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: 31.48). 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.

Download full-text


Available from: Gurol Tuncman, Aug 25, 2015
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Cell Reports 07/2015; 12(3). DOI:10.1016/j.celrep.2015.06.041 · 8.36 Impact Factor
  • Source
    • "Pioneering epidemiological studies connecting AD to diabetes initiated in the 1990s (Ott et al., 1996, 1999; Kalmijin et al., 1997) and were followed by several reports providing both clinical and experimental evidence into how these two disorders may course together (de la Monte, 2009; Matsuzaki et al., 2010; Crane et al., 2013; De Felice, 2013; De Felice et al., 2014). Metabolic derangements, including inflammation, insulin resistance and endoplasmic reticulum (ER) stress, are known to underlie glucose intolerance and type 2 diabetes mellitus (T2DM) in peripheral tissues (Hotamisligil et al., 1995, 1996; Ozcan et al., 2004, 2006; Hotamisligil, 2006). A similar scenario has been recently described in the brains of patients that suffer from neurodegenerative disorders, such as AD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Brain metabolic dysfunction is known to influence brain activity in several neurological disorders, including Alzheimer's disease (AD). In fact, deregulation of neuronal metabolism has been postulated to play a key role leading to the clinical outcomes observed in AD. Besides deficits in glucose utilization in AD patients, recent evidence has implicated neuroinflammation and endoplasmic reticulum (ER) stress as components of a novel form of brain metabolic stress that develop in AD and other neurological disorders. Here we review findings supporting this novel paradigm and further discuss how these mechanisms seem to participate in synapse and cognitive impairments that are germane to AD. These deleterious processes resemble pathways that act in peripheral tissues leading to insulin resistance and glucose intolerance, in an intriguing molecular connection linking AD to diabetes. The discovery of detailed mechanisms leading to neuronal metabolic stress may be a key step that will allow the understanding how cognitive impairment develops in AD, thereby offering new avenues for effective disease prevention and therapeutic targeting.
    Frontiers in Aging Neuroscience 05/2015; 7:94. DOI:10.3389/fnagi.2015.00094 · 2.84 Impact Factor
  • Source
    • "Please cite this article in press as: Nakamura et al., A Critical Role for PKR Complexes with TRBP in Immunometabolic Regulation and eIF2a Phosphorylation in Obesity, Cell Reports (2015), 2009; Gregor et al., 2009; Oyadomari et al., 2008; Ozcan et al., 2004; Sharma et al., 2008; Sreejayan et al., 2008). However, our findings demonstrate that PKR dominates this regulation in obese liver. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aberrant stress and inflammatory responses are key factors in the pathogenesis of obesity and metabolic dysfunction, and the double-stranded RNA-dependent kinase (PKR) has been proposed to play an important role in integrating these pathways. Here, we report the formation of a complex between PKR and TAR RNA-binding protein (TRBP) during metabolic and obesity-induced stress, which is critical for the regulation of eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation and c-Jun N-terminal kinase (JNK) activation. We show that TRBP phosphorylation is induced in the setting of metabolic stress, leading to PKR activation. Suppression of hepatic TRBP reduced inflammation, JNK activity, and eIF2α phosphorylation and improved systemic insulin resistance and glucose metabolism, while TRBP overexpression exacerbated the impairment in glucose homeostasis in obese mice. These data indicate that the association between PKR and TRBP integrates metabolism with translational control and inflammatory signaling and plays important roles in metabolic homeostasis and disease. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 274(2). DOI:10.1016/j.celrep.2015.03.021 · 8.36 Impact Factor
Show more