Grp78 heterozygosity promotes adaptive unfolded protein response and attenuates diet-induced obesity and insulin resistance.
Grp78 heterozygosity promotes adaptive unfolded protein response and attenuates diet-induced obesity and insulin resistance.
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作者：
Ye R;Jung DY;Jun JY;Li J;Luo S;Ko HJ;Kim JK;Lee AS
探讨内质网（ER）伴侣糖调节蛋白（GRP） 78/BiP在肥胖、胰岛素抵抗和2型糖尿病发病机制中的作用。雄性Grp78+/−小鼠及其野生型仔鼠采用高脂肪饮食（HFD）方案。肥胖症和2型糖尿病的发病机制通过多种代谢表型方法进行了研究。采用高胰岛素-正糖钳分析组织特异性胰岛素敏感性。通过免疫印迹和组织培养方法探讨其分子机制。Grp78杂合性增加能量消耗，减轻hfd诱导的肥胖。Grp78+/−小鼠对饮食诱导的高胰岛素血症、肝脂肪变性、白色脂肪组织（WAT）炎症和高血糖具有抗性。高胰岛素-正糖钳夹研究表明，Grp78杂合性改善了独立于肥胖的葡萄糖代谢，并且在高脂饮食后主要增加了WAT的胰岛素敏感性。从机制上解释，高热量胁迫下WAT中的Grp78杂合性促进适应性未折叠蛋白反应（UPR），减弱翻译阻滞，上调内质网降解增强α-甘露糖苷酶样蛋白（EDEM）和内质网伴侣蛋白，从而提高内质网质量控制和折叠能力。此外，ATF6活性形式的过表达诱导保护性UPR并改善内质网应激时的胰岛素信号传导。在Grp78+/−小鼠中，hfd诱导的肥胖和2型糖尿病得到改善。WAT中的适应性UPR可能有助于这种改善，将内质网稳态与能量平衡和葡萄糖代谢联系起来。
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. 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. 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. 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.
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影响因子：
7.8
作者：
Bass, J;Chiu, G;Argon, Y;Steiner, DF
通讯作者：
Steiner, DF
影响因子：
11.8
作者：
Rutkowski, D. Thomas;Wu, Jun;Back, Sung-Hoon;Callaghan, Michael U.;Ferris, Sean P.;Iqbal, Jahangir;Clark, Robert;Miao, Hongzhi;Hassler, Justin R.;Fornek, Jamie;Katze, Michael G.;Hussain, M. Mahmood;Song, Benbo;Swathirajan, Jayanth;Wang, Junying;Yau, Grace D. -Y.;Kaufman, Randal J.
通讯作者：
Kaufman, Randal J.
影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere
影响因子：
4.8
作者：
Guo, L;Nakamura, K;Michalak, M
通讯作者：
Michalak, M
DOI：
10.1073/pnas.0807691105
发表时间：
2008-12-09
影响因子：
11.1
作者：
Fu, Yong;Wey, Shiuan;Lee, Amy S.
通讯作者：
Lee, Amy S.