Menthol to Induce Non-shivering Thermogenesis via TRPM8/PKA Signaling for Treatment of Obesity

Abstract

Increasing basal energy expenditure via uncoupling protein 1 (UCP1)-dependent non-shivering thermogenesis is an attractive therapeutic strategy for treatment of obesity. Transient receptor potential melastatin 8 (TRPM8) channel activation by cold and cold mimetics induces UCP1 transcription and prevents obesity in animals, but the clinical relevance of this relationship remains incompletely understood. A review of TRPM8 channel agonism for treatment of obesity focusing on menthol was undertaken. Adipocyte TRPM8 activation results in Ca²⁺ influx and protein kinase A (PKA) activation, which induces mitochondrial elongation, mitochondrial localization to lipid droplets, lipolysis, β-oxidation, and UCP1 expression. Ca²⁺-induced mitochondrial reactive oxygen species activate UCP1. In animals, TRPM8 agonism increases basal metabolic rate, non-shivering thermogenesis, oxygen consumption, exercise endurance, and fatty acid oxidation and decreases abdominal fat percentage. Menthol prevents high-fat diet-induced obesity, glucose intolerance, insulin resistance, and liver triacylglycerol accumulation. Hypothalamic TRPM8 activation releases glucagon, which activates PKA and promotes catabolism. TRPM8 polymorphisms are associated with obesity. In humans, oral menthol and other TRPM8 agonists have little effect. However, topical menthol appears to increase core body temperature and metabolic rate. A randomized clinical control trial of topical menthol in obese patients is warranted.

Keywords: Brown adipose tissue; Mitochondrial uncoupling proteins; Obesity; Thermogenesis; Weight loss.

Fig. 1

Mechanisms of transient receptor potential melastatin 8 (TRPM8)-mediated uncoupled respiration and mitochondrial elongation. Cold, menthol, icilin, and other cooling agents open brown, beige, and white adipocyte TRPM8 channels. ^,,,- Extracellular Ca²⁺ ions influx through TRPM8 channels into the adipocyte cytoplasm. Peri-plasma membrane Ca²⁺ activates adenylyl cyclase 1 and 8, which generate cyclic adenosine monophosphate (cAMP). cAMP activates protein kinase A (PKA) to induce uncoupling protein 1 (UCP1) transcription.^,-,,, Once translated, UCP1 proteins are imported into mitochondria and localized to the inner mitochondrial membrane, where they allow protons to diffuse down an electrochemical gradient into the mitochondrial matrix, dissipating the energy of the proton motive force as heat instead of generating adenosine triphosphate. PKA also phosphorylates and thereby activates dynamin-related protein 1 (Drp1), which induces mitochondrial fusion and elongation around lipid droplets.^,