Regulation of obesity, heart function, and lifespan by the nutrient sensing TOR pathway

Abstract

Metabolic homeostasis is a highly regulated process, with dysregulation causing increased susceptibility to diseases like obesity, diabetes, cardiovascular disease, and cancer. Unfortunately, solving this biomedical problem is difficult because of the polygenic and multi‐organ nature of metabolic homeostasis. Here we establish Drosophila as a genetic model to study the genes and environmental interactions responsible for mediating High Fat Diet (HFD) induced obesity. We see that the nutrient sensing pathway Target of Rapamycin (TOR) is activated and that loss of TOR function can block the detrimental effects of a HFD. We then examined heart function to see if HFD‐induced heart defects can be autonomously and non‐autonomously blocked by TOR. We found that alteration of TOR function in the adipose tissue produced beneficial effects on heart function. This would suggest that TOR regulated peripheral effects like alterations in metabolites, hormone and lipid regulation may be key factors in regulating the adverse effects of HFD. We also examined the effects of altering TOR function both systemically and tissue specifically on feeding and behavior. Lastly, we show that TOR has additional roles regulating metabolism and lifespan by mimicking Dietary Restriction (DR). These phenotypes include lowered glucose and lipid levels, increased longevity, and a block in the age‐dependent decline in heart function. Thus, our findings indicate that the TOR pathway is an important mediator of HFD‐induced obesity and aging, and that alterations of TOR activity may be a critical link from HFD‐induced obesity to diabetes and cardiovascular disease.