Obesity and diabetes mellitus are significant healthcare concerns worldwide that afflict millions of individuals leading to neuropathies, cardiovascular disease, hypertension, and stroke. The rising incidence of obesity and type 2 diabetes, especially among children, raises future concerns in regards to financial and patient care resources that will be necessary to care for these individuals with debilitating complications that dramatically affect quality of life as well as life expectancy. Mounting experimental and clinical evidence has established c- Jun N-terminal kinase (JNK) signaling pathways as a critical link between the accumulation of fat mass with obesity and the rise of insulin resistance contributing to diabetes. While much has been learned concerning the role of upstream events that activate JNK signaling, little information has emerged regarding mechanisms that deactivate this pathway and their effect on biological outcome. The objectives of this application is to determine the mechanistic role of dual specificity phosphatases (DUSPs) in regulating JNK dephosphorylation and functional consequences under conditions of oxidative stress that lead to a loss of insulin sensitivity in adipocytes. In preliminary studies, we demonstrate that the extent of JNK phosphorylation is markedly different between undifferentiated preadipocytes and insulin-responsive adipocytes under conditions of oxidative stress, that JNK is dephosphorylated rapidly in the presence of continuing stimuli through mechanisms involving RNA and protein synthesis, and that DUSPs are dramatically regulated at the level of gene expression consistent with a role in mediating the phenotypic difference in the extent of JNK activation. Based on these data, we developed the central hypothesis that compartmentalized JNK activation and function in response to oxidative stress is controlled via regulation of specific DUSPs in an adipocyte phenotype-specific manner. We will test the central hypothesis in two aims. The first determines the mechanistic role of DUSPs in regulating JNK activity in adipocytes. The second examines how DUSPs afford protection against insulin resistance by forming a regulatory feedback loop linking JNK activation with JNK dephosphorylation. Once we understand how DUSPs regulate JNK signaling in adipocytes, it is expected that it will become possible to modulate that regulation for the therapeutic purpose of treating obesity and diabetes and associated complications.
The rising incidence of obesity and diabetes has been universally established as among the most important health concerns of all developed nations. Although consider the most costly and preventable of all chronic disease epidemics, nearly 180 million Americans are overweight and 54 million are pre-diabetic in addition to 20 million with diabetes. While it is has been established that activation of JNK signaling is an important step in the development of insulin resistance, there is a critical gap in the knowledge base that centers on mechanisms which deactivate this pathway affording protection against the loss of insulin sensitivity associated with diabetes. The proposed research will establish functional relationship between protein phosphatases and JNK activity in adipocytes under condition leading to insulin resistance. The positive impact of understanding mechanisms that attenuate JNK activity and the relevance to the link between obesity and diabetes will be significant.
