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Obesity is associated with chronic low-grade inflammation. Inflammatory signals interfere with insulin action and disrupt metabolic homeostasis. The c-Jun N-terminal kinase (JNK) has been identified as a central mediator of insulin resistance. Recent studies showed that in obesity compromising endoplasmic reticulum (ER) function results in insulin resistance and type 2 diabetes that are dependent on JNK activation. In contrast, enhancing ER function in transgenic mice or by the use of chemical chaperones protects against diet-induced insulin resistance. Hence, ER stress and the related signaling networks present a critical mechanism underlying obesity-induced JNK activity, inflammatory response and insulin resistance.
Obesity is associated with chronic, low grade, inflammatory responses in metabolically active sites, most notably, adipose tissue.1 This increased chronic inflammatory status triggered by metabolic cues, which differs from the classic inflammation, is a critical link between obesity and other associated pathologies, such as insulin resistance and type 2 diabetes.2,3 The principal mechanism by which the inflammatory signals interfere with insulin action involves posttranslational modification of insulin receptor substrate molecules, particularly through serine phosphorylation. This modification is essentially universal to all forms of insulin resistance whether they are chemically or genetically induced in cells, animal models, or human disease.1 In efforts to identify the mechanisms leading to insulin resistance in general and serine phosphorylation of insulin receptor substrate molecules in particular, we have previously identified c-Jun N-terminal kinase (JNK) as a central mediator of insulin resistance in cultured cells and obese animal models.4 These studies showed that obesity results in marked JNK activation in insulin-sensitive tissues, such as fat and liver, and specifically the JNK1 isoform played a dominant role in insulin receptor substrate-1 serine phosphorylation and subsequent inhibition of insulin action. Genetic deletion of JNK1 gene in mice resulted in marked protection against insulin resistance, type 2 diabetes and fatty liver disease.4,5 Furthermore, blocking JNK activity using chemical, biochemical, or molecular strategies in obese mice also results in enhanced insulin sensitivity and correction of hyperglycemia, indicating a potential for utilizing JNK inhibition as therapeutic strategy against type 2 diabetes. Interestingly, there is also genetic proof of principle supporting a role for JNK activation in rare forms of human diabetes resulting from mutations in JNK inhibitory protein in humans. In my talk, I reviewed the current landscape in efforts to utilize this target as a therapeutic strategy and the evidence supporting the role of this mechanism in human disease.6 In addition, I presented recent studies examining the role of JNK activity in bone marrow-derived cells as they relate to adipose tissue and liver inflammation and systemic insulin sensitivity.6-8 These studies showed that while the JNK activity in the bone marrow-derived cells contributed to metabolic homeostasis, this effect was minor compared with that of the parenchymal cells.8 These results support the hypothesis that inflammatory output of metabolic cells is the dominant regulators of obesity-induced inflammatory alterations, insulin resistance and type 2 diabetes.6,8 As JNK presents a central mechanism leading to metabolic disease, there has been a widespread interest in the pathways leading to JNK activation in obesity and type 2 diabetes, particularly in adipose and liver tissues. These efforts recently led to our discovery of organelle dysfunction, particularly endoplasmic reticulum (ER) stress as a potential mechanism leading to JNK activation and insulin resistance in obese animal models.9
The ER is a vast membranous network responsible for the trafficking of a wide range of proteins. The ER is a principal site of protein synthesis, maturation and, together with the Golgi apparatus, the transportation and release of correctly folded proteins. As the ER plays a central role in integrating multiple metabolic signals critical in cellular homeostasis, it is of paramount importance to the cell to maintain proper ER function and to adapt organelle capacity to manage metabolic and other adverse conditions.10 Therefore, under conditions that challenge ER function, particularly its folding capacity, the organelle has evolved an adaptive response system known as the unfolded protein response. Conditions that may trigger unfolded protein response activation include increased protein synthesis, the presence of mutant or misfolded proteins, inhibition of protein glycosylation, imbalance of ER calcium levels, glucose and energy deprivation, hypoxia, pathogens or pathogen-associated components and toxins.10 Recently, studies in my laboratory also linked constitutively elevated mammalian target of rapamycin activity as another condition leading to ER stress. Many of these conditions, including high mammalian target of rapamycin activity are characteristic of obesity, especially in metabolically active sites such as liver, adipose tissue, and pancreatic islets. Interestingly, during the unfolded protein response, there is also activation of JNK.
Given that the unfolded protein response is closely integrated with stress signaling, inflammation and JNK activation, as well as the fact that obesity features many conditions to challenge ER (from increase in synthetic demand to energy availability and fluxes), we hypothesized that obesity may lead to a condition of ER stress in metabolically active tissues and organs. In an attempt to address this hypothesis, we have showed that inducing ER stress in liver cells using either tunicamycin or thapsigargin, agents commonly used to stimulate ER stress, increases serine phosphorylation of insulin receptor substrate-1 in an inositol requiring-1- and JNK-dependent manner and blocks insulin action.11 Alterations in cellular ER stress responses through experimental modulation of the transcription factor XBP-1 strongly modulate insulin receptor signaling capacity. In mice, compromising ER function through targeted mutations in the Xbp-1 gene results in insulin resistance and type 2 diabetes that are also dependent on JNK activation. In contrast, enhancing ER folding capacity by transgenic strategies protects mice against diet-induced insulin resistance. Recently, we showed that in addition to genetic models, modulation of ER function by chemical chaperones phenyl butyric acid and taurine-conjugatedursodeoxycholicacid provide strong insulin sensitizing effects and normalize hyperglycemia in animal models.12 These treatments lead to markedly enhanced insulin receptor signaling in peripheral tissues and restored proper insulin action. Hyperinsulinemiceugylcemic clamp studies showed that chemical chaperones significantly impact both hepatic glucose production and peripheral glucose disposal rates with significantly increased adipose tissue and muscle glucose uptake. Moreover, both phenyl butyric acid and taurine-conjugatedursodeoxycholicacid treatments resulted in a marked reduction in fatty infiltration of liver, which is frequently observed in obesity. Taken together, these studies illustrate that ER stress is a critical mechanism underlying obesity-induced JNK activity, inflammatory and stress responses, and insulin resistance and offer potential new therapeutic opportunities against obesity, insulin resistance and type 2 diabetes.
In my presentation, I covered recent developments in this field and also provided a summary of the data supporting the relevance of ER stress and related inflammatory pathways in human disease.
I am grateful for the contribution of fellows and students to the studies presented here. The research programs in Hotamisligil laboratory are supported by grants from the National Institutes of Health USA, American Diabetes Association and Juvenile Diabetes Research Foundation.
Conflict of interest
Gokhan S Hotamisligil has received lecture fees from Merck, Schering Plough, Pfizer and Glaxo Smith Kline and is a member of the SAB of Lipomics Technologies Inc. and Syndexa Pharmaceuticals. In addition, Gokhan S Hotamisligil owns stock options with Lipomics Technologies Inc. and Syndexa Pharmaceuticals and has received grant support from Syndexa.