TRPM8 modulates temperature regulation in a sex-dependent manner without affecting cold-induced bone loss.

Josep A. Villena,Adriana Lelis Carvalho,Mary L Bouxsein,Katherine J Motyl,Ryan J Neilson,Samantha Costa,Daniel J Brooks,Annika Treyball,Michaela R Reagan

doi:10.1371/journal.pone.0231060

Abstract

Trpm8 (transient receptor potential cation channel, subfamily M, member 8) is expressed by sensory neurons and is involved in the detection of environmental cold temperatures. TRPM8 activity triggers an increase in uncoupling protein 1 (Ucp1)-dependent brown adipose tissue (BAT) thermogenesis. Bone density and marrow adipose tissue are both influenced by rodent housing temperature and brown adipose tissue, but it is unknown if TRPM8 is involved in the co-regulation of thermogenesis and bone homeostasis. To address this, we examined the bone phenotypes of one-year-old Trpm8 knockout mice (Trpm8-KO) after a 4-week cold temperature challenge. Male Trpm8-KO mice had lower bone mineral density than WT, with smaller bone size (femur length and cross-sectional area) being the most striking finding, and exhibited a delayed cold acclimation with increased BAT expression of Dio2 and Cidea compared to WT. In contrast to males, female Trpm8-KO mice had low vertebral bone microarchitectural parameters, but no genotype-specific alterations in body temperature. Interestingly, Trpm8 was not required for cold-induced trabecular bone loss in either sex, but bone marrow adipose tissue in females was significantly suppressed by Trpm8 deletion. In summary, we identified sex differences in the role of TRPM8 in maintaining body temperature, bone microarchitecture and marrow adipose tissue. Identifying mechanisms through which cold temperature and BAT influence bone could help to ameliorate potential bone side effects of obesity treatments designed to stimulate thermogenesis.

Highlights

Maintaining body temperature homeostasis involves both the regulation of heat loss and generation of heat
Because significant changes in two-dimensional Dual-energy X-ray absorptiometry (DXA) data are most likely to indicate alterations in cortical microarchitecture, we examined whether Trpm8 deletion led to changes in cortical bone by micro Computed Tomography (Fig 2)
Deletion of Trpm8 did not influence volumetric trabecular architecture in male or female mice (Fig 3). These results indicate smaller bone size in the male Trpm8-KO mice may have led to the reduced total body bone mineral content and density

Summary

Introduction

Maintaining body temperature homeostasis involves both the regulation of heat loss and generation of heat (i.e. thermogenesis). Trpm knockout (Trpm8-KO) mice are hyperphagic and have reduced fat oxidation when housed at 21 ̊C, promoting the development of obesity [12] It is unknown whether TRPM8 has a role in regulating bone density in vivo and by inference, whether modulation of TRPM8 by obesity therapeutics might influence bone. We conducted this study to determine whether the cold-sensing TRPM8 channel would be required for any cold-induced changes in the skeleton and bone marrow adipose tissue. We hypothesized that Trpm deletion would impair body temperature regulation but may protect mice from cold-induced bone loss and marrow adipose tissue changes. We challenged one-year-old male and female WT and Trpm knockout (KO) mice to cold temperature housing (4 ̊C) and examined body temperature, peripheral and marrow adipose tissue, and bone microarchitecture and turnover. There were, sex and genotype specific effects on the utilization of peripheral adipose tissue stores, suggesting TRPM8 regulates thermogenic tissues in a sex-dependent manner

Materials and methods

Results

Discussion

Limitations