Neural Mechanisms Underlying Central Induction of Skeletal Muscle Thermogenesis Individual health and the US health-care system as a whole both suffer from the deleterious consequences of obesity. Yet, weight loss and maintenance have proven difficult for the majority of people. Developing methods to amplify energy expenditure would ease this process. We have found that exposing rats or mice to the odor of their natural predator (ferret) provokes a rapid and robust rise in skeletal muscle (gastrocnemius) temperature, with a corresponding increase in caloric expenditure. We have found that, at the level of skeletal muscle, uncoupling of sarco/endoplasmic reticulum ATPase (SERCA) Ca2+ cycling occurs in response to predator threat in rats. Within the brain, activation of steroidogenic factor 1 (SF1) neurons in the central and dorsomedial ventromedial hypothalamus (VMH) are sufficient to provoke muscle thermogenesis in mice. Here, we investigate the ability of AMPK inactivation in the VMH to induce skeletal muscle thermogenesis, specifically in response to predator threat. First, using Western blots to probe phospho-AMPK and total AMPK from brain micropunches of the VMH, we will determine if AMPK is rapidly dephosphorylated and inactivated in the VMH after exposure to predator (ferret) odor. Immunofluorescence will identify activation of potential cell subpopulations in the VMH. We will probe the VMH active kinome using kinomics arrays and bioinformatics analyses. We will also compare the ability of predator odor to alter AMPK activation in contrasting rat models of leanness and obesity that show differential muscle thermogenesis and response to predator odor. Second, we will assess the ability of inhibition and activation of VMH AMPK to modulate muscle thermogenesis. Specifically, we will determine if inhibition of AMPK using microinjections of SBI-0206965 into the VMH induces muscle thermogenesis and augments energy expenditure, and conversely if the AMPK activator AICAR will block the ability of predator odor to trigger muscle thermogenesis. Altogether, these aims will demonstrate the importance of an intracellular metabolic fuel sensor in the ability of a contextual stimulus to alter metabolic outcomes. In the process, we will continue to engage undergraduate students in meaningful research experience.

Narrative The brain can alter skeletal muscle metabolism, increasing calories burned by prompting the muscle to generate heat, a process called thermogenesis. We have shown that exposing animals like rats and mice to the odor of a predator triggers muscle thermogenesis, and that this involves activation of a brain region that is important in both metabolic regulation and determining how an animal responds to predators. Here, we probe the role of a cellular fuel sensor as the key brain mechanism triggering muscle thermogenesis, with the ultimate goal of identifying targets to increase muscle thermogenesis and caloric expenditure to combat weight gain.