Abstract

Obesity is predicted to affect half of American adults by 2030, many of whom will suffer from type 2 diabetes as a complication. Fat tissue plays a central role in this disease because fat helps control how chemical energy is distributed throughout the body for utilization. In obesity, inflammation arises in fat and fat’s metabolic functions become impaired. A resulting vicious cycle of inflammation and metabolic dysfunction likely contributes to the persistent nature of metabolic disease.

Our recent work has revealed that mRNA translation—the fundamental process by which cells build proteins from the individual genes they express—plays unexpected roles in metabolism and fat inflammation. During obesity, remodeling of mRNA translation in fat cells (adipocytes) leads to mitochondrial dysfunction and triggers adipocyte pathogen-sensing pathways, the latter perhaps because mitochondria share structural similarities with pathogenic bacteria. We hypothesize that the resulting pro-inflammatory signals contribute to tissue dysfunction and to diabetes pathogenesis during obesity.

To test these ideas, we will examine how obesity affects the cellular machinery responsible for mRNA translation and ask why such changes alter the translation of mRNAs important for adipocyte mitochondrial function. In complementary studies, we will use mouse models to determine adipocyte-derived signals through which metabolic dysfunction is communicated to nearby cells of the immune system. With a better understanding of the connections between fat metabolism and inflammation, we hope to provide new means to prevent or treat human metabolic disease.