Sanders Owen Davis, Rajagopal Jayalekshmi Archa, Rajagopal Lekshmy
Department of Biology, Portland State University, Portland, OR, USA.
Department of Pathology, D.Y. Patil Medical College, Kolhapur, India.
J Obes Metab Syndr. 2021 Mar 30;30(1):4-11. doi: 10.7570/jomes20038.
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 Ca influx and protein kinase A (PKA) activation, which induces mitochondrial elongation, mitochondrial localization to lipid droplets, lipolysis, β-oxidation, and UCP1 expression. Ca-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.
通过解偶联蛋白1（UCP1）依赖性非寒战产热增加基础能量消耗是治疗肥胖症的一种有吸引力的治疗策略。寒冷和冷模拟物激活瞬时受体电位香草酸亚型8（TRPM8）通道可诱导UCP1转录并预防动物肥胖，但这种关系的临床相关性仍未完全明确。本文对以薄荷醇为重点的TRPM8通道激动剂治疗肥胖症进行了综述。脂肪细胞TRPM8激活导致钙离子内流和蛋白激酶A（PKA）激活，进而诱导线粒体延长、线粒体定位于脂滴、脂肪分解、β-氧化和UCP1表达。钙离子诱导的线粒体活性氧激活UCP1。在动物中，TRPM8激动作用可提高基础代谢率、非寒战产热、耗氧量、运动耐力和脂肪酸氧化，并降低腹部脂肪百分比。薄荷醇可预防高脂饮食诱导的肥胖、葡萄糖不耐受、胰岛素抵抗和肝脏三酰甘油积累。下丘脑TRPM8激活释放胰高血糖素，激活PKA并促进分解代谢。TRPM8基因多态性与肥胖有关。在人类中，口服薄荷醇和其他TRPM8激动剂几乎没有效果。然而，局部应用薄荷醇似乎可提高核心体温和代谢率。有必要对肥胖患者进行局部应用薄荷醇治疗的随机临床对照试验。
