Abstract
Pharmacological stimulation of brown adipose tissue (BAT) thermogenesis to increase energy expenditure is progressively being pursued as a viable anti-obesity strategy. Here, we report that pharmacological activation of the cold receptor transient receptor potential cation channel subfamily M member 8 (TRPM8) with agonist icilin mimics the metabolic benefits of cold exposure. In diet-induced obese (DIO) mice, treatment with icilin enhances energy expenditure, and decreases body weight, without affecting food intake. To further potentiate the thermogenic action profile of icilin and add complementary anorexigenic mechanisms, we set out to identify pharmacological partners next to icilin. To that end, we specifically targeted nicotinic acetylcholine receptor (nAChR) subtype alpha3beta4 (α3β4), which we had recognized as a potential regulator of energy homeostasis and glucose metabolism. Combinatorial targeting of TRPM8 and nAChR α3β4 by icilin and dimethylphenylpiperazinium (DMPP) orchestrates synergistic anorexic and thermogenic pathways to reverse diet-induced obesity, dyslipidemia, and glucose intolerance in DIO mice.
Highlights
Pharmacological stimulation of brown adipose tissue (BAT) thermogenesis to increase energy expenditure is progressively being pursued as a viable anti-obesity strategy
We report that the small molecule icilin stimulates the cold receptor TRPM8 to elicit thermogenesis and lower body weight without influencing appetite
We discovered that the nicotinic acetylcholine receptor (nAChR) α3β4 agonist DMPP suppresses appetite and reverses diet-induced glucose intolerance
Summary
Pharmacological stimulation of brown adipose tissue (BAT) thermogenesis to increase energy expenditure is progressively being pursued as a viable anti-obesity strategy. We report that pharmacological activation of the cold receptor transient receptor potential cation channel subfamily M member 8 (TRPM8) with agonist icilin mimics the metabolic benefits of cold exposure. Combinatorial targeting of TRPM8 and nAChR α3β4 by icilin and dimethylphenylpiperazinium (DMPP) orchestrates synergistic anorexic and thermogenic pathways to reverse diet-induced obesity, dyslipidemia, and glucose intolerance in DIO mice. The transient receptor potential cation channel subfamily M member 8 (TRPM8) is a proximate regulator of the cold-sensing cascade that culminates in the induction of BAT thermogenesis to defend body temperature in response to environmental cold[7]. We report that a potent TRPM8 agonist, icilin, enhances energy expenditure to lower body weight in diet-induced obese (DIO) mice. We reveal that central melanocortin signaling as well as sympathetic nervous system-linked thermogenesis are indispensable for the orchestration of the complete metabolic benefits of this novel combination strategy
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