Despite extensive evidence implicating excess circulating non-esterified fatty acids (NEFA) in the induction of systemic insulin resistance, the mechanisms underlying elevated plasma NEFA levels remain unclear. Adipose tissue is the largest NEFA depot. The amount of NEFA released from adipocytes, determined mainly by the balance between lipolysis and intra-adipocyte NEFA re-esterification, is linearly related to plasma NEFA levels. Thus, identification of the regulatory mechanisms controlling adipocyte NEFA release should provide a guide to new therapies for insulin resistance. The JNK1 and JNK2 pathways have been implicated in obesity-linked type 2 diabetes. We recently demonstrated that 1) removal of JNK1 and JNK2 stimulates both the kinetics and magnitude of baseline lipolysis while decreasing NEFA release over 24 h;2) JNK1/JNK2-deficiency increases NEFA re-esterification and oxidation;and 3) JNK1/JNK2-deficiency profoundly up-regulates a subset of PPAR-?-target genes including pepck, a key gene involved in glyceroneogenesis and NEFA re-esterification. These data provoke three pivotal questions. First, how does JNK1/JNK2 deficiency increase the transcription of PPAR-?-target genes? Second, what mechanisms underlie JNK1/JNK2-deficiency-stimulated lipolysis and NEFA re-esterification? Third, is JNK1/JNK2-deficiency sufficient to override TNF-?-stimulated NEFA release? The Aims are: 1) using co-immunoprecipitation and interaction cloning strategy to test the hypothesis that the JNK pathway inhibits PPAR-? activity in adipocytes through activation of c-Jun and/or through regulation of the activities of PAPR-? co-factors;2) to test the hypothesis that removal of JNK1 and JNK2 stimulates the expression and/or activities of proteins involved in triglyceride turnover by characterizing the phenotypes of JNK1/JNK2-deficient adipocytes;and 3) to test the hypothesis that JNK1/JNK2-deficiency-mediated increase in NEFA utilization is sufficient to delay or prevent TNF-?-stimulated NEFA release in adipocytes.
This proposal aims to identify the molecular mechanisms controlling adipocyte non-esterified fatty acid (NEFA) release, a key step in the induction of insulin resistance during obesity and type 2 diabetes. Given the current epidemic of obesity and obesity-induced type 2 diabetes, there is a compelling need for research that will investigate the molecular mechanisms driving the development of insulin resistance and ultimately contribute to the development of an effective therapy for type 2 diabetes.
| Vijayvargia, Ravi; Mann, Kara; Weiss, Harvey R et al. (2010) JNK deficiency enhances fatty acid utilization and diverts glucose from oxidation to glycogen storage in cultured myotubes. Obesity (Silver Spring) 18:1701-9 |
