Endoplasmic Reticulum Stress Promotes LIPIN2-Dependent Hepatic Insulin Resistance

OBJECTIVE-Diet-induced obesity (DIO) is linked to peripheral insulin resistance-a major predicament in type 2 diabetes. This study aims to identify the molecular mechanism by which DIO-triggered endoplasmic reticulum (ER) stress promotes hepatic insulin resistance in mouse models. RESEARCH DESIGN AND METHODS-C57BL/6 mice and primary hepatocytes were used to evaluate the role of LIPIN2 in ER stress-induced hepatic insulin resistance. Tunicamycin, thapsigargin, and lipopolysaccharide were used to invoke acute ER stress conditions. To promote chronic ER stress, mice were fed with a high-fat diet for 8-12 weeks. To verify the role of LIPIN2 in hepatic insulin signaling, adenoviruses expressing wild-type or mutant LIPIN2, and shRNA for LIPIN2 were used in animal studies. Plasma glucose, insulin levels as well as hepatic free fatty acids, diacylglycerol (DAG), and triacylglycerol were assessed. Additionally, glucose tolerance, insulin tolerance, and pyruvate tolerance tests were performed to evaluate the metabolic phenotype of these mice. RESULTS-LIPIN2 expression was enhanced in mouse livers by acute ER stress-inducers or by high-fat feeding. Transcriptional activation of LIPIN2 by ER stress is mediated by activating transcription factor 4, as demonstrated by LIPIN2 promoter assays, Western blot analyses, and chromatin immunoprecipitation assays. Knockdown of hepatic LIPIN2 in DIO mice reduced fasting hyperglycemia and improved hepatic insulin signaling. Conversely, overexpression of LIPIN2 impaired hepatic insulin signaling in a phosphatidic acid phosphatase activity-dependent manner. CONCLUSIONS-These results demonstrate that ER stress-induced LIPIN2 would contribute to the perturbation of hepatic insulin signaling via a DAG-protein kinase C epsilon-dependent manner in DIO mice. Diabetes 60:1072-1081, 2011