Temperature Sensing and the Regulation of Fuel Metabolism

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The long-term objective of my NSERC program is to examine how environmental, nutritional and exercise stressors modulate adipose tissue and liver metabolism, the underlying mechanisms therein, and how this influences systemic carbohydrate and fat homeostasis. To address these basic, fundamental questions, we use rodent models coupled with cell/tissue culture approaches and examine endpoints ranging from whole body energy expenditure to the regulation of gene expression. Over the past 6 years we have published 58 papers, 22 that were NSERC funded with myself as senior/corresponding author and led by HQP, many of whom were supported by NSERC scholarships (3 PGS-D, 3 CGS-D, 2 CGS-M). We have demonstrated, amongst other findings, that regularly performed exercise confers protection against immuno-metabolic challenges, that the exercise inducible signaling factor interleukin 6 (IL-6) enhances liver insulin action, and that IL-6 signaling is attenuated in conditions of chronic nutrient excess, through a mechanism involving endoplasmic reticulum stress. A new direction we have started to explore is the impact of cold stress on adipose tissue and systemic metabolism. We have examined this broad question from several different perspectives and findings from this new line of research, which serve as the basis for the current application, demonstrated that glucagon is involved in the mechanisms through which cold induces adaptations in white adipose tissue, that housing temperature has profound effects on the response of adipose tissue to exercise, and that intermittent cold exposure uncouples hyperphagia and weight gain from impairments in glucose homeostasis. Building upon these discoveries, and further guided by exciting preliminary data, over the next 5 years we will examine how the sensation of cold triggers metabolic adaptations, specifically examining the role of the cold sensing cation channel TRPM8 (Transient Receptor Potential cation channel subfamily Melastatin member 8) in these processes. In the first two aims we will decipher the mechanisms through which activation of TRPM8 acutely increases thermogenesis (Aim 1) and how the repeated activation of TRPM8 induces the expression of mitochondrial/thermogenic genes and proteins (Aim 2). In Aim 3 we will investigate the necessity of TRPM8 in mediating the metabolic response to cold and in Aim 4 will explore interactions between TRPM8 activation and exercise in the regulation of adipose tissue and systemic metabolism. The experiments outlined in this proposal will increase our basic, fundamental understanding of adipose tissue biology and how these changes impact systemic fuel metabolism. A diverse group of HQP will receive a rich training experience which will prepare them for careers, or further training, in the natural sciences.