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

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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Trpm8 modulates thermogenesis in a sex-dependent manner without influencing cold-induced bone loss

10.1101/2020.03.18.996694 ◽

2020 ◽

Author(s):

Adriana Lelis Carvalho ◽

Annika Treyball ◽

Daniel J. Brooks ◽

Samantha Costa ◽

Ryan J. Neilson ◽

...

Keyword(s):

Adipose Tissue ◽

Body Temperature ◽

Bone Density ◽

Bone Loss ◽

Brown Adipose Tissue ◽

Cold Temperature ◽

Dependent Manner ◽

Bone Homeostasis ◽

Marrow Adipose Tissue ◽

Brown Adipose

AbstractTrpm8 (transient receptor potential cation channel, subfamily M, member 8) is expressed by sensory neurons, and it is involved in the detection of cold temperatures. Increased TRPM8 activity triggers an increase in uncoupling protein 1 (Ucp1)-dependent brown adipose tissue (BAT) thermogenesis. Bone density and marrow adipose tissue are regulated by rodent housing temperature and brown adipose tissue, suggesting one mediator of this effect may be TRPM8. In order to test whether TRPM8 was involved in the co-regulation of thermogenesis and bone homeostasis, we examined the bone phenotypes of one-year-old Trpm8 knockout mice (Trpm8-KO) and then exposed them to 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 Ucp1, Dio2 and Cidea at the end of the study. 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 may be required for cold-induced changes in marrow adiposity in males. Furthermore, bone marrow adipose tissue accumulation in females was significantly blunted by Trpm8 deletion. In summary, we identified sex differences in the role of TRPM8 in maintaining body temperature, bone density and marrow adipose tissue. Identifying mechanisms through which cold temperature and brown adipose tissue influence bone could help to ameliorate potential bone side effects of obesity treatments designed to stimulate thermogenesis.

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Activating dopamine D2 receptors reduces brown adipose tissue thermogenesis induced by psychological stress and by activation of the lateral habenula

Scientific Reports ◽

10.1038/s41598-019-56125-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Mariana Brizuela ◽

Anna Antipov ◽

William W. Blessing ◽

Youichirou Ootsuka

Keyword(s):

Adipose Tissue ◽

Body Temperature ◽

Brown Adipose Tissue ◽

Male Rats ◽

Dependent Manner ◽

Lateral Habenula ◽

Anesthetized Rats ◽

Brown Adipose ◽

Medullary Raphe ◽

Nerve Discharge

AbstractEmotional hyperthermia is the increase in body temperature that occurs as a response to an animal detecting a salient, survival-relevant stimulus. Brown adipose tissue (BAT) thermogenesis, controlled via its sympathetic innervation, contributes to this temperature increase. Here, we have used an intruder rat experimental model to determine whether quinpirole-mediated activation of dopamine D2 receptors attenuates emotional hyperthermia in conscious rats. In anesthetized rats, we determined whether systemic quinpirole reduces BAT nerve discharge induced by activation of the medullary raphé and the lateral habenula (LHb). We measured BAT and body temperature with chronically implanted thermistors in conscious, freely moving, individually housed, male rats (resident rats). Either vehicle or quinpirole was administered, intraperitoneally, to the resident rat 30 min before introduction of a caged intruder rat. Quinpirole, in a dose-dependent manner, reduced intruder-elicited increases in BAT and body temperature. Pre-treatment with the D2 antagonist spiperone, but not the selective D1 antagonist SCH-23390, prevented this quinpirole-elicited decrease. In anesthetized rats, quinpirole abolished BAT sympathetic nerve discharge elicited by bicuculline-mediated activation of the LHb, but not the medullary raphé. Thus, activation of dopamine D2 receptors reduces the BAT thermogenesis that contributes to emotional hyperthermia. We provide evidence that these dopamine D2 receptors are located in the thermogenic pathway between the LHb and the lower brainstem pre-sympathetic control centre in the medullary raphé.

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Impaired Thermogenesis and a Molecular Signature for Brown Adipose Tissue inId2Null Mice

Journal of Diabetes Research ◽

10.1155/2016/6785948 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Peng Zhou ◽

Maricela Robles-Murguia ◽

Deepa Mathew ◽

Giles E. Duffield

Keyword(s):

Adipose Tissue ◽

Body Temperature ◽

Brown Adipose Tissue ◽

Energy Homeostasis ◽

Core Body Temperature ◽

Specific Pattern ◽

Molecular Signature ◽

Brown Adipose ◽

Core Body ◽

The Impact

Inhibitor of DNA binding 2 (ID2) is a helix-loop-helix transcriptional repressor rhythmically expressed in many adult tissues. Our previous studies have demonstrated thatId2null mice have sex-specific elevated glucose uptake in brown adipose tissue (BAT). Here we further explored the role ofId2in the regulation of core body temperature over the circadian cycle and the impact ofId2deficiency on genes involved in insulin signaling and adipogenesis in BAT. We discovered a reduced core body temperature inId2−/− mice. Moreover, inId2−/− BAT, 30 genes includingIrs1,PPARs, andPGC-1s were identified as differentially expressed in a sex-specific pattern. These data provide valuable insights into the impact ofId2deficiency on energy homeostasis of mice in a sex-specific manner.

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Regulatory effects of brown adipose tissue thermogenesis on maternal metabolic adaptation, placental efficiency, and fetal growth in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00192.2018 ◽

2018 ◽

Vol 315 (6) ◽

pp. E1224-E1231 ◽

Cited By ~ 6

Author(s):

Liping Qiao ◽

Samuel Lee ◽

Amanda Nguyen ◽

William W. Hay ◽

Jianhua Shao

Keyword(s):

Adipose Tissue ◽

Body Temperature ◽

Brown Adipose Tissue ◽

Fetal Growth ◽

Core Body Temperature ◽

Metabolic Adaptation ◽

Glucose Transporter 1 ◽

Brown Adipose ◽

Placental Efficiency ◽

Core Body

To determine the role of UCP1-mediated thermogenesis in controlling maternal metabolic adaptation to pregnancy, energy metabolism of C57BL/6 wild-type (WT) and Ucp1 gene knockout ( Ucp1−/−) mice was studied during pregnancy. With the progression of pregnancy, maternal energy expenditure rates (EERs), expression of UCP1, and core body temperature steadily declined in WT dams. Despite no significant alterations in core body temperature and weight gain during pregnancy, Ucp1−/− dams exhibited lower rates in EER decline. High-fat (HF) feeding not only robustly increased maternal UCP1 expression and core body temperature but also abolished gestation-suppressed EER in WT dams. However, HF-increased EERs were significantly attenuated in Ucp1−/− dams. Significantly increased fetal body weights and fetal/placental weight ratio were detected in fetuses from Ucp1−/− dams compared with fetuses from WT dams. Markedly increased expression levels of glucose transporter 1 and amino acid transporters were also observed in placentas from Ucp1−/− dams. Furthermore, blood glucose concentrations of fetuses from Ucp1−/− dams were significantly higher than those of fetuses from WT dams, indicating that maternal UCP1 has an inhibitory effect on placental efficiency and fetal growth. Taken all together, this study demonstrated that maternal brown adipose tissue plays an important role in controlling maternal metabolic adaptation and placental nutrient transport.

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Bone marrow adipose tissue does not express UCP1 during development or adrenergic-induced remodeling

Scientific Reports ◽

10.1038/s41598-019-54036-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Clarissa S. Craft ◽

Hero Robles ◽

Madelyn R. Lorenz ◽

Eric D. Hilker ◽

Kristann L. Magee ◽

...

Keyword(s):

Bone Marrow ◽

Adipose Tissue ◽

Uncoupling Protein ◽

Enrichment Analysis ◽

Whole Body ◽

Mineral Density ◽

Bone Marrow Adipose Tissue ◽

Marrow Adipose Tissue ◽

Reporter Mice ◽

Brown Adipose

AbstractAdipocytes within the skeleton are collectively termed bone marrow adipose tissue (BMAT). BMAT contributes to peripheral and local metabolism, however, its capacity for cell-autonomous expression of uncoupling protein 1 (UCP1), a biomarker of beige and brown adipogenesis, remains unclear. To overcome this, Ucp1-Cre was used to drive diphtheria toxin expression in cells expressing UCP1 (Ucp1Cre+/DTA+). Despite loss of brown adipose tissue, BMAT volume was not reduced in Ucp1Cre+/DTA+ mice. Comparably, in mTmG reporter mice (Ucp1Cre+/mTmG+), Ucp1-Cre expression was absent from BMAT in young (3-weeks) and mature (16-weeks) male and female mice. Further, β3-agonist stimulation failed to induce Ucp1-Cre expression in BMAT. This demonstrates that BMAT adipocytes are not UCP1-expressing beige/brown adipocytes. Thus, to identify novel and emerging roles for BMAT adipocytes in skeletal and whole-body homeostasis, we performed gene enrichment analysis of microarray data from adipose tissues of adult rabbits. Pathway analysis revealed genetic evidence for differences in BMAT including insulin resistance, decreased fatty acid metabolism, and enhanced contributions to local processes including bone mineral density through candidate genes such as osteopontin. In sum, this supports a paradigm by which BMAT adipocytes are a unique subpopulation that is specialized to support cells within the skeletal and hematopoietic niche.

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Effects of central injection of l-carnosine on sympathetic nerve activity innervating brown adipose tissue and body temperature in rats

Regulatory Peptides ◽

10.1016/j.regpep.2007.06.001 ◽

2007 ◽

Vol 144 (1-3) ◽

pp. 62-71 ◽

Cited By ~ 24

Author(s):

Mamoru Tanida ◽

Hitoshi Gotoh ◽

Hiroyuki Taniguchi ◽

Hiroto Otani ◽

Jiao Shen ◽

...

Keyword(s):

Adipose Tissue ◽

Body Temperature ◽

Brown Adipose Tissue ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Nerve Activity ◽

Brown Adipose

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Characterization of brown adipose tissue thermogenesis in the naked mole-rat (Heterocephalus glaber), a poikilothermic mammal

10.1101/2020.04.28.062737 ◽

2020 ◽

Author(s):

Yuki Oiwa ◽

Kaori Oka ◽

Hironobu Yasui ◽

Kei Higashikawa ◽

Hidemasa Bono ◽

...

Keyword(s):

Adipose Tissue ◽

Body Temperature ◽

Brown Adipose Tissue ◽

The Body ◽

Cold Environment ◽

Body Temperatures ◽

Cold Environments ◽

Mole Rat ◽

Brown Adipose ◽

Naked Mole Rat

AbstractThe naked mole-rat (NMR) is a poikilothermic mammal that forms eusocial colonies consisting of one breeding queen, several breeding kings, and subordinates. Despite their poikilothermic feature, NMRs possess brown adipose tissue (BAT), which in homeothermic mammals induces thermogenesis in cold environments. However, NMR-BAT thermogenic potential is controversial, and its physiological roles are unknown. Here, we show that NMR-BAT has beta-3 adrenergic receptor (ADRB3)-dependent thermogenic potential, which contributes to thermogenesis in the isolated queen in non-cold environments. NMR-BAT expressed several brown adipocyte marker genes and showed noradrenaline-dependent thermogenic activity in vitro and in vivo. Although our ADRB3 inhibition experiments revealed that NMR-BAT thermogenesis slightly delays the decrease in body temperature in a cold environment, it was insufficient to maintain the body temperatures of the NMRs. In a non-cold environment, NMRs are known to increase their body temperature by a heat-sharing behavior. Interestingly, we found that the body temperatures of NMRs isolated from the colony were also significantly higher than the ambient temperature. We also show that queens, but not subordinates, induce BAT thermogenesis in isolated, non-cold conditions. Our research provides novel insights into the role and mechanism of thermoregulation in this unique poikilothermic mammal.

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Characterization of brown adipose tissue thermogenesis in the naked mole-rat (Heterocephalus glaber), a heterothermic mammal

Scientific Reports ◽

10.1038/s41598-020-74929-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yuki Oiwa ◽

Kaori Oka ◽

Hironobu Yasui ◽

Kei Higashikawa ◽

Hidemasa Bono ◽

...

Keyword(s):

Adipose Tissue ◽

Body Temperature ◽

Brown Adipose Tissue ◽

The Body ◽

Brown Adipocyte ◽

Marker Genes ◽

Cold Environments ◽

Mole Rat ◽

Brown Adipose ◽

Naked Mole Rat

Abstract The naked mole-rat (NMR) is a heterothermic mammal that forms eusocial colonies consisting of one reproductive female (queen), several reproductive males, and subordinates. Despite their heterothermy, NMRs possess brown adipose tissue (BAT), which generally induces thermogenesis in cold and some non-cold environments. Previous studies suggest that NMR-BAT induces thermogenesis by cold exposure. However, detailed NMR-BAT characteristics and whether NMR-BAT thermogenesis occurs in non-cold environments are unknown. Here, we show beta-3 adrenergic receptor (ADRB3)-dependent thermogenic potential of NMR-BAT, which contributes to thermogenesis in the isolated queen in non-cold environments (30 °C). NMR-BAT expressed several brown adipocyte marker genes and showed noradrenaline-dependent thermogenic activity in vitro and in vivo. Although our ADRB3 inhibition experiments revealed that NMR-BAT thermogenesis slightly delays the decrease in body temperature in a cold environment (20 °C), it was insufficient to prevent the decrease in the body temperatures. Even at 30 °C, NMRs are known to prevent the decrease of and maintain their body temperature by heat-sharing behaviors within the colony. However, isolated NMRs maintained their body temperature at the same level as when they are in the colony. Interestingly, we found that queens, but not subordinates, induce BAT thermogenesis in this condition. Our research provides novel insights into NMR thermoregulation.

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SR59230A, a beta-3 adrenoceptor antagonist, inhibits ultradian brown adipose tissue thermogenesis and interrupts associated episodic brain and body heating

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00085.2011 ◽

2011 ◽

Vol 301 (4) ◽

pp. R987-R994 ◽

Cited By ~ 21

Author(s):

Youichirou Ootsuka ◽

Keerthi Kulasekara ◽

Rodrigo Cunha de Menezes ◽

William W. Blessing

Keyword(s):

Blood Flow ◽

Adipose Tissue ◽

Body Temperature ◽

Brown Adipose Tissue ◽

Neural Control ◽

Substantial Contribution ◽

Artery Blood Flow ◽

Body Temperatures ◽

Tail Artery ◽

Brown Adipose

Brown adipose tissue (BAT) thermogenesis occurs episodically in an ultradian manner approximately every 80–100 min during the waking phase of the circadian cycle, together with highly correlated increases in brain and body temperatures, suggesting that BAT thermogenesis contributes to brain and body temperature increases. We investigated this in conscious Sprague-Dawley rats by determining whether inhibition of BAT thermogenesis via blockade of beta-3 adrenoceptors with SR59230A interrupts ultradian episodic increases in brain and body temperatures and whether SR59230A acts on BAT itself or via sympathetic neural control of BAT. Interscapular BAT (iBAT), brain, and body temperatures, tail artery blood flow, and heart rate were measured in unrestrained rats. SR59230A (1, 5, or 10 mg/kg ip), but not vehicle, decreased iBAT, body, and brain temperatures in a dose-dependent fashion (log-linear regression P < 0.01, R2 = 0.3, 0.4, and 0.4, respectively, n = 10). Ultradian increases in BAT, brain, and body temperature were interrupted by administration of SR59230A (10 mg/kg ip) compared with vehicle, resuming after 162 ± 24 min (means ± SE, n = 10). SR59230A (10 mg/kg ip) caused a transient bradycardia without any increase in tail artery blood flow. In anesthetized rats, SR59230A reduced cooling-induced increases in iBAT temperature without affecting cooling-induced increases in iBAT sympathetic nerve discharge. Inhibition of BAT thermogenesis by SR59230A, thus, reflects direct blockade of beta-3 adrenoceptors in BAT. Interruption of episodic ultradian increases in body and brain temperature by SR59230A suggests that BAT thermogenesis makes a substantial contribution to these increases.

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