Grp78 heterozygosity promotes adaptive unfolded protein response and attenuates diet-induced obesity and insulin resistance.
OBJECTIVE
To investigate the role of the endoplasmic reticulum (ER) chaperone glucose-regulated protein (GRP) 78/BiP in the pathogenesis of obesity, insulin resistance, and type 2 diabetes.


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 hyperinsulinemic-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 resistant to diet-induced hyperinsulinemia, liver steatosis, white adipose tissue (WAT) inflammation, and hyperglycemia. Hyperinsulinemic-euglycemic clamp studies revealed that Grp78 heterozygosity improves glucose metabolism independent of adiposity and following an HFD increases insulin sensitivity predominantly in WAT. As mechanistic explanations, Grp78 heterozygosity in WAT under HFD stress promotes adaptive unfolded protein response (UPR), attenuates translational block, and upregulates ER degradation-enhancing alpha-mannosidase-like protein (EDEM) and ER chaperones, thus improving ER quality control and folding capacity. Further, overexpression of the active form of ATF6 induces protective UPR and improves insulin signaling upon ER stress.


CONCLUSIONS
HFD-induced obesity and type 2 diabetes are improved in Grp78(+/-) mice. Adaptive UPR in WAT could contribute to this improvement, linking ER homeostasis to energy balance and glucose metabolism.
Ye
Risheng
R
Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
Jung
Dae Young
DY
Jun
John Y
JY
Li
Jianze
J
Luo
Shengzhan
S
Ko
Hwi Jin
HJ
Kim
Jason K
JK
Lee
Amy S
AS
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004734:Energy Metabolism; D006360:Heat-Shock Proteins / Q000235:genetics*; D006579:Heterozygote; D015151:Immunoblotting; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000517:prevention & control; D011489:Protein Denaturation; D014162:Transfection; D056811:Unfolded Protein Response / Q000235:genetics*
D001786:Blood Glucose; D004041:Dietary Fats; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007328:Insulin