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.
Highlights
Obesity-related metabolic diseases such as type 2 diabetes and metabolic-associated fatty liver disease (MAFLD) are often accompanied by white adipose tissue (WAT) dysfunction [1, 2]
We hypothesize that a short-term HFD causes White adipose tissue (WAT) insulin resistance (IR) through plasma membrane (PM) sn-1,2-diacylglycerol accumulation, which promotes protein kinase C-ε (PKCε) activation to impair insulin signaling by phosphorylating insulin receptor (Insr) Thr1160
In order to examine the role of Insr Thr1160 phosphorylation in mediating lipid-induced WAT IR, we examined these same parameters in InsrT1150A mice and found that HFD feeding induced WAT IR in WT control mice but not in InsrT1150A mice
Summary
Obesity-related metabolic diseases such as type 2 diabetes and metabolic-associated fatty liver disease (MAFLD) are often accompanied by white adipose tissue (WAT) dysfunction [1, 2]. Accumulation of sn-1,2-DAGs in the PM activates protein kinase C-ε (PKCε), which phosphorylates insulin receptor (Insr) at Thr1160 to impair Insr kinase (IRK) autophosphorylation/activation and subsequent activation of downstream signaling events [1, 5,6,7] This simple model can explain the development of lipid-induced liver and muscle insulin resistance in obese rodents and humans [1, 4,5,6,7,8,9,10], as well as the mechanism by which weight loss [11], adiponectin [12], and liver-targeted mitochondrial uncouplers reverse insulin resistance in HFD-fed obese [13, 14] and lipodystrophic [15] insulin–resistant rodents. Overfed human subjects can develop peripheral insulin resistance prior to WAT immune cell infiltration [19, 20]
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