, and Janseen Research and Development, and he has served as a consultant for Novo Nordisk, Gilead Sciences, 89bio, and Generian. GIS receives investigator-initiated support from AstraZeneca and Merck. GIS is an inventor on Yale patents (nos. 10,781,161 and 10,786,466) for liver-targeted mitochondrial uncoupling agents and controlled-release mitochondrial uncoupling agents for the treatment of NAFLD, NASH, T2D, and related metabolic disorders and is a scientific-cofounder for TLC Inc.

Figures

Figure 1
Figure 1. Seven-day HFD causes WAT insulin resistance reflected by reductions in WAT glucose uptake and insulin’s suppression of WAT lipolysis.
(A) Plasma NEFA under basal (overnight fasting) and hyperinsulinemic-euglycemic clamp conditions. (B) Insulin’s suppression of plasma NEFA during the clamp. (C and D) Whole-body glycerol turnover and its suppression by insulin during the hyperinsulinemic-euglycemic clamp. (E and F) Whole-body fatty acid turnover and its suppression by insulin during the hyperinsulinemic-euglycemic clamp. (G) Insulin-stimulated WAT glucose uptake. In all panels, data are the mean ± SEM of n = 7–10 per group, with comparisons by 2-tailed unpaired Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.
Figure 2
Figure 2. Seven-day HFD feeding impairs insulin-stimulated insulin signaling cascade in WAT associated with increases in plasma membrane sn-1,2-DAGs and PKCε translocation.
(A–C) Insulin-stimulated phosphorylation of Insr, Akt, and PDE3B in WAT. (D and E) WAT cAMP and PKA activity during the hyperinsulinemic-euglycemic clamp. (F–H) Insulin-stimulated phosphorylation of HSL, perilipin, and ATGL. (I) WAT PKCε membrane/cytosol ratio. (J) Separation of 5 subcellular compartments in WAT: plasma membrane (PM), mitochondria (Mito), ER, cytosol (C), and lipid droplet (LD). (K) WAT sn-1,2-DAGs in 5 compartments. In A–H, rats (after overnight fasting) were under hyperinsulinemic-euglycemic clamp conditions. Data are the mean ± SEM of n = 5–10 per group. In I–K, rats were under 6-hour fasting basal condition; data are the mean ± SEM of n = 4–5 per group. In all panels, groups are compared by 2-tailed unpaired Student’s t test. *P < 0.05, **P < 0.01.
Figure 3
Figure 3. InsrT1150A mice retain insulin’s ability to suppress WAT lipolysis after 7-day HFD.
(A) Plasma NEFA under basal (overnight fasting) and hyperinsulinemic-euglycemic clamp conditions. (B) Insulin’s suppression of plasma NEFA during the hyperinsulinemic-euglycemic clamp. (C and D) Whole-body glycerol turnover and its suppression by insulin during the hyperinsulinemic-euglycemic clamp. (E and F) Whole-body fatty acid turnover and its suppression by insulin during the hyperinsulinemic-euglycemic clamp. In all panels, data are the mean ± SEM of n = 5–6 per group, with comparisons by 2-tailed unpaired Student’s t test. *P < 0.05, **P < 0.01.
Figure 4
Figure 4. InsrT1150A mice were protected from HFD-induced WAT insulin resistance.
(A–C) Insulin-stimulated phosphorylation of Insr, Akt, and PDE3B in WAT. (D and E) WAT cAMP content and PKA activity during the clamp. (F–H) Insulin-stimulated phosphorylation of HSL, perilipin, and ATGL. In all panels, mice (after overnight fasting) were under hyperinsulinemic-euglycemic clamp condition; data are the mean ± SEM of n = 6 per group, with comparisons by 2-tailed unpaired Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.
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