Regulation of Thermogenesis in Adipocytes Through TRPA1

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Project Summary Obesity is a global epidemic that is linked to a number of devastating diseases, such as type 2 diabetes and heart disease. Studies of obesity and adipose tissue function can help us comprehend these diseases and identify possible strategies to prevent them. Thermogenic adipocytes are a type of fat cell that upregulates a thermogenic program in response to cold stimuli. This upregulation of the thermogenic program causes adipocytes to disperse energy as heat, as opposed to storing it. Thermogenic adipocytes recently have been identified in adult humans, and studies have shown that active thermogenic adipocytes in humans are correlated with improved metabolic parameters, suggesting that these cells are a promising target for diabetes and obesity therapies. My preliminary data show that treatment of adipocytes with the transient receptor potential cation channel A1 (TRPA1) agonists cinnamaldehyde (CA) and allyl isothiosyanate (AITC) increases thermogenic gene expression. I hypothesize that TRPA1 mediates a thermogenic response in adipocytes and that TRPA1 agonism will improve cold tolerance and counteract obesity. I propose to study the thermogenesis- associated changes in mouse and human thermogenic adipocytes in response to TRPA1 activation and the effect that TRPA1 agonism or knockout has on regulating thermogenesis and glucose metabolism in vivo. Aim 1: To characterize the mechanisms by which TRPA1 mediates regulation of thermogenesis at the cellular level. My preliminary data have shown that both mouse and human subcutaneous adipocytes upregulate thermogenic gene expression in response to treatment with the TRPA1 agonists CA and AITC. Additionally, both mouse and human subcutaneous cells upregulate thermogenic gene expression in response to cold exposure. In this aim I will characterize the mechanisms by which TRPA1 agonism upregulates thermogenesis in fat cells by investigating the role that TRPA1 agonism plays in regulating both mitochondrial function and lipolysis. Aim 2: To determine the role that TRPA1 plays in regulating whole-body metabolism. Past studies have shown that inducing thermogenesis in thermogenic fat can counteract obesity and improve glucose metabolism. In this aim I will use mouse models to investigate the role that TRPA1 knockout or agonism has on regulating the thermogenic response to cold and improving glucose metabolism by studying the effects that TRPA1 agonist oral gavage has on regulating thermogenesis in fat tissue and in counteracting high fat diet induced obesity.