Adipose Tissue Metabolic Stress Responses

Project Summary 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. The cJun NH2-terminal kinase (JNK) signaling pathway functions during stress responses, including metabolic stress caused by feeding a high fat diet (HFD). Importantly, loss-of-function studies using mice demonstrate that deficiency of JNK1 plus JNK2 in adipocytes prevents adipose tissue inflammation and the development of systemic insulin resistance. However, the mechanisms that mediate the actions of JNK signaling in adipocytes are unclear. We will focus our studies on two questions: a) What is the physiologically relevant form of JNK that drives adipose tissue inflammation and insulin resistance? Adipocytes express two genes that encode JNK (Mapk8 & Mapk9 encode JNK1 & JNK2, respectively) and transcripts of both genes are alternatively spliced by mutually exclusive inclusion of exons 7a & 7b. These alternative exons encode a segment of the substrate binding site. The JNK17a & JNK27a exhibit similar substrate specificities that differ from the similar substrate preferences of JNK17b & JNK27b. We will determine which of these JNK spliceoforms mediates effects of JNK on adipose tissue inflammation and systemic insulin resistance. b) What mechanism mediates the actions of adipocyte JNK? It has been proposed that the effects of JNK on inflammation may be mediated by increased adipocyte IL6 expression and that the effects of JNK on systemic insulin resistance may be mediated by decreased FGF21 expression. A rigorous test of the sufficiency of these JNK-mediated actions on adipokine expression is required to confirm the actions of these JNK- responsive adipokines and to identify whether there are additional targets of JNK signaling. The overall goal of this research program is to identify molecular mechanisms that account for JNK function in adipocytes. Achievement of this goal 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.