Deletion of C/EBP homologous protein (Chop) in C57Bl/6 mice dissociates obesity from insulin resistance

Abstract

Aims/hypothesis Endoplasmic reticulum (ER) stress has been implicated in the development of type 2 diabetes, via effects on obesity, insulin resistance and pancreatic beta cell health. C/EBP homologous protein (CHOP) is induced by ER stress and has a central role in apoptotic execution pathways triggered by ER stress. The aim of this study was to characterise the role of CHOP in obesity and insulin resistance.Methods Metabolic studies were performed in Chop −/− and wild-type C57Bl/6 mice, and included euglycaemichyperinsulinaemic clamps and indirect calorimetry. The inflammatory state of liver and adipose tissue was determined by quantitative RT-PCR, immunohistology and macrophage cultures. Viability and absence of ER stress in islets of Langerhans was determined by electron microscopy, islet culture and quantitative RT-PCR. Results Systemic deletion of Chop induced abdominal obesity and hepatic steatosis. Despite marked obesity, Chop −/− mice had preserved normal glucose tolerance and insulin sensitivity. This discrepancy was accompanied by lower levels of pro-inflammatory cytokines and less infiltration of immune cells into fat and liver. Conclusions/interpretation These observations suggest that insulin resistance is not induced by fat accumulation per se, but rather by the inflammation induced by ectopic fat. CHOP may play a key role in the crosstalk between excessive fat deposition and induction of inflammation-mediated insulin resistance.

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

“…47 It has been reported that CHOP − / − mice on C57B1/J background preserve normal glucose tolerance and insulin sensitivity. 48 Moreover, CHOP-deficient mice did not develop albuminuria and ER stress-induced apoptosis in proximal tubular cells. 49 Caspase-12 is a member of the caspase family and is located in the ER.…”

Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

“…In line with this hypothesis, exposure of human pancreatic cells to the saturated NEFA palmitate induces ER stress, NF-κB activation and upregulation of IL-1β (also known as IL1B), TNF, IL-6 (also known as IL6), IL-8 (also known as IL8), CCL2 and CXCL1 expression [14]. Moreover, CHOP deletion decreases the induction of inflammation caused by excessive fat accumulation in liver and fat and, importantly, prevents insulin resistance [15].…”

“…Studies of diabetes in Chop knockout mice are difficult to interpret, since these mice are often obese [15]. Preliminary observations in diabetes-prone NOD mice indicate that administration of a chemical chaperone, tauroursodeoxycholic acid, reduces diabetes incidence, improves survival and morphology of beta cells and reduces beta cell apoptosis [30].…”

“…The proinflammatory effect of CHOP in beta cells may require a second signal, provided by cytokines, since CHOP induction by CPA does not amplify NF-κB activation stimulated by a low concentration of IL-1β [20]. The role of CHOP in inflammatory responses (including chemokine and cytokine production) has been observed in different disease models, including myocardial inflammation [47], lung damage induced by LPS [48], inflammatory bowel disease [49] and obesity [15].…”

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

“…CHOP contributes to rodent and human β-cell apoptosis and its expression is upregulated in islets from both T1D and T2D patients (Laybutt et al 2007, Cunha et al 2008. Besides its proapoptotic role, recent studies revealed a pro-inflammatory role for CHOP in different disease models, including myocardial inflammation (Miyazaki et al 2011), lung damage induced by LPS (Endo et al 2005), chemical hepatocarcinogenesis (DeZwaan-McCabe et al 2013), and high fat diet-induced diabetes (Maris et al 2012)…”