Obesity is at epidemic proportions in the US. Over 60% of the population is either overweight (Body Mass Index [BMI] ?25 to <30 kg/m2) or obese (BMI ?30 kg/m2), placing them at risk for a large number of chronic diseases, including insulin resistance, metabolic syndrome, and type 2 diabetes. The annual costs of obesity exceed $100 billion, making it one of the most significant public health and economic issues facing the country. Unfortunately, the treatment of obesity is unsatisfactory. Lifestyle and behavioral approaches have a modest, and often transient, effect while FDA-approved therapeutic options targeting appetite or fat absorption have poor tolerability and, in some cases, safety concerns. Thus, there is a critical need for novel approaches to treat obesity. Agents acting via peripheral mechanisms to increase energy expenditure would be valuable. The sympathetic nervous system (SNS) is well-known as an activator of brown adipose tissue (BAT) and the ?browning? of cells in white adipose tissue (WAT) depots to increase uncoupled mitochondrial respiration and energy expenditure. Our earlier work established a signaling cascade from ?-adrenergic receptors (?ARs) ? cAMP ? protein kinase A (PKA) ? p38 MAP kinase (MAPK) to drive the transcription of brown adipocyte genes such as uncoupling protein-1 (UCP1), PPAR-gamma coativator-1? (PGC-1?), and the broader program of mitochondrial biogenesis. Now we have discovered that the mTOR complex-1 (mTORC1) components mTOR and Raptor are phosphorylated by PKA. This is a highly novel observation. From in vivo studies in mice we find that blockade of mTORC1 with rapamycin, or genetic deletion of Raptor specifically in adipose tissue, suppresses the ability of the ?AR pathway in increase the amount of UCP1-expressing `beige' adipocytes within white fat depots, and dampens UCP1 expression and respiration in interscapular brown fat. The ability of laboratory animals and humans to expand these `beige' adipocytes is closely correlated with resistance to weight gain and improved insulin sensitivity. We have identified the phosphorylation sites on mTOR and Raptor and propose to test the physiological consequences of cells and mice expressing Raptor lacking the Ser791 site of phosphorylation by engineering a `knock-in' of 791Ala in place of Ser. These experiments will shed important mechanistic and physiological insight into the steps needed for `beige' cell expansion. .
The goal of this project is to establish the contribution of the mTORC1 complex and role of Raptor in particular in adipose tissue and the ?AR and PKA-dependent generation of energy burning UCP1-expressing `beige' adipocytes in white fat depots. The goal is to understand the mechanics of this pathway to ultimately find molecules that can selectively increase fat burning to fight obesity.
