Topical menthol, a pharmacological cold mimic, induces cold sensitivity, adaptive thermogenesis and brown adipose tissue activation in mice

Abstract

AbstractAimBrown adipose tissue (BAT) thermogenesis has profound energy‐expanding potential, which makes it an attractive target tissue to combat ever‐increasing obesity and its other associated metabolic complications. Although it is fairly accepted that cold is a potent inducer of BAT activation and function, there are limited studies on the mechanisms of pharmacological cold‐mimicking agents, such as the TRPM8 agonist, menthol, on BAT thermogenesis and activation.MethodsHerein, we sought to determine the effect of topical application of menthol (10% w/v [4 g/kg] cream formulation/day for 15 days) on temperature sensitivity behaviour (thermal gradient assay, nesting behaviour), adaptive thermogenesis (infrared thermography, core body temperature), BAT sympathetic innervation (tyrosine hydroxylase immunohistochemistry) and activation (18F‐FDG PET‐CT analysis, Uncoupling Protein 1 immunohistochemistry and BAT gene expression), whole‐body energy expenditure (indirect calorimetry) and other metabolic variables in male C57BL/6N mice.ResultsWe show that male C57BL/6N mice: (a) develop a warm‐seeking and cold‐avoiding thermal preference phenotype; (b) display increased locomotor activity and adaptive thermogenesis; (c) show augmented sympathetic innervation in BAT and its activation; (d) exhibit enhanced gluconeogenic capacity (increased glucose excursion in response to pyruvate) and insulin sensitivity; and (e) show enhanced whole‐body energy expenditure and induced lipid‐utilizing phenotype after topical menthol application. Conclusions: Taken together, our findings highlight that pharmacological cold mimicking using topical menthol application presents a potential therapeutic strategy to counter weight gain and related complications.