Metabolic Stress Signaling

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Human obesity represents a serious world-wide health problem. One consequence of obesity is the development of metabolic syndrome, characterized by insulin resistance and hyperglycemia, that can lead to b-cell dysfunction and type 2 diabetes. It is therefore important that we gain an understanding of the physiology and pathophysiology of the development of obesity because this knowledge represents a basis for the design of potential therapeutic interventions. Recent studies have identified the cJun NH2-terminal kinase (JNK) signal transduction pathway as a mediator of metabolic stress responses. Feeding a high fat diet (HFD) causes increased JNK activity and promotes both obesity and insulin resistance. Studies using tissue-specific knockout mice demonstrate a central role for JNK in the regulation of energy expenditure and the development of obesity. In contrast, JNK in peripheral tissues can cause insulin resistance without changes in obesity. The mechanism that accounts for JNK-dependent insulin resistance caused by feeding a HFD has not been defined. This research program is focused on the metabolic function of hepatic JNK signaling. During the initial period of research support, we identified the PPARa pathway as a major target of hepatic JNK signaling that contributes to HFD-induced insulin resistance. We demonstrated that JNK activation caused by feeding a HFD potently suppresses PPARa activity. A key target of PPARa -mediated hepatic gene expression is the hepatokine fibroblast growth factor 21 (FGF21). Consequently, disruption of JNK signaling in the liver causes increased hepatic PPARa activity, increased amounts of FGF21 circulating in the blood, and improved glycemia in HFD-fed mice. Disruption of hepatic Fgf21 expression prevents the effects of JNK deficiency to cause improved glycemia. The PPARa/FGF21 axis therefore represents a major target of hepatic JNK signaling that promotes systemic insulin sensitivity. The overall goal of this research program is to identify mechanisms of hepatic JNK signaling that contribute to the regulation of insulin sensitivity. Our analysis establishes a key role for hepatic PPARa. However, the molecular target(s) that mediate the effects of JNK on PPARa have not been established. The identification of molecular mechanism is the focus of this renewal application. Achievement of the goals of this proposal will increase understanding of the molecular response to obesity. We anticipate that the successful completion of this research program will lead to the identification of new mechanisms that contribute to the obesity response. This knowledge may represent a basis for the design of novel therapeutic strategies for the treatment of metabolic syndrome and type 2 diabetes.