Grp78 Heterozygosity Promotes Adaptive Unfolded Protein Response and Attenuates Diet-Induced Obesity and Insulin Resistance

OBJECTIVE—To investigate the role of the endoplasmic retic-ulum (ER) chaperone glucose-regulated protein (GRP) 78/BiP in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. RESEARCH DESIGN AND METHODS—Male Grp78/ mice and their wild-type littermates were subjected to a high-fat diet (HFD) regimen. Pathogenesis of obesity and type 2 diabetes was examined by multiple approaches of metabolic phenotyping. Tissue-specific insulin sensitivity was analyzed by hyperinsuline-mic-euglycemic clamps. Molecular mechanism was explored via immunoblotting and tissue culture manipulation. RESULTS—Grp78 heterozygosity increases energy expenditure and attenuates HFD-induced obesity. Grp78/ mice are resis-tant to diet-induced hyperinsulinemia, liver steatosis, white adipose tissue (WAT) inflammation, and hyperglycemia. Hyper