Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes

Department of Immunology and Infectious Diseases, Harvard University, Cambridge, Massachusetts, United States
Science (Impact Factor: 33.61). 11/2004; 306(5695):457-61. DOI: 10.1126/science.1103160
Source: PubMed

ABSTRACT Obesity contributes to the development of type 2 diabetes, but the underlying mechanisms are poorly understood. Using cell
culture and mouse models, we show that obesity causes endoplasmic reticulum (ER) stress. This stress in turn leads to suppression
of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation
of insulin receptor substrate–1 (IRS-1). Mice deficient in X-box–binding protein–1 (XBP-1), a transcription factor that modulates
the ER stress response, develop insulin resistance. These findings demonstrate that ER stress is a central feature of peripheral
insulin resistance and type 2 diabetes at the molecular, cellular, and organismal levels. Pharmacologic manipulation of this
pathway may offer novel opportunities for treating these common diseases.

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    • "A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 8 response[19] [25] "
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    • "In liver cells, PA induces ER stress resulting in decreased insulin action, but in obese mice, ER stress was not detected in skeletal muscle [21] [22]. "
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    ABSTRACT: We recently reported that lowering the high, habitual palmitic acid (PA) intake in ovulating women improved insulin sensitivity and both inflammatory and oxidative stress. In vitro studies indicate that PA can activate both cell membrane toll-like receptor-4 and the intracellular nucleotide oligomerization domain-like receptor protein (NLRP3). To gain further insight into the relevance to human metabolic disease of dietary PA, we studied healthy, lean and obese adults enrolled in a randomized, crossover trial comparing 3-week, high-PA (HPA) and low-PA/high-oleic-acid (HOA) diets. After each diet, both hepatic and peripheral insulin sensitivities were measured, and we assessed cytokine concentrations in plasma and in supernatants derived from lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMCs) as well as proinflammatory gene expression in skeletal muscle. Insulin sensitivity was unaffected by diet. Plasma concentration of tumor necrosis factor-α was higher during the HPA diet. Lowering the habitually high PA intake by feeding the HOA diet resulted in lower secretion of interleukin (IL)-1β, IL-18, IL-10, and tumor necrosis factor-α by PBMCs, as well as lower relative mRNA expression of cJun and NLRP3 in muscle. Principal components analysis of 156 total variables coupled to analysis of covariance indicated that the mechanistic pathway for the differential dietary effects on PBMCs involved changes in the PA/OA ratio of tissue lipids. Our results indicate that lowering the dietary and tissue lipid PA/OA ratio resulted in lower leukocyte production of proinflammatory cytokines and muscle expression of redox-sensitive genes, but the relevance to diabetes risk is uncertain. Copyright © 2015. Published by Elsevier Inc.
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    • "Perturbations in ER performance, and the subsequent development of ER stress, have been implicated in the pathophysiology of metabolic disorders such as obesity and type-2 diabetes (T2D) (Ozcan et al., 2004, 2006). In particular, the hypothalamus has emerged as a key area of the CNS, causally linking ER stress, leptin resistance, and overweight (Cakir et al., 2013; Contreras et al., 2014; Hosoi et al., 2008; Ozcan et al., 2009; Won et al., 2009; Zhang et al., 2008). "
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    ABSTRACT: Alterations in ER homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here, we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (α-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic α-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective α-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress and establish α-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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