Title: Unveiling cold induced-metabolic adaptations and the metabolic and molecular interactions between TRPM8 mediated thermosensation and exercise training in C57BL/6J mice
Thesis Supervisor: Dr. David Wright
Committee Members: Dr. Sarah Gray, Dr. Cameron Mitchell
Chair: Dr. Jean-Sébastien Blouin
Abstract: Preclinical studies in rodent models suggest that cold-induced thermogenesis in brown adipose tissue (BAT) may protect against diet-induced obesity. However, cold exposure had limited to no effects on fat mass and adiposity in humans, likely due to differences in housing conditions in preclinical studies, as rodents are often housed at sub-thermoneutral temperatures. Therefore, recent studies suggested using thermoneutral housing in preclinical metabolic research, which uncouples the effects of intermittent cold exposure on glucose and energy homeostasis. Indeed, ICE (Intermittent Cold Exposure) has been shown to exacerbate rather than attenuate diet-induced obesity in mice housed at thermoneutrality. Therefore, pharmacological sympathomimetics is one way to circumvent the hyperphagia induced by intermittent cold exposure in rodents and understand the potential role of BAT-induced thermogenesis. Notably, L-menthol, a TRPM8 agonist, has been shown to activate UCP1-dependent BAT thermogenesis and reduce weight gain in both obese and lean mice. However, it remains unclear whether this cold mimetic can enhance the benefits of exercise for overall health.
To date, no effective pharmacological strategy has been paired with intermittent cold exposure to reduce hyperphagia or weight gain in rodent models. Therefore, given the limited impact of cold exposure on fat mass reduction, the emerging GLP-1/GIP agonist tirzepatide, known to promote thermogenesis and improve glucose tolerance, might represent a potential avenue for further research. Thus, this thesis aims to explore the metabolic and molecular interactions between TRPM8-mediated thermosensation and exercise training and investigate the effects of cold exposure and the GLP-1/GIP agonist tirzepatide on food intake, adiposity, glucose tolerance, and insulin sensitivity in C57BL/6J mice.