Effects of β-estradiol on cold-sensitive receptor channel TRPM8 in ovariectomized rats

Kubo, Takuro; Tsuji, Shunichiro; Amano, Tsukuru; Yoshino, Fumi; Niwa, Yuichi; Kasahara, Kyoko; Yoshida, Saori; Mukaisho, Ken‐ichi; Sugihara, Hiroyuki; Tanaka, Sachiko; Kimura, Fuminori; Takahashi, Kentaro; Murakami, Takashi

doi:10.1538/expanim.17-0028

Cited by 12 publications

(11 citation statements)

References 33 publications

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“…Estrogen also has been described to play a critical role in cold sensitivity and hyperalgesia [ 40 , 41 ], which are also functions thought to be regulated by Trpm8 [ 42 , 43 ]. However, interestingly, a previous preclinical study observed that Trpm8 expression was upregulated in the skin of ovariectomized rats compared to sham control rats [ 44 ] and β-estradiol treatment might reduce Trpm8 overexpression in the skin of ovariectomized rats [ 45 ]. These findings support our data that suggest regulation of energy metabolism in female mice is independent of Trpm8 cold-sensing function and estrogen might be a more relevant factor to normal thermoregulation in females.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…E2 did not affect TRPM8 mRNA expression in the spinal ganglia of ovariectomized rats treated with menthol, which means that TRPM8 expression did not affect the inhibitory action of E2 on menthol-induced hyperthermia. E2 induced a decreasing trend in TRPM8 mRNA expression, but did not affect the protein level in the lumbar skin of ovariectomized rats (5). TRPM8 mRNA and protein in the lumbar skin of ovariectomized rats were lower than those in sham rats after exposure to cold (4˚C, 20 min) (9).…”

Section: Discussionmentioning

confidence: 83%

“…First, we planned to investigate the TRPM8 protein that expressed after several hours after menthol stimulation; however, we dropped the idea because we could not obtain the appropriate antibodies. The unpublished immunohistological data of Prof. Miyata showed that all commercial antibodies (5,9) showed the positive responses in the TRPM8 2/2 mice tissues. Thus, we tried to assess the TRPM8 mRNA in the tissues.…”

Section: Discussionmentioning

confidence: 99%

UCP1 and TRPM8 Expression in the Brown Fat Did Not Affect the Restriction of Menthol-Induced Hyperthermia by Estradiol in Ovariectomized Rats

Uchida

Sato

Atsumi

et al. 2021

J Nutr Sci Vitaminol

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Estradiol (E2) modulates the central and peripheral thermoregulatory responses to cold. Menthol is an agonist of transient receptor potential melastatin type 8 (TRPM8), which is a peripheral cold receptor. E2 suppresses menthol-induced elevation of body temperature (Tb) in ovariectomized rats, but the mechanism is unknown. The aim of the present study is to investigate the effect of E2 on uncoupling protein 1 (UCP1), a thermogenic gene, and TRPM8 mRNA levels in ovariectomized rats applied menthol. A silastic tube was implanted in ovariectomized rats with and without E2 underneath the dorsal skin (E2(1) and E2(2) groups), and data loggers for Tb measurement into peritoneal cavity. After application of 10% l-menthol or vehicle to the skin of the whole trunk of rats, Tb was measured for 2 h. The interscapular brown adipose tissue (BAT) and spinal ganglia of cervical, thoracic, and lumbar parts were obtained for RT-qPCR assay. In the menthol application, Tb in the E2(1) group was lower than that in the E2(2) group. The UCP1 mRNA in the BAT, TRPM8 mRNA in the BAT and spinal ganglia in all areas did not differ between the E2(1) and E2(2) groups. In conclusion, the UCP1 and TRPM8 expression in the brown fat did not affect the restriction of the menthol-induced hyperthermia by estradiol in ovariectomized rats.

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“…It could also be that, in the absence of high TST levels, TRPM8 channels are more active. Nevertheless, recent studies have shown that estrogens and their receptor have a genomic effect on TRPM8 in cancer and dermal tissue 37‐39 . The authors of two of these studies have suggested that the lack of estrogens induces TRPM8 overexpression in the skin, and therefore, hypersensitivity to cold in menopausal women 38,39 …”

Section: Discussionmentioning

confidence: 99%

Testosterone‐androgen receptor: The steroid link inhibiting TRPM8‐mediated cold sensitivity

et al. 2020

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Recent studies have revealed gender differences in cold perception, and pointed to a possible direct action of testosterone (TST) on the cold‐activated TRPM8 (Transient Receptor Potential Melastatin Member 8) channel. However, the mechanisms by which TST influences TRPM8‐mediated sensory functions remain elusive. Here, we show that TST inhibits TRPM8‐mediated mild‐cold perception through the noncanonical engagement of the Androgen Receptor (AR). Castration of both male rats and mice increases sensitivity to mild cold, and this effect depends on the presence of intact TRPM8 and AR. TST in nanomolar concentrations suppresses whole‐cell TRPM8‐mediated currents and single‐channel activity in native dorsal root ganglion (DRG) neurons and HEK293 cells co‐expressing recombinant TRPM8 and AR, but not TRPM8 alone. AR cloned from rat DRGs shows no difference from standard AR. However, biochemical assays and confocal imaging reveal the presence of AR on the cell surface and its interaction with TRPM8 in response to TST, leading to an inhibition of channel activity.

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Effects of β-estradiol on cold-sensitive receptor channel TRPM8 in ovariectomized rats

Cited by 12 publications

References 33 publications

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

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

UCP1 and TRPM8 Expression in the Brown Fat Did Not Affect the Restriction of Menthol-Induced Hyperthermia by Estradiol in Ovariectomized Rats

Testosterone‐androgen receptor: The steroid link inhibiting TRPM8‐mediated cold sensitivity

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