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

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.
Diabetes (Impact Factor: 8.1). 10/2009; 59(1):6-16. DOI: 10.2337/db09-0755
Source: PubMed


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 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.
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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    • "Our study confirmed the existence of glucotoxic effects on INS-1 cell survival and secretory function and also demonstrated that the deleterious effects of high glucose were additive to those of PSCs. One important mechanism of β-cell failure in T2DM is the development of ER stress as a response to an imbalance between the rate of protein synthesis and folding capacity of the endoplasmic reticulum in hypersecreting β-cells, eventually resulting in β-cell apoptosis [37, 38]. Our measurements of increased CHOP mRNA and protein levels in response to PSCs-CM and/or high glucose suggest that the detrimental effects of PSCs on β-cells may be associated with the activation of the ER stress response. "
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    • "Markers of UPR activation have been detected in FLD samples from multiple species (Imrie and Sadler, 2012; Malhi and Kaufman, 2011) and inducing ER stress with Tm is sufficient to cause FLD in mice (Lee et al., 2012; Rutkowski et al., 2008; Teske et al., 2011; Wu et al., 2007; Yamamoto et al., 2010; Zhang et al., 2011) and zebrafish (Cinaroglu et al., 2011; Thakur et al., 2011). Moreover, steatosis can be influenced by altering the expression of key UPR mediators, including BiP (Ji et al., 2011; Kammoun et al., 2009; Ye et al., 2010), PERK (Teske et al., 2011), IRE1A/XBP1 (Lee et al., 2008; Ozcan et al., 2006; Zhang et al., 2011) and ATF6 (Cinaroglu et al., 2011; Howarth et al., 2014; Rutkowski et al., 2008; Wu et al., 2007; Yamamoto et al., 2010). Our recent finding that Atf6 overexpression is sufficient to cause steatosis in zebrafish (Howarth et al., 2014) definitively shows that activation of this pathway is a culprit in FLD. "
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