Neural Mechanisms Underlying Central Induction of Skeletal Muscle Thermogenesis Though individual health and the US health-care system as a whole suffer from the deleterious consequences of obesity, weight loss and maintenance have proven difficult for the majority of people. Developing methods to increase energy expenditure would ease this process. We have found that exposing rats to the odor of their natural predator (ferret) provokes a rapid and robust rise in skeletal muscle (gastrocnemius) temperature, with a corresponding increase in energy expenditure. Here, we probe the most likely brain and muscle mediators of this response. First, we will use a chemogenetic tool we developed to target neurons expressing steroidogenic factor 1 (SF-1) in the dorsomedial/central subregions of the ventromedial hypothalamus (dmVMH), specifically predicting that inhibition of this cell population will decrease the ability of predator odor to induce muscle thermogenesis in rats. Second, we will investigate the most probable mechanism underlying the thermogenic induction at the level of the skeletal myocyte, namely sarcolipin uncoupling of sarco/endoplasmic reticulum ATPase (SERCA) Ca2+ cycling. We will determine if predator odor exposure suppresses SERCA Ca2+ transport relative to ATPase activity, while increasing sarcolipin expression. We also predict that, since unilateral sympathetic neural (lumbar sympathetic nerve) surgical denervation inhibits the ability of predator odor to induce thermogenesis in the denervated gastrocnemius muscle relative to the contralateral (intact) muscle, SERCA uncoupling and sarcolipin expression will similarly be altered in the denervated muscle compared to the intact muscle in the same rat. These studies will demonstrate the roles of brain SF-1 neurons and muscle SERCA uncoupling in central induction of skeletal muscle non-shivering thermogenesis. Altogether, we will establish multiple components of this brain-muscle thermogenic pathway as viable targets to counter weight gain, while engaging undergraduate students in research.
We are investigating a brain-muscle pathway that rapidly increases heat generated my skeletal muscle, thereby burning calories. Because this thermogenesis is stimulated by the odor of a predator in rats, we will investigate the role of a specific group of cells in the brain that is implicated in both the behavioral response to predator threat and peripheral (including muscle) metabolic control. We will also investigate the role of a likely thermogenic mediator in muscle, with the ultimate goal of identifying targets to increase muscle thermogenesis and caloric expenditure to combat weight gain.
