What is the best housing temperature to translate mouse experiments to humans?

Keijer, Jaap; Li, Min; Speakman, John R.

doi:10.1016/j.molmet.2019.04.001

Cited by 82 publications

(83 citation statements)

References 50 publications

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“…In contrast, when housed at thermoneutrality, Ucp1 knockout mice have increased sensitivity to diet-induced obesity (42,43). The fundamental difference in thermoregulation between mice and humans and the growing number of examples that housing temperature influences experimental outcomes (3,(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59) argue strongly that thermoneutral housing of mice more accurately reflects the thermal environment in humans and preclinical studies performed in mice should be conducted at housing temperatures that minimize cold stress.…”

Section: Discussionmentioning

confidence: 99%

Effects of Propranolol on Bone, White Adipose Tissue, and Bone Marrow Adipose Tissue in Mice Housed at Room Temperature or Thermoneutral Temperature

et al. 2020

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Growing female mice housed at room temperature (22 • C) weigh the same but differ in body composition compared to mice housed at thermoneutrality (32 • C). Specifically, mice housed at room temperature have lower levels of white adipose tissue (WAT). Additionally, bone marrow adipose tissue (bMAT) and cancellous bone volume fraction in distal femur metaphysis are lower in room temperature-housed mice. The metabolic changes induced by sub-thermoneutral housing are associated with lower leptin levels in serum and higher levels of Ucp1 gene expression in brown adipose tissue. Although the precise mechanisms mediating adaptation to sub-thermoneutral temperature stress remain to be elucidated, there is evidence that increased sympathetic nervous system activity acting via β-adrenergic receptors plays an important role. We therefore evaluated the effect of the non-specific β-blocker propranolol (primarily β 1 and β 2 antagonist) on body composition, femur microarchitecture, and bMAT in growing female C57BL/6 mice housed at either room temperature or thermoneutral temperature. As anticipated, cancellous bone volume fraction, WAT and bMAT were lower in mice housed at room temperature. Propranolol had small but significant effects on bone microarchitecture (increased trabecular number and decreased trabecular spacing), but did not attenuate premature bone loss induced by room temperature housing. In contrast, propranolol treatment prevented housing temperature-associated differences in WAT and bMAT. To gain additional insight, we evaluated a panel of genes in tibia, using an adipogenesis PCR array. Housing temperature and treatment with propranolol had exclusive as well as shared effects on gene expression. Of particular interest was the finding that room temperature housing reduced, whereas propranolol increased, expression of the gene for acetyl-CoA carboxylase (Acacb), the rate-limiting step for fatty acid synthesis and a key regulator of β-oxidation. Taken together, these findings provide evidence that increased activation of β 1 and/or β 2 receptors contributes to reduced bMAT by regulating adipocyte metabolism, but that this pathway is unlikely to be responsible for premature cancellous bone loss in room temperature-housed mice.

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Section: Discussionmentioning

confidence: 99%

Effects of Propranolol on Bone, White Adipose Tissue, and Bone Marrow Adipose Tissue in Mice Housed at Room Temperature or Thermoneutral Temperature

et al. 2020

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“…These environmental differences have diverse effects on physiology, immunity and metabolism [17, 18]. Whilst the use of thermoneutrality has been suggested as the optimal environment to mimic human physiology there is ongoing debate as to ‘how high’ we should go [18, 27, 28]. Here, using thermoneutral housing, we show exercise training induces an oxidative phenotype in BAT of obese animals that is associated with an enrichment of GO terms involved in skeletal muscle physiology and of multiple pathways associated with altered mitochondrial metabolism (i.e.…”

Section: Discussionmentioning

confidence: 99%

Exercise does not induce browning of WAT at thermoneutrality and induces an oxidative, myogenic signature in BAT

Aldiss

Lewis

Lupini

et al. 2019

Preprint

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Background and aimExercise training elicits diverse effects on brown (BAT) and white adipose tissue (WAT) physiology in rodents. However, these animals are typically housed below their thermoneutral zone (i.e. 28-32°C). In these conditions, BAT is chronically hyperactive and, unlike human residence, closer to thermoneutrality. Therefore, we set out to determine the effects of exercise training in obese animals at 28°C (i.e. thermoneutrality) on BAT and WAT in its basal (i.e. inactive) state.MethodsSprague-Dawley rats (n=12) were housed at thermoneutrality from 3 weeks of age and fed a high-fat diet (HFD). At 12 weeks of age half these animals were randomised to 4-weeks of exercise exercise training, i.e. swim-training (1 hour/day, 5 days per week). Metabolic assessment was undertaken during the final 48h and was followed by interscapular and perivascular BAT and inguinal (I)WAT sampling for the analysis of thermogenic genes and the proteome.ResultsExercise attenuated weight gain but did not affect fat mass or general metabolic parameters (i.e. fasting insulin and glucose). Interestingly, although BAT mass was increased, there was no change in thermogenic gene expression. Differentially regulated proteins in BAT enriched gene ontology (GO) terms including 2-oxoglutarate metabolic process, cytochrome-c activity and mitochondrial respiratory chain complex IV. This was accompanied by an upregulation of multiple proteins and GO terms involved in skeletal muscle physiology suggesting an adipocyte to myocyte switch in BAT. UCP1 mRNA was undetectable in IWAT despite an increase in classical ‘browning’ markers (i.e. PGC1a and ADRB3) with exercise. Enriched GO terms in IWAT included DNA binding and positive regulation of apoptosis. Impact analysis highlighted carbon metabolism and OXPHOS pathways were regulated by exercise in BAT whilst HIF-1 signalling and cytokine-cytokine receptor interaction were among those modified in IWAT.ConclusionExercise training reduces weight gain in obese animals at thermoneutrality and is accompanied by an oxidative, myogenic signature in BAT, rather than induction of thermogenic genes. This may represent a new, UCP1-independent pathway through which BAT regulates body weight at thermoneutrality.

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“…In contrast, cold-induced thermogenesis contributes a very small fraction to total energy expenditure in humans 42 . Increasing housing temperatures (27°C - 30°C) improves the metabolic similarity between humans and mice and has been suggested to be a better housing strategy 9,10,26,27,33 . To the best of our knowledge, this is the first study to show that housing temperature markedly influences exercise training adaptations, clearly demonstrating that housing temperature is an important consideration when investigating such parameters in mice.…”

Section: Discussionmentioning

confidence: 99%

“…Evidently, markedly dissimilar results have been obtained when testing the same processes in mice housed at different temperatures, including mitochondrial uncoupling 17 , whole-body glucose tolerance 18,19 (although recently contradicted by 20 ), inflammation 21 , immune responses 22 , atherosclerosis 23 , and cancer 24,25 . Instead, optimal housing conditions of mice to better mimic the metabolic rate of humans have been studied and discussed in recent years with temperatures from 27°C 26 to 30°C 27,28 being reported as the optimal housing temperature. Exercise markedly affects metabolism but to the best of our knowledge, the voluntary wheel running mouse model of exercise training has never been tested at thermoneutral conditions.…”

Section: Introductionmentioning

confidence: 99%

Housing temperature influences exercise training adaptations in mice

Raun

Olguín

Karavaeva

et al. 2019

Preprint

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Highlights Housing at 30°C blunts several adaptations to exercise training in mice  Exercise-sensitive protein induction is dampened at 30°C in skeletal muscle  30°C-housing blunts training-induced increase in insulin-stimulated glucose uptake 105 day and night in untrained mice, in contrast with previous reports 20,27 , with no effect of ET on resting 106 RER (Fig. 2C). Chronically housing mice at thermoneutrality increased habitual (+90%) activity 107 during the night in UT mice (Fig. 2D) underlining the importance of adequate acclimatization time 108 Raun et al. Housing temperature influences exercise training adaptations in mice 2019 page 8 of 34during temperature changes, as acute temperature did not change habitual activity (Suppl. Fig. 1g). 109Increased habitual activity was despite lower food intake compared to UT mice at ambient 110 temperature (Suppl. Fig. 1i). This contrasts with the nightly running volume that tended to remain 111 lower (p=0.064, -35%, Fig. 2E) in mice housed at 30°C compared to ambient temperature, while 112 running volume during daytime was increased at 30 o C (Fig. 2F). Overall mice housed at 30°C ran 113 35% less than when housed at 22°C (p=0.06, Fig. 2G) accompanied by a tendency to a lower maximal 114 (p=0.054, Fig. 2H) and decreased average ( Fig. 2I) running speed. To test if reduced running volume 115 could be due to over-heating during exercise, we measured core temperature during the day (when 116 the mice are resting/inactive) and in the early dark period (when the mice are running the most). UT 117 mice displayed 0.6°C lower core temperature during the inactive period when housed at 22 o C 118compared with 30 o C, highlighting the mild cold stress inflicted by 22°C housing (Fig. 2J). Core 119 temperature increased to the same absolute values in all groups during the dark period (Fig. 2J). Thus, 120 reduced running of mice housed at 30°C is likely not due to overheating. 121 Overall, mice in 30°C displayed lower energy consumption, lesser improvements in body 122 composition, as well as no improvement in glucose tolerance following the standard laboratory 123 exercise model of voluntary wheel running, despite similar improvements in running performance. 124 Adaptations in glucose tolerance, but not performance or body composition, are ascribed to 125 training volume. 126 Having established remarkable differences in exercise training adaptations with this model in mice 127 housed at different temperatures, we next sought to determine if these alterations were due to the 128 lower running volume in 30 o C housed mice. Thus, we restricted voluntary running in mice housed at 129 22°C (Fig. 3A) to mimic the training volume of thermoneutrally housed mice ("paired 22°C ET", Fig. 130 3B).131 Raun et al. Housing temperature influences exercise training adaptations in mice 2019 page 9 of 34Body weight (Fig. 3C) and food intake (Fig. 3D) were unaffected by paired 22°C ET. Similar to 22°C 132 housing ( Fig. 1D), paired 22°C ET reduced fat mass gain (Fig. 3E). As such, mice trai...

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What is the best housing temperature to translate mouse experiments to humans?

Cited by 82 publications

References 50 publications

Effects of Propranolol on Bone, White Adipose Tissue, and Bone Marrow Adipose Tissue in Mice Housed at Room Temperature or Thermoneutral Temperature

Effects of Propranolol on Bone, White Adipose Tissue, and Bone Marrow Adipose Tissue in Mice Housed at Room Temperature or Thermoneutral Temperature

Exercise does not induce browning of WAT at thermoneutrality and induces an oxidative, myogenic signature in BAT

Housing temperature influences exercise training adaptations in mice

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