Article

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.

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Available from: Gurol Tuncman, Jul 27, 2015
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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.
    Cell Reports 07/2015; DOI:10.1016/j.celrep.2015.06.041 · 7.21 Impact Factor
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    • "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), http://dx.doi.org/10.1016/j.celrep.2015.03.021 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. "
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    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. DOI:10.1016/j.celrep.2015.03.021 · 7.21 Impact Factor
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    • "The signs of chronic ERS have recently been found in obese and insulin resistant subjects [10] [11]. The significance of ERS for metabolic health was confirmed by experiments on rodents corroborating ERS as a trigger of insulin resistance and other metabolic disturbances caused by obesity [12]. Importantly, ERS and consequently UPR were found to be important regulators of lipogenesis in liver [13]. "
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    ABSTRACT: Adipocytes are cells specialized for storage of neutral lipids. This storage capacity is dependent on lipogenesis and is diminished in obesity. The reason for the decline in lipogenic activity of adipocytes in obesity remains unknown. Recent data show that lipogenesis in liver is regulated by pathways initiated by endoplasmic reticulum stress (ERS). Thus, we aimed at investigating the effect of ERS on lipogenesis in adipose cells. Preadipocytes were isolated from subcutaneous abdominal adipose tissue from obese volunteers and in vitro differentiated into adipocytes. ERS was induced pharmacologically by thapsigargin (TG) or tunicamycin (TM). Activation of Unfolded Protein Response pathway (UPR) was monitored on the level of eIF2a phosphorylation and mRNA expression of downstream targets of UPR sensors. Adipogenic and lipogenic capacity was evaluated by Oil Red O staining, measurement of incorporation of radio-labelled glucose or acetic acid into lipids and mRNA analysis of adipogenic/lipogenic markers. Exposition of adipocytes to high doses of TG (100 nM) and TM (1 μg/ml) for 1-24 hours enhanced expression of several UPR markers (HSPA5, EDEM1, ATF4, XBP1s) and phosphorylation of eIF2α. This acute ERS substantially inhibited expression of lipogenic genes (DGAT2, FAS, SCD1) and glucose incorporation into lipids. Moreover, chronic exposure of preadipocytes to low dose of TG (2.5 nM) during the early phases of adipogenic conversion of preadipocytes impaired both, lipogenesis and adipogenesis. On the other hand, chronic low ERS had no apparent effect on lipogenesis in mature adipocytes. Acute ERS weakened a capacity of mature adipocytes to store lipids and chronic ERS diminished adipogenic potential of preadipocytes. Copyright © 2015 Elsevier Inc. All rights reserved.
    Biochemical and Biophysical Research Communications 03/2015; 460(3). DOI:10.1016/j.bbrc.2015.03.090 · 2.28 Impact Factor
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