Globally, obesity rates are expected to rise from 1.6 billion to 2.3 billion between 2006 and 2015, while deaths due to diabetes will increase by over 80% in developed nations during the same time. Our long-term goal is to delineate the molecular and cellular the mechanisms that couple the onset of obesity with the rising incidence of diabetes. Mounting evidence established c-Jun N terminal kinase (JNK) signaling as a key mediator during infiammatory stress coupling obesity to insulin resistance (IR), yet few studies have examined mechanisms that deactivate this pathway, potentially improving insulin sensitivity. Recent evidence demonstrates a role for dual specificity phosphatases (DUSPs) in the deactivation of JNK during inflammatory stress (e.g. TNF). Our data demonstrate that JNK activity is transient in the presence of continuing stimuli via mechanisms that require RNA synthesis, with concomitant increases in DUSP gene expression in response to TNF. Therefore, we developed the central hypothesis that DUSPs regulate localized JNK activation and biological function in an adipocyte phenotype-specific manner in response to TNFalpha. Understanding DUSP regulation of JNK in adipocytes will allow for the development of alternative targets in the treatment of obesity and diabetes. We plan to test our central hypothesis by pursuing the following two specific aims:
Aim 1. Examine the mechanistic role of DUSPs on JNK signaling in adipocytes. We will test our central hypothesis by: 1) establishing which DUSPs are induced, 2) where they are compartmentalized, and 3) what role they play on localized biological outcome in response to TNFalpha in an adipocyte phenotype-specific manner.
Aim 2. Elucidate the role of JNK activity on DUSP expression. We will test our hypothesis by determining: 1) which DUSPs are downstream targets of JNK activity, 2) which transcription factor downstream of JNK regulates DUSP gene expression, and 3) how JNK regulates DUSP1 protein stability in a phenotype-specific manner. Using RNAi, ectopic expression, immunoblot analysis, qRT-PCR, and glucose uptake we will be able to examine the role of DUSPs on localized JNK activity and Function (e.g. insulin resistance), as well as feedback regulation ofthe DUSPs by JNK and its downstream transcription factors. While several pathways relay inflammatory signals during obesity-induced insulin resistance and ultimately diabetes, the JNK pathway has emerged as a critical mediator in these metabolic diseases. This study will establish new therapeutic targets that regulate JNK signaling, and provide alternative strategies for the treatment of obesity-induced diabetes.
|Ferguson, Bradley S; Nam, Heesun; Morrison, Ron F (2016) Curcumin Inhibits 3T3-L1 Preadipocyte Proliferation by Mechanisms Involving Post-transcriptional p27 Regulation. Biochem Biophys Rep 5:16-21|