Role of Ppm1k in Macrophage Activation and Metabolic Disease - PROJECT SUMMARY: Obesity is a complex disease that greatly increases the risk of developing insulin resistance, type 2 diabe- tes, and other cardiometabolic diseases. Obesity is also associated with chronic low-grade inflammation and a dramatic increase in the number of adipose tissue macrophages. Macrophages are the predominant immune cell within adipose tissue, and in obesity, these macrophages become activated and elicit an inflammatory re- sponse that has been associated with insulin resistance. Importantly, macrophage activation is tightly linked with metabolic reprogramming. Specifically, inflammatory macrophages exhibit high rates of anaerobic glycoly- sis while pro-resolving macrophages rely more on oxidative phosphorylation. However, very little is known about macrophage branched chain amino acid (BCAA; leucine, isoleucine, and valine) metabolism. This is a critical gap in knowledge since obesity is linked with elevated plasma BCAA concentrations, which are predic- tive of the future development of type 2 diabetes. Since elevated BCAA levels and adipose tissue macro- phages are both correlated with obesity and insulin resistance, there is a critical need to understand how mac- rophages process BCAAs in metabolic disease and to determine whether BCAA metabolism influences macro- phage activation and tissue insulin resistance. Our long-term goal is to define the pathways controlling macrophage function to develop novel therapeutic options that improve the health of people affected by metabolic disease. The overall objective of this applica- tion is to determine how macrophage BCAA metabolism contributes to the development of obesity-related met- abolic dysfunction. The rate-limiting step of BCAA catabolism is catalyzed by branched chain keto acid dehy- drogenase (BCKDH). BCKDH activity is negatively regulated via phosphorylation by the BCKDH kinase. In contrast, protein phosphatase 1K (PPM1K) activates BCKDH by removing the inhibitory phosphate group to increase BCAA catabolism. This proposal seeks to test the novel hypothesis that macrophage Ppm1k in- creases BCAA catabolism to reduce mTOR signaling and limit inflammatory cytokine production to prevent adi- pocyte insulin resistance. Our studies are designed to identify how PPM1K affects macrophage metabolism and activation, and determine how macrophage Ppm1k influences adipocyte function. Completion of our re- search proposal will uncover a novel aspect of macrophage metabolism and provide further clarity to uncover the role of BCAAs in the development and progression of metabolic dysfunction, which may provide insights into innovative targets to decrease the burden of metabolic disease.
