Role of mTORC2 Signaling in Hypothalamic Neurons

Cole Purdy using a pipette




Associate Professor of Physiology

Project Summary

Neuronal mechanisms that control physical activity are not well understood. Several brain regions, including the hypothalamus, have been implicated in the regulation of physical activity.


Through PURM, I had the opportunity to work in Dr. Baurs Lab in the Institute of Diabetes, Obesity and Metabolism within the Perelman School of Medicine. One of the main subjects of investigation in the Baur lab is the mechanistic target of rapamycin (mTOR), a serine threonine kinase that is a critical regulator of cell growth and metabolism. mTOR exists in two distinct complexes, mTORC1 and mTORC2. Dr. Baur’s lab recently established that disruption of mTORC2 signaling in hypothalamic neurons (RictorNkx2.1-/-) leads to reduced physical activity, both spontaneous home cage activity and voluntary exercise. Given that insulin, an upstream activator of mTORC2, acts on pro-opiomelanocortin (POMC) neurons to influence locomotor activity, we hypothesized that mTORC2 signaling in POMC neurons mediates insulin’s action.


My project was to assist a post-doctoral researcher in determining whether a specific subpopulation of neurons, starting with POMC expressing neurons, regulates locomotor activity in a cell autonomous manner. To do this, we generated a mouse line in which mTORC2 signaling was disrupted only in the POMC neurons of the hypothalamus, and then measured home cage as well as voluntary activity. Spontaneous home cage activity was assessed by surgical implantation of telemetry probes in control and RictorPomc-/- mice. We monitored voluntary exercise by providing access to running wheels in home cage environment. We did not observe any difference in physical activity between control and RictorPomc-/- mice in both males and females.  Our findings suggest that mTORC2 in POMC neurons is dispensable for locomotor activity. This leads us to propose that mTORC2 in another neuronal population, such as steroidogenic factor 1 expressing neurons (SF1), or multiple neuronal subtypes drives the hypoactive phenotype observed in RictorNkx2.1-/- mice.


My responsibilities included monitoring mouse food intake, body weight, and activity. Additionally, I had the privilege of learning genotyping and western blotting. This project helped me gain a clear understanding of the theoretical function of Cre-Lox Technology and supplemented my knowledge of the physiological mechanisms underlying food intake and energy expenditure. I hope to further study obesity and diabetes in the future.