Role of Endoplasmic Reticulum Stress and c-Jun NH2-Terminal Kinase Pathways in Inflammation and Origin of Obesity and Diabetes

  1. Gökhan S. Hotamisligil
  1. From the Departments of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts
  1. Address correspondence and reprint requests to Gökhan S. Hotamisligil, MD, PhD, 665 Huntington Ave., Bldg. I, Rm. 205, Boston, MA 02115. E-mail: ghotamis{at}hsph.harvard.edu

Abstract

Metabolic and immune systems are the most fundamental requirements for survival, and many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily highly conserved. Consequently, metabolic and immune pathways are also highly integrated and interdependent. In the past decade, it became apparent that this interface plays a critical role in the pathogenesis of chronic metabolic diseases, particularly obesity and type 2 diabetes. Importantly, the inflammatory component in obesity and diabetes is now firmly established with the discovery of causal links between inflammatory mediators, such as tumor necrosis factor (TNF)-α and insulin receptor signaling and the elucidation of the underlying molecular mechanisms, such as c-Jun NH2-terminal kinase (JNK)- and inhibitor of nuclear factor-κB kinase–mediated transcriptional and posttranslational modifications that inhibit insulin action. More recently, obesity-induced endoplasmic reticulum stress has been demonstrated to underlie the initiation of obesity-induced JNK activation, inflammatory responses, and generation of peripheral insulin resistance. This article will review the link between stress, inflammation, and metabolic disease, particularly type 2 diabetes, and discuss the mechanistic and therapeutic opportunities that emerge from this platform by focusing on JNK and endoplasmic reticulum stress responses.

Footnotes

  • G.S.H. has received honoraria from Merck, Lilly, and Taisho Pharm for speaking engagements and has received research funding from Eli Lilly.

    This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    • Accepted June 6, 2005.
    • Received April 14, 2005.
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