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

Risheng Ye; Dae Young Jung; Jun, John Y.; Jianze Li; Shengzhan Luo; Hwi Jin Ko; Kim, Jason K.; Lee, Amy S.
January 2010
Diabetes;Jan2010, Vol. 59 Issue 1, p6
Academic Journal
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. 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 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 α-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. Diabetes 59:6-16, 2010


Related Articles

  • Infusion of Glucose and Lipids at Physiological Rates Causes Acute Endoplasmic Reticulum Stress in Rat Liver. Boden, Guenther; Weiwei Song; Xunbao Duan; Cheung, Peter; Kresge, Karen; Barrero, Carlos; Merali, Salim // Obesity (19307381);Jul2011, Vol. 19 Issue 7, p1366 

    Endoplasmic reticulum (ER) stress has recently been implicated as a cause for obesity-related insulin resistance; however, what causes ER stress in obesity has remained uncertain. Here, we have tested the hypothesis that macronutrients can cause acute (ER) stress in rat liver. Examined were the...

  • Berberine reduces endoplasmic reticulum stress and improves insulin signal transduction in Hep G2 cells. Zeng-si WANG; Fu-er LU; Li-jun XU; Hui DONG // Acta Pharmacologica Sinica;May2010, Vol. 31 Issue 5, p578 

    AbstractAim:Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of insulin resistance and pancreatic β-cell dysfunction. The aim of this study is to investigate whether the insulin-sensitizing action of berberine is related to reducing ER stress.Methods:ER stress in...

  • The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Yiguo Wang; Vera, Liliana; Fischer, Wolfgang H.; Montminy, Marc // Nature;7/23/2009, Vol. 460 Issue 7254, p534 

    In fasted mammals, circulating pancreatic glucagon stimulates hepatic gluconeogenesis in part through the CREB regulated transcription coactivator 2 (CRTC2, also referred to as TORC2). Hepatic glucose production is increased in obesity, reflecting chronic increases in endoplasmic reticulum (ER)...

  • Nifedipine Protects INS-1 β-Cell from High Glucose-Induced ER Stress and Apoptosis. Yao Wang; Lu Gao; Yuan Li; Hong Chen; Zilin Sun // International Journal of Molecular Sciences;Nov2011, Vol. 12 Issue 11, p7569 

    Sustained high concentration of glucose has been verified toxic to β-cells. Glucose augments Ca2+-stimulated insulin release in pancreatic β-cells, but chronic high concentration of glucose could induce a sustained level of Ca2+ in β-cells, which leads to cell apoptosis. However, the...

  • Mechanisms of Control of the Free Ca2+ Concentration in the Endoplasmic Reticulum of Mouse Pancreatic β-Cells. Ravier, Magalie A.; Daro, Dorothée; Roma, Leticia Prates; Jonas, Jean-Christophe; Cheng-Xue, Rui; Schuit, Frans C.; Gilon, Patrick // Diabetes;Oct2011, Vol. 60 Issue 10, p2533 

    OBJECTIVE-Sarco-endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and SERCA3 pump Ca2+ in the endoplasmic reticulum (ER) of pancreatic β-cells. We studied their role in the control of the free ER Ca2+ concentration ([Ca2+]ER) and the role of SERCA3 in the control of insulin secretion and ER...

  • Endoplasmic Reticulum Stress Promotes LIPIN2-Dependent Hepatic Insulin Resistance. Dongryeol Ryu; Woo-Young Seo; Young-Sil Yoon; Yo-Na Kim; Su Sung Kim; Hye-Jin Kim; Tae-Sik Park; Cheol Soo Choi; Seung-Hoi Koo // Diabetes;Apr2011, Vol. 60 Issue 4, p1072 

    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...

  • Inflammation and endoplasmic reticulum stress in obesity and diabetes. Hotamisligil, G. S. // International Journal of Obesity;Dec2008 Supplement 7, Vol. 32, pS52 

    Obesity is associated with chronic low-grade inflammation. Inflammatory signals interfere with insulin action and disrupt metabolic homeostasis. The c-Jun N-terminal kinase (JNK) has been identified as a central mediator of insulin resistance. Recent studies showed that in obesity compromising...

  • Tauroursodeoxycholic Acid May Improve Liver and Muscle but Not Adipose Tissue Insulin Sensitivity in Obese Men and Women. Kars, Marleen; Ling Yang; Gregor, Margaret F.; Mohammed, B. Selma; Pietka, Terri A.; Finck, Brian N.; Patterson, Bruce W.; Horton, Jay D.; Mittendorfer, Bettina; Hotamisligil, Gökhan S.; Klein, Samuel // Diabetes;Aug2010, Vol. 59 Issue 8, p1899 

    OBJECTIVE--Insulin resistance is commonly associated with obesity. Studies conducted in obese mouse models found that endoplasmic reticulum (ER) stress contributes to insulin resistance, and treatment with tauroursodeoxycholic acid (TUDCA), a bile acid derivative that acts as a chemical...

  • Endoplasmic Reticulum Stress: Another Link Between Obesity and Insulin Resistance/Inflammation? Boden, Guenther // Diabetes;March2009, Vol. 58 Issue 3, p518 

    The article focuses on endoplasmic reticulum (ER) stress and its suspected role in obesity-associated insulin resistance and inflammation. It notes that blood levels of free fatty acids (FFAs) play an important role in the development of obesity-related insulin resistance and inflammation. It...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics