The Il 4 Stat6 Signaling Pathway In The Development Of Obesity Induced Insulin Resistance

Download or read book The IL-4/STAT6 Signaling Pathway in the Development of Obesity Induced Insulin Resistance written by Alexander Robert Red Eagle and published by . This book was released on 2011 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Obesity is recognized as a state of chronic inflammation associated with the development of insulin resistance and type 2 diabetes. Macrophages play an important role in this process by homing to adipose tissue and perpetuating this inflammatory state. In the setting of obesity, there is a recruitment of "classically activated, " or inflammatory macrophages. However, macrophages are present throughout the body in important metabolic organs such as adipose tissue and the liver before the development of obesity. Resident tissue macrophages in these metabolic organs reside in a state of "alternative activation, " an anti-inflammatory activation state driven by the Interleukin-4/STAT6 signaling pathway. Alternatively activated macrophages activated by the IL-4/STAT6 axis rely on fatty acid metabolism to drive their metabolic demand. Peroxisome proliferatoractivated receptors, or PPARs are fatty acid sensors that drive metabolic processes in a variety of tissues. In the first two chapters, we demonstrate that PPAR[lowercase Gamma] and PPAR[lowercase Delta] are required for alternative macrophage activation in adipose tissue macrophages and Kupffer cells of the liver respectively. Absence of either transcription factor in macrophages leads to the development of obesity induced insulin resistance. Macrophage co-culture experiments with adipocytes or hepatocytes demonstrate the important metabolic impact that PPAR[lowercase Gamma] and PPAR[lowercase Delta] play in macrophages from these two tissues. The IL-4/STAT6 axis also plays an important role in metabolic tissues as well as tissue macrophages. In the final chapter, we demonstrate that IL-4 is capable of activating STAT6 is the liver. We demonstrate that IL-4 acts through STAT6 to repress the transcriptional activity of PPAR[Alpha] in the liver and improves insulin sensitivity in the setting of obesity. Induction of an inflammatory response producing IL-4 also leads to an improvement in insulin sensitivity, indicating that not all inflammation is deleterious to insulin signaling. Together, these results demonstrate that the IL-4/STAT6 signaling pathway plays an important role in both the immune system and metabolic tissues to improve insulin sensitivity.