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

• DOI: 10.1371/journal.pone.0231060
• Publication Date: 2021-06-04T18:39:20Z
• Authors: Adriana Lelis Car...; Annika Treyball; Daniel J. Brooks; Samantha Costa; Ryan J. Neilson; Michaela R. Reagan; Mary L. Bouxsein; Katherine J. Motyl

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-oldTrpm8knockout mice (Trpm8-KO) after a 4-week cold temperature challenge. MaleTrpm8-KOmice 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 ofDio2andCideacompared to WT. In contrast to males, femaleTrpm8-KOmice had low vertebral bone microarchitectural parameters, but no genotype-specific alterations in body temperature. Interestingly,Trpm8was not required for cold-induced trabecular bone loss in either sex, but bone marrow adipose tissue in females was significantly suppressed byTrpm8deletion. 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.