Topical application of the pharmacological cold mimetic menthol stimulates brown adipose tissue thermogenesis through a TRPM8, UCP1, and norepinephrine dependent mechanism in mice housed at thermoneutrality

Abstract

Increasing whole-body energy expenditure via the pharmacological activation of uncoupling protein 1 (UCP1)-dependent brown adipose tissue (BAT) thermogenesis is a promising weight management strategy, yet most therapeutics studied in rodents to date either induce compensatory increases in energy intake, have thermogenic effects that are confounded by sub-thermoneutral housing temperatures or are not well tolerated in humans. Here, we sought to determine whether the non-invasive topical application of the pharmacological cold mimetic and transient receptor potential (TRP) cation channel subfamily M member 8 (TRPM8) agonist L-menthol (MNTH), could be used to stimulate BAT thermogenesis and attenuate weight gain in mice housed at thermoneutrality. Using three different strains of mice and multiple complimentary approaches to quantify thermogenesis in vivo, coupled with ex vivo models to quantify direct thermogenic effects, we were able to convincingly demonstrate the following: (1) acute topical MNTH application induces BAT thermogenesis in a TRPM8-and UCP1-dependent manner; (2) MNTH-induced BAT thermogenesis is sufficient to attenuate weight gain over time without affecting energy intake in lean and obese mice; (3) the ability of topical MNTH application to stimulate BAT thermogenesis is mediated, in part, by a central mechanism involving the release of norepinephrine. These data collectively suggest that topical application of MNTH may be a promising weight management strategy.

Continuous Stimulation of Subcutaneously Implanted Xenogeneic Protein Thread Recruited Treg Cells and M2 Macrophages to Induce Inguinal White Adipose Tissue Browning

“…A series of studies have revealed that the browning of subcutaneous WAT has the potential to combat obesity and metabolic disorders through oxidating glucose and lipid substrates in the form of nonshivering thermogenesis [21,22] . However, the present strategies targeting at inducing the browning of subcutaneous WAT, including topical cold treatment and microneedle-mediated rosiglitazone release system, are limited by the possible side effects, complex operation processes or unendurable high cost [23,24] .…”

Impact of housing temperature on adipose tissue HDAC9 expression and adipogenic differentiation in high fat‐fed mice

“…Cold exposure (8-26 C) and compounds such as menthol activate TRPM8 channels [21,29]. Activation of TRPM8 channels by topical menthol administration has previously been shown to increase thermogenesis and reduce weight gain in HFD-fed mice [30][31][32]. To test the role of TRPM8 channels on HDAC expression in adipose tissue, we treated thermoneutral-housed CD-fed mice with topical menthol.…”

Natural compounds as obesity pharmacotherapies

“…Menthol also has a weak therapeutic effect on obesity. DIO mice lost 1.6% BW after menthol treatment at 2 g/kg (s.c.) once daily for five consecutive days over 2 weeks (McKie et al, 2022).…”

“…Menthol has been identified as a potent agonist of the transient receptor potential melastatin 8 (TRPM8) channel (Xu, Han, et al, 2020) to increase EE in rats (Vizin et al, 2018) and mice (Ma et al, 2012; McKie et al, 2022). Menthol could induce BAT thermogenesis by up‐regulating UCP1 expression via the Ca 2+ ‐dependent protein kinase A (PKA) phosphorylation (Ma et al, 2012) and via TRPM8‐norepinephrine‐β3AR signaling (McKie et al, 2022).…”

“…Menthol has been identified as a potent agonist of the transient receptor potential melastatin 8 (TRPM8) channel (Xu, Han, et al, 2020) to increase EE in rats (Vizin et al, 2018) and mice (Ma et al, 2012; McKie et al, 2022). Menthol could induce BAT thermogenesis by up‐regulating UCP1 expression via the Ca 2+ ‐dependent protein kinase A (PKA) phosphorylation (Ma et al, 2012) and via TRPM8‐norepinephrine‐β3AR signaling (McKie et al, 2022). Menthol also promotes iWAT browning in HFD‐fed mice (Jiang, Zhai, et al, 2017) and thermogenic gene expression in white adipocytes (Khare et al, 2019) by increasing the intracellular Ca 2+ concentration to promote PKA phosphorylation via activating TRPM8 (Jiang, Zhai, et al, 2017).…”