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


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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    • "The effectors of IR in HF diet-induced inflammation are suggested to involve hyperactivation of stress-sensitive Ser/Thr kinases, such as JNK and IKKβ, which in turn inhibits insulin receptor/IRS1 axis. Several mechanisms were proposed to explain the link between inflammation and IR: endoplasmic reticulum (ER) stress (Ozcan et al., 2004;Lionetti et al., 2009;Mollica et al., 2011), oxidative stress (Lark et al., 2012), signaling through inflammation-associated receptors, such as TLR4 signaling (Uysal et al., 1997;Shi et al., 2006), and partitioning/activation of c-SRC (a key mediator of JNK activation) by saturated FA (Holzer et al., 2011; Figure 1A). In recent years, different reviews focused on mechanism(s) by which mitochondrial bioenergetics (Wellman and Neufer, 2012;Lark et al., 2012;Muoio and Neufer, 2012;Holloszy, 2013) and morphology (Liesa and Shirihai, 2013;Montgomery and Turner, 2015) may be linked to the etiology of IR in skeletal muscle. "
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    ABSTRACT: It has been suggested that skeletal muscle mitochondria play a key role in high fat diet induced insulin resistance. Two opposite views are debated on mechanisms by which mitochondrial function could be involved in skeletal muscle insulin resistance. In one theory, mitochondrial dysfunction is suggested to cause intramyocellular lipid accumulation leading to insulin resistance. In the second theory, excess fuel within mitochondria in the absence of increased energy demand stimulates mitochondrial oxidant production and emission, ultimately leading to the development of insulin resistance. Noteworthy, mitochondrial bioenergetics is strictly associated with the maintenance of normal mitochondrial morphology by maintaining the balance between the fusion and fission processes. A shift towards mitochondrial fission with reduction of fusion protein, mainly mitofusin 2, has been associated with reduced insulin sensitivity and inflammation in obesity and insulin resistance development. However, dietary fat source during chronic overfeeding differently affects mitochondrial morphology. Saturated fatty acids induce skeletal muscle insulin resistance and inflammation associated with fission phenotype, whereas ω-3 polyunsaturated fatty acids improve skeletal muscle insulin sensitivity and inflammation, associated with a shift toward mitochondrial fusion phenotype. The present minireview focuses on mitochondrial bioenergetics and morphology in skeletal muscle insulin resistance, with particular attention to the effect of different dietary fat sources on skeletal muscle mitochondria morphology and fusion/fission balance.
    Preview · Article · Jan 2016 · Frontiers in Physiology
    • "One potential explanation of EAT adipocyte death in CAD may be their increased size. In fact, it is known that adipocyte hypertrophy associated to deregulated cellular metabolism might promote adipocyte death[7,25]. Moreover, the hypertrophic state observed may be a peculiarity of CAD pathology regardless of the anthropometric characteristics of the patients. "
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    ABSTRACT: Background and aims: In coronary artery disease (CAD) epicardial adipose tissue (EAT) shows an elevated inflammatory infiltrate. Toll-like receptors (TLRs) are important mediators of adipose tissue inflammation and they are able to recognize endogenous products released by damaged cells. Because adipocyte death may be driven by hypertrophy, our aim was to investigate in CAD and non-CAD patients the association between EAT adipocyte size, macrophage infiltration/polarization and TLR-2 and TLR-4 expression. Methods and results: EAT biopsies were collected from CAD and non-CAD patients. The adipocyte size was determined by morphometric analysis. Microarray technology was used for gene expression analysis; macrophage phenotype and TLRs expression were analyzed by immunofluorescence and immunohistochemical techniques. Inflammatory mediator levels were determined by immunoassays. EAT adipocytes were larger in CAD than non-CAD patients and do not express perilipin A, a marker of lipid droplet integrity. In CAD, EAT is more infiltrated by CD68-positive cells which are polarized toward an M1 state (CD11c positive) and presents an increased pro-inflammatory profile. Both TLR-2 and TLR-4 expression is higher in EAT from CAD and observed on all the CD68-positive cells. Conclusions: Our findings suggested that EAT hypertrophy in CAD promotes adipocyte degeneration and drives local inflammation through increased infiltration of macrophages which are mainly polarized towards an M1 state and express both TLR-2 and TLR-4.
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    • "In the context of obesity, it is well known that high circulating levels of pro-inflammatory cytokines such as tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β), and increases in free saturated fatty acids such as palmitate, activate JNK signalling in insulin target cells. Additionally, the induction of endoplasmic reticulum stress leads to activation of the JNK pathway (Urano et al. 2000) and this is proposed to be a key driver of JNK activation in obesity (Ozcan et al. 2004). Another potentially important factor for the activation of JNK during obesity are reactive oxygen species (ROS) (Houstis et al. 2006). "
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    ABSTRACT: Obesity is currently at epidemic levels worldwide and is associated with a wide range of diseases such as type 2 diabetes, cardiovascular disease, fatty liver disease and certain forms of cancer. Obesity-induced chronic inflammation is central to the disrupted metabolic homeostasis which underlies many of these conditions. While research over the past decade has identified many of the cells and signalling molecules that contribute to obesity-induced inflammation, perhaps the best characterised are the stress-activated c-Jun NH2 -terminal kinases (JNKs). JNKs are activated in obesity in numerous metabolically important cells and tissues such as adipose tissue, macrophages, liver, skeletal muscle and regions of the brain and pituitary. Elegant in vivo mouse studies using Cre-LoxP mediated recombination of the JNK1 and JNK2 genes have revealed the remarkably diverse roles that JNKs play in the development of obesity-induced inflammation, impaired glucose homeostasis and hepatic steatosis. While JNK activation in classical metabolically active tissues such as skeletal muscle and adipose tissue only appears to play a minor role on the induction of the above mentioned pathologies, recent studies have clearly established the important roles JNK signalling fulfils in macrophages, the liver and cells of the anterior pituitary. Collectively, these studies place JNKs as important mediators of obesity and obesity-associated disruptions to metabolic homeostasis. This article is protected by copyright. All rights reserved.
    Full-text · Article · Nov 2015 · The Journal of Physiology
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