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Most metabolic studies in mice are carried out at room temperature, although under these conditions, unlike humans, mice expend a lot of energy maintaining internal temperature. Here, we describe normal weight and diet-induced obesity (DIO) in C57BL/6J mice fed chow chow or a 45% high fat diet, respectively. Mice were placed for 33 days at 22, 25, 27.5 and 30° C. in an indirect calorimetry system. We show that energy expenditure increases linearly from 30°C to 22°C and is about 30% higher at 22°C in both mouse models. In normal weight mice, food intake counteracted EE. Conversely, DIO mice did not decrease food intake when EE decreased. Thus, at the end of the study, mice at 30°C had higher body weight, fat mass and plasma glycerol and triglycerides than mice at 22°C. The imbalance in DIO mice may be due to increased pleasure-based dieting.
The mouse is the most commonly used animal model for the study of human physiology and pathophysiology, and is often the default animal used in the early stages of drug discovery and development. However, mice differ from humans in several important physiological ways, and while allometric scaling can be used to some extent to translate into humans, the huge differences between mice and humans lie in thermoregulation and energy homeostasis. This demonstrates a fundamental inconsistency. The average body mass of adult mice is at least a thousand times less than that of adults (50 g vs. 50 kg), and the surface area to mass ratio differs by about 400 times due to the non-linear geometric transformation described by Mee. Equation 2. As a result, mice lose significantly more heat relative to their volume, so they are more sensitive to temperature, more prone to hypothermia, and have an average basal metabolic rate ten times higher than that of humans. At standard room temperature (~22°C), mice must increase their total energy expenditure (EE) by about 30% to maintain core body temperature. At lower temperatures, EE increases even more by about 50% and 100% at 15 and 7°C compared to EE at 22°C. Thus, standard housing conditions induce a cold stress response, which could compromise the transferability of mouse results to humans, as humans living in modern societies spend most of their time in thermoneutral conditions (because our lower area ratio surfaces to volume makes us less sensitive to temperature, as we create a thermoneutral zone (TNZ) around us. EE above basal metabolic rate) spans ~19 to 30°C6, while mice have a higher and narrower band spanning only 2–4°C7,8 In fact, this important aspect has received considerable attention in recent years4, 7,8,9,10,11,12 and it has been suggested that some “species differences” can be mitigated by increasing shell temperature 9. However, there is no consensus on the temperature range that constitutes thermoneutrality in mice. Thus, whether the lower critical temperature in the thermoneutral range in single-knee mice is closer to 25°C or closer to 30°C4, 7, 8, 10, 12 remains controversial. EE and other metabolic parameters have been limited to hours to days, so the extent to which prolonged exposure to different temperatures can affect metabolic parameters such as body weight is unclear. consumption, substrate utilization, glucose tolerance, and plasma lipid and glucose concentrations and appetite-regulating hormones. In addition, further research is needed to ascertain to what extent diet may influence these parameters (DIO mice on a high-fat diet may be more oriented towards a pleasure-based (hedonic) diet). To provide more information on this topic, we examined the effect of rearing temperature on the aforementioned metabolic parameters in normal-weight adult male mice and diet-induced obese (DIO) male mice on a 45% high-fat diet. Mice were kept at 22, 25, 27.5, or 30°C for at least three weeks. Temperatures below 22°C have not been studied because standard animal housing is rarely below room temperature. We found that normal-weight and single-circle DIO mice responded similarly to changes in enclosure temperature in terms of EE and regardless of enclosure condition (with or without shelter/nesting material). However, while normal weight mice adjusted their food intake according to EE, the food intake of DIO mice was largely independent of EE, resulting in mice gaining more weight. According to body weight data, plasma concentrations of lipids and ketone bodies showed that DIO mice at 30°C had a more positive energy balance than mice at 22°C. The underlying reasons for differences in balance of energy intake and EE between normal weight and DIO mice require further study, but may be related to pathophysiological changes in DIO mice and the effect of pleasure-based dieting as a result of an obese diet.
EE increased linearly from 30 to 22°C and was about 30% higher at 22°C compared to 30°C (Fig. 1a,b). The respiratory exchange rate (RER) was independent of temperature (Fig. 1c, d). Food intake was consistent with EE dynamics and increased with decreasing temperature (also ~30% higher at 22°C compared to 30°C (Fig. 1e,f). Water intake. Volume and activity level did not depend on temperature (Fig. 1g ). -to).
Male mice (C57BL/6J, 20 weeks old, individual housing, n=7) were housed in metabolic cages at 22° C. for one week prior to the start of the study. Two days after the collection of background data, the temperature was raised in 2°C increments at 06:00 hours per day (beginning of the light phase). Data are presented as mean ± standard error of the mean, and the dark phase (18:00–06:00 h) is represented by a gray box. a Energy expenditure (kcal/h), b Total energy expenditure at various temperatures (kcal/24 h), c Respiratory exchange rate (VCO2/VO2: 0.7–1.0), d Mean RER in light and dark (VCO2 /VO2) phase (zero value is defined as 0.7). e cumulative food intake (g), f 24h total food intake, g 24h total water intake (ml), h 24h total water intake, i cumulative activity level (m) and j total activity level (m/24h) . ). The mice were kept at the indicated temperature for 48 hours. Data shown for 24, 26, 28 and 30°C refer to the last 24 hours of each cycle. The mice remained fed throughout the study. Statistical significance was tested by repeated measurements of one-way ANOVA followed by Tukey’s multiple comparison test. Asterisks indicate significance for initial value of 22°C, shading indicates significance between other groups as indicated. *P < 0.05, **P < 0.01, **P < 0.001, ****P < 0.0001. *P < 0.05, **P < 0.01, **P < 0.001, ****P < 0.0001. *P <0,05, **P <0,01, **P <0,001, ****P <0,0001. *P<0.05, **P<0.01, **P<0.001, ****P<0.0001. *P < 0.05，**P < 0.01，**P < 0.001，****P < 0.0001。 *P < 0.05，**P < 0.01，**P < 0.001，****P < 0.0001。 *P <0,05, **P <0,01, **P <0,001, ****P <0,0001. *P<0.05, **P<0.01, **P<0.001, ****P<0.0001. Average values were calculated for the entire experimental period (0-192 hours). n = 7.
As in the case of normal weight mice, EE increased linearly with decreasing temperature, and in this case, EE was also about 30% higher at 22°C compared to 30°C (Fig. 2a,b). RER did not change at different temperatures (Fig. 2c, d). In contrast to normal weight mice, food intake was not consistent with EE as a function of room temperature. Food intake, water intake, and activity level were independent of temperature (Figs. 2e–j).
Male (C57BL/6J, 20 weeks) DIO mice were individually housed in metabolic cages at 22° C. for one week prior to the start of the study. Mice can use 45% HFD ad libitum. After acclimatization for two days, baseline data were collected. Subsequently, the temperature was raised in increments of 2°C every other day at 06:00 (beginning of the light phase). Data are presented as mean ± standard error of the mean, and the dark phase (18:00–06:00 h) is represented by a gray box. a Energy expenditure (kcal/h), b Total energy expenditure at various temperatures (kcal/24 h), c Respiratory exchange rate (VCO2/VO2: 0.7–1.0), d Mean RER in light and dark (VCO2 /VO2) phase (zero value is defined as 0.7). e cumulative food intake (g), f 24h total food intake, g 24h total water intake (ml), h 24h total water intake, i cumulative activity level (m) and j total activity level (m/24h) . ). The mice were kept at the indicated temperature for 48 hours. Data shown for 24, 26, 28 and 30°C refer to the last 24 hours of each cycle. Mice were maintained at 45% HFD until the end of the study. Statistical significance was tested by repeated measurements of one-way ANOVA followed by Tukey’s multiple comparison test. Asterisks indicate significance for initial value of 22°C, shading indicates significance between other groups as indicated. *P < 0.05, ***P < 0.001, ****P < 0.0001. *P < 0.05, ***P < 0.001, ****P < 0.0001. *Р<0,05, ***Р<0,001, ****Р<0,0001. *P<0.05, ***P<0.001, ****P<0.0001. *P < 0.05，***P < 0.001，****P < 0.0001。 *P < 0.05，***P < 0.001，****P < 0.0001。 *Р<0,05, ***Р<0,001, ****Р<0,0001. *P<0.05, ***P<0.001, ****P<0.0001. Average values were calculated for the entire experimental period (0-192 hours). n = 7.
In another series of experiments, we examined the effect of ambient temperature on the same parameters, but this time between groups of mice that were constantly kept at a certain temperature. Mice were divided into four groups to minimize statistical changes in the mean and standard deviation of body weight, fat, and normal body weight (Fig. 3a–c). After 7 days of acclimatization, 4.5 days of EE were recorded. EE is significantly affected by the ambient temperature both during daylight hours and at night (Fig. 3d), and increases linearly as the temperature decreases from 27.5°C to 22°C (Fig. 3e). Compared to other groups, the RER of the 25°C group was somewhat reduced, and there were no differences between the remaining groups (Fig. 3f,g). Food intake parallel to EE pattern a increased by approximately 30% at 22°C compared to 30°C (Fig. 3h,i). Water consumption and activity levels did not differ significantly between groups (Fig. 3j,k). Exposure to different temperatures for up to 33 days did not lead to differences in body weight, lean mass, and fat mass between the groups (Fig. 3n-s), but resulted in a decrease in lean body mass of approximately 15% compared to self-reported scores (Fig. 3n-s). 3b, r, c)) and the fat mass increased by more than 2 times (from ~1 g to 2–3 g, Fig. 3c, t, c). Unfortunately, the 30°C cabinet has calibration errors and cannot provide accurate EE and RER data.
- Body weight (a), lean mass (b) and fat mass (c) after 8 days (one day before transfer to the SABLE system). d Energy consumption (kcal/h). e Average energy consumption (0–108 hours) at various temperatures (kcal/24 hours). f Respiratory exchange ratio (RER) (VCO2/VO2). g Mean RER (VCO2/VO2). h Total food intake (g). i Mean food intake (g/24 hours). j Total water consumption (ml). k Average water consumption (ml/24 h). l Cumulative activity level (m). m Average activity level (m/24 h). n body weight on the 18th day, o change in body weight (from -8th to 18th day), p lean mass on the 18th day, q change in lean mass (from -8th to 18th day ), r fat mass on day 18, and change in fat mass (from -8 to 18 days). The statistical significance of repeated measures was tested by Oneway-ANOVA followed by Tukey’s multiple comparison test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. *P <0,05, **P <0,01, ***P <0,001, ****P <0,0001. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. *P < 0.05，**P < 0.01，***P < 0.001，****P < 0.0001。 *P < 0.05，**P < 0.01，***P < 0.001，****P < 0.0001。 *P <0,05, **P <0,01, ***P <0,001, ****P <0,0001. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. Data are presented as mean + standard error of the mean, the dark phase (18:00-06:00 h) is represented by gray boxes. The dots on the histograms represent individual mice. Average values were calculated for the entire experimental period (0-108 hours). n = 7.
Mice were matched in body weight, lean mass, and fat mass at baseline (Figs. 4a–c) and maintained at 22, 25, 27.5, and 30°C as in studies with normal weight mice. . When comparing groups of mice, the relationship between EE and temperature showed a similar linear relationship with temperature over time in the same mice. Thus, mice kept at 22°C consumed about 30% more energy than mice kept at 30°C (Fig. 4d, e). When studying effects in animals, temperature did not always affect RER (Fig. 4f,g). Food intake, water intake, and activity were not significantly affected by temperature (Figs. 4h–m). After 33 days of rearing, mice at 30°C had a significantly higher body weight than mice at 22°C (Fig. 4n). Compared to their respective baseline points, mice reared at 30°C had significantly higher body weights than mice reared at 22°C (mean ± standard error of the mean: Fig. 4o). The relatively higher weight gain was due to an increase in fat mass (Fig. 4p, q) rather than an increase in lean mass (Fig. 4r, s). Consistent with the lower EE value at 30°C, the expression of several BAT genes that increase BAT function/activity was reduced at 30°C compared to 22°C: Adra1a, Adrb3, and Prdm16. Other key genes that also increase BAT function/activity were not affected: Sema3a (neurite growth regulation), Tfam (mitochondrial biogenesis), Adrb1, Adra2a, Pck1 (gluconeogenesis) and Cpt1a. Surprisingly, Ucp1 and Vegf-a, associated with increased thermogenic activity, did not decrease in the 30°C group. In fact, Ucp1 levels in three mice were higher than in the 22°C group, and Vegf-a and Adrb2 were significantly elevated. Compared to the 22 °C group, mice maintained at 25 °C and 27.5 °C showed no change (Supplementary Figure 1).
- Body weight (a), lean mass (b) and fat mass (c) after 9 days (one day before transfer to the SABLE system). d Energy consumption (EE, kcal/h). e Average energy consumption (0–96 hours) at various temperatures (kcal/24 hours). f Respiratory exchange ratio (RER, VCO2/VO2). g Mean RER (VCO2/VO2). h Total food intake (g). i Mean food intake (g/24 hours). j Total water consumption (ml). k Average water consumption (ml/24 h). l Cumulative activity level (m). m Average activity level (m/24 h). n Body weight at day 23 (g), o Change in body weight, p Lean mass, q Change in lean mass (g) at day 23 compared to day 9, Change in fat mass (g) at 23 -day, fat mass (g) compared to day 8, day 23 compared to -8th day. The statistical significance of repeated measures was tested by Oneway-ANOVA followed by Tukey’s multiple comparison test. *P < 0.05, ***P < 0.001, ****P < 0.0001. *P < 0.05, ***P < 0.001, ****P < 0.0001. *Р<0,05, ***Р<0,001, ****Р<0,0001. *P<0.05, ***P<0.001, ****P<0.0001. *P < 0.05，***P < 0.001，****P < 0.0001。 *P < 0.05，***P < 0.001，****P < 0.0001。 *Р<0,05, ***Р<0,001, ****Р<0,0001. *P<0.05, ***P<0.001, ****P<0.0001. Data are presented as mean + standard error of the mean, the dark phase (18:00-06:00 h) is represented by gray boxes. The dots on the histograms represent individual mice. Mean values were calculated for the entire experimental period (0-96 hours). n = 7.
Like humans, mice often create microenvironments to reduce heat loss to the environment. To quantify the importance of this environment for EE, we evaluated EE at 22, 25, 27.5, and 30°C, with or without leather guards and nesting material. At 22°C, the addition of standard skins reduces EE by about 4%. The subsequent addition of nesting material reduced the EE by 3–4% (Fig. 5a,b). No significant changes in RER, food intake, water intake, or activity levels were observed with the addition of houses or skins + bedding (Figure 5i–p). The addition of skin and nesting material also significantly reduced EE at 25 and 30°C, but the responses were quantitatively smaller. At 27.5°C no difference was observed. Notably, in these experiments, EE decreased with increasing temperature, in this case about 57% lower than EE at 30°C compared to 22°C (Fig. 5c–h). The same analysis was performed only for the light phase, where the EE was closer to the basal metabolic rate, since in this case the mice mostly rested in the skin, resulting in comparable effect sizes at different temperatures (Supplementary Fig. 2a–h).
Data for mice from shelter and nesting material (dark blue), home but no nesting material (light blue), and home and nest material (orange). Energy consumption (EE, kcal/h) for rooms a, c, e and g at 22, 25, 27.5 and 30 °C, b, d, f and h means EE (kcal/h). ip Data for mice housed at 22°C: i respiratory rate (RER, VCO2/VO2), j mean RER (VCO2/VO2), k cumulative food intake (g), l average food intake (g/24 h) , m total water intake (mL), n average water intake AUC (mL/24h), o total activity (m), p average activity level (m/24h). Data are presented as mean + standard error of the mean, the dark phase (18:00-06:00 h) is represented by gray boxes. The dots on the histograms represent individual mice. The statistical significance of repeated measures was tested by Oneway-ANOVA followed by Tukey’s multiple comparison test. *P < 0.05, **P < 0.01. *P < 0.05, **P < 0.01. *Р<0,05, **Р<0,01. *P<0.05, **P<0.01. *P < 0.05，**P < 0.01。 *P < 0.05，**P < 0.01。 *Р<0,05, **Р<0,01. *P<0.05, **P<0.01. Average values were calculated for the entire experimental period (0-72 hours). n = 7.
In normal weight mice (2-3 hours of fasting), rearing at different temperatures did not result in significant differences in plasma concentrations of TG, 3-HB, cholesterol, ALT, and AST, but HDL as a function of temperature. Figure 6a-e). Fasting plasma concentrations of leptin, insulin, C-peptide, and glucagon also did not differ between groups (Figures 6g–j). On the day of the glucose tolerance test (after 31 days at different temperatures), the baseline blood glucose level (5-6 hours of fasting) was approximately 6.5 mM, with no difference between the groups. Administration of oral glucose increased blood glucose concentrations significantly in all groups, but both peak concentration and incremental area under the curves (iAUCs) (15–120 min) were lower in the group of mice housed at 30 °C (individual time points: P < 0.05–P < 0.0001, Fig. 6k, l) compared to the mice housed at 22, 25 and 27.5 °C (which did not differ amongst each other). Administration of oral glucose increased blood glucose concentrations significantly in all groups, but both peak concentration and incremental area under the curves (iAUCs) (15–120 min) were lower in the group of mice housed at 30 °C (individual time points: P < 0.05–P < 0.0001, Fig. 6k, l) compared to the mice housed at 22, 25 and 27.5 °C (which did not differ among each other). Пероральное введение глюкозы значительно повышало концентрацию глюкозы в крови во всех группах, но как пиковая концентрация, так и площадь приращения под кривыми (iAUC) (15–120 мин) были ниже в группе мышей, содержащихся при 30 °C (отдельные временные точки: P < 0,05–P < 0,0001, рис. 6k, l) по сравнению с мышами, содержащимися при 22, 25 и 27,5 ° C (которые не различались между собой). Oral administration of glucose significantly increased blood glucose concentrations in all groups, but both peak concentration and incremental area under the curves (iAUC) (15–120 min) were lower in the 30°C mice group (separate time points: P < 0.05–P < 0.0001, Fig. 6k, l) compared to mice kept at 22, 25 and 27.5 °C (which did not differ from each other).口服葡萄糖的给药显着增加了所有组的血糖浓度，但在30 °C 饲养的小鼠组中，峰值浓度和曲线下增加面积(iAUC) (15-120 分钟) 均较低（各个时间点：P < 0.05–P < 0.0001，图6k，l）与饲养在22、25 和27.5°C 的小鼠（彼此之间没有差异）相比。口服 葡萄糖 的 给 药 显着 了 所有组 的 血糖 浓度 但 在 在 在 30 ° C 饲养 小鼠组 中 ， 浓度 和 曲线 下 增加 面积 面积 (IAUC) (15-120 分钟) 均 较 低 各 个 点 点 点 点 点：P < 0.05–P < 0.0001，图6k，l）与饲养在22、25和27.5°C 的小鼠（彼此之间没有差异）相比。 Oral administration of glucose significantly increased blood glucose concentrations in all groups, but both peak concentration and area under the curve (iAUC) (15–120 min) were lower in the 30°C-fed mice group (all time points). : P < 0,05–P < 0,0001, рис. : P < 0.05–P < 0.0001, Fig. 6l, l) compared with mice kept at 22, 25 and 27.5°C (no difference from each other).
Plasma concentrations of TG, 3-HB, cholesterol, HDL, ALT, AST, FFA, glycerol, leptin, insulin, C-peptide, and glucagon are shown in adult male DIO(al) mice after 33 days of feeding at the indicated temperature. Mice were not fed 2-3 hours before blood sampling. The exception was an oral glucose tolerance test, which was performed two days before the end of the study on mice fasted for 5-6 hours and kept at the appropriate temperature for 31 days. Mice were challenged with 2 g/kg body weight. The area under the curve data (L) is expressed as incremental data (iAUC). Data are presented as mean ± SEM. The dots represent individual samples. *P < 0.05, **P < 0.01, **P < 0.001, ****P < 0.0001, n = 7. *P < 0.05, **P < 0.01, **P < 0.001, ****P < 0.0001, n = 7. *P <0,05, **P <0,01, **P <0,001, ****P <0,0001, n = 7. *P<0.05, **P<0.01, **P<0.001, ****P<0.0001, n=7. *P < 0.05，**P < 0.01，**P < 0.001，****P < 0.0001，n = 7。 *P < 0.05，**P < 0.01，**P < 0.001，****P < 0.0001，n = 7。 *P <0,05, **P <0,01, **P <0,001, ****P <0,0001, n = 7. *P<0.05, **P<0.01, **P<0.001, ****P<0.0001, n=7.
In DIO mice (also fasted for 2-3 hours), plasma cholesterol, HDL, ALT, AST, and FFA concentrations did not differ between groups. Both TG and glycerol were significantly elevated in the 30°C group compared to the 22°C group (Figures 7a–h). In contrast, 3-GB was about 25% lower at 30°C compared to 22°C (Figure 7b). Thus, although mice maintained at 22°C had an overall positive energy balance, as suggested by weight gain, differences in plasma concentrations of TG, glycerol, and 3-HB suggest that mice at 22°C when sampling was less than at 22°C. °C. Mice reared at 30 °C were in a relatively more energetically negative state. Consistent with this, liver concentrations of extractable glycerol and TG, but not glycogen and cholesterol, were higher in the 30 °C group (Supplementary Fig. 3a-d). To investigate whether the temperature-dependent differences in lipolysis (as measured by plasma TG and glycerol) are the result of internal changes in epididymal or inguinal fat, we extracted adipose tissue from these stores at the end of the study and quantified free fatty acid ex vivo. and release of glycerol. In all experimental groups, adipose tissue samples from epididymal and inguinal depots showed at least a two-fold increase in glycerol and FFA production in response to isoproterenol stimulation (Supplementary Fig. 4a–d). However, no effect of shell temperature on basal or isoproterenol-stimulated lipolysis was found. Consistent with higher body weight and fat mass, plasma leptin levels were significantly higher in the 30°C group than in the 22°C group (Figure 7i). On the contrary, plasma levels of insulin and C-peptide did not differ between temperature groups (Fig. 7k, k), but plasma glucagon showed a dependence on temperature, but in this case almost 22°C in the opposite group was twice compared to 30°C. FROM. Group C (Fig. 7l). FGF21 did not differ between different temperature groups (Fig. 7m). On the day of OGTT, baseline blood glucose was approximately 10 mM and did not differ between mice housed at different temperatures (Fig. 7n). Oral administration of glucose increased blood glucose levels and peaked in all groups at a concentration of about 18 mM 15 minutes after dosing. There were no significant differences in iAUC (15–120 min) and concentrations at different time points post-dose (15, 30, 60, 90 and 120 min) (Figure 7n, o).
Plasma concentrations of TG, 3-HB, cholesterol, HDL, ALT, AST, FFA, glycerol, leptin, insulin, C-peptide, glucagon, and FGF21 were shown in adult male DIO (ao) mice after 33 days of feeding. specified temperature. Mice were not fed 2-3 hours before blood sampling. The oral glucose tolerance test was an exception as it was performed at a dose of 2 g/kg body weight two days before the end of the study in mice that were fasted for 5-6 hours and kept at the appropriate temperature for 31 days. The area under the curve data (o) is shown as incremental data (iAUC). Data are presented as mean ± SEM. The dots represent individual samples. *P < 0.05, **P < 0.01, **P < 0.001, ****P < 0.0001, n = 7. *P < 0.05, **P < 0.01, **P < 0.001, ****P < 0.0001, n = 7. *P <0,05, **P <0,01, **P <0,001, ****P <0,0001, n = 7. *P<0.05, **P<0.01, **P<0.001, ****P<0.0001, n=7. *P < 0.05，**P < 0.01，**P < 0.001，****P < 0.0001，n = 7。 *P < 0.05，**P < 0.01，**P < 0.001，****P < 0.0001，n = 7。 *P <0,05, **P <0,01, **P <0,001, ****P <0,0001, n = 7. *P<0.05, **P<0.01, **P<0.001, ****P<0.0001, n=7.
The transferability of rodent data to humans is a complex issue that plays a central role in interpreting the importance of observations in the context of physiological and pharmacological research. For economic reasons and to facilitate research, mice are often kept at room temperature below their thermoneutral zone, resulting in the activation of various compensatory physiological systems that increase the metabolic rate and potentially impair translatability9. Thus, exposure of mice to cold may render mice resistant to diet-induced obesity and may prevent hyperglycemia in streptozotocin-treated rats due to increased non-insulin dependent glucose transport. However, it is not clear to what extent prolonged exposure to various relevant temperatures (from room to thermoneutral) affects the different energy homeostasis of normal weight mice (on food) and DIO mice (on HFD) and metabolic parameters, as well as the extent to which they were able to balance an increase in EE with an increase in food intake. The study presented in this article aims to bring some clarity to this topic.
We show that in normal weight adult mice and male DIO mice, EE is inversely related to room temperature between 22 and 30°C. Thus, EE at 22°C was about 30% higher than at 30°C. in both mouse models. However, an important difference between normal weight mice and DIO mice is that while normal weight mice matched EE at lower temperatures by adjusting food intake accordingly, food intake of DIO mice varied at different levels. The study temperatures were similar. After one month, DIO mice kept at 30°C gained more body weight and fat mass than mice kept at 22°C, whereas normal humans kept at the same temperature and for the same period of time did not lead to fever. dependent difference in body weight. weight mice. Compared to temperatures near thermoneutral or at room temperature, growth at room temperature resulted in DIO or normal weight mice on a high fat diet but not on a normal weight mouse diet to gain relatively less weight. body. Supported by other studies17,18,19,20,21 but not by all22,23.
The ability to create a microenvironment to reduce heat loss is hypothesized to shift thermal neutrality to the left8, 12. In our study, both the addition of nesting material and concealment reduced EE but did not result in thermal neutrality up to 28°C. Thus, our data do not support that the low point of thermoneutrality in single-knee adult mice, with or without environmentally enriched houses, should be 26-28°C as shown8,12, but it does support other studies showing thermoneutrality. temperatures of 30°C in low point mice7, 10, 24. To complicate matters, the thermoneutral point in mice has been shown not to be static during the day as it is lower during the resting (light) phase, possibly due to lower calorie production as a result of activity and diet-induced thermogenesis. Thus, in the light phase, the lower point of thermal neutrality turns out to be ~29°С, and in the dark phase, ~33°С25.
Ultimately, the relationship between ambient temperature and total energy consumption is determined by heat dissipation. In this context, the ratio of surface area to volume is an important determinant of thermal sensitivity, affecting both heat dissipation (surface area) and heat generation (volume). In addition to surface area, heat transfer is also determined by insulation (rate of heat transfer). In humans, fat mass can reduce heat loss by creating an insulating barrier around the body shell, and it has been suggested that fat mass is also important for thermal insulation in mice, lowering the thermoneutral point and reducing temperature sensitivity below the thermal neutral point (curve slope). ambient temperature compared to EE)12. Our study was not designed to directly assess this putative relationship because body composition data were collected 9 days before energy expenditure data were collected and because fat mass was not stable throughout the study. However, since normal weight and DIO mice have 30% lower EE at 30°C than at 22°C despite at least a 5-fold difference in fat mass, our data do not support that obesity should provide basic insulation. factor, at least not in the investigated temperature range. This is in line with other studies better designed to explore this4,24. In these studies, the insulating effect of obesity was small, but fur was found to provide 30-50% of total thermal insulation4,24. However, in dead mice, thermal conductivity increased by about 450% immediately after death, suggesting that the insulating effect of the fur is necessary for physiological mechanisms, including vasoconstriction, to work. In addition to species differences in fur between mice and humans, the poor insulating effect of obesity in mice may also be influenced by the following considerations: The insulating factor of human fat mass is mainly mediated by subcutaneous fat mass (thickness)26,27. Typically in rodents Less than 20% of total animal fat28. In addition, total fat mass may not even be a suboptimal measure of an individual’s thermal insulation, as it has been argued that improved thermal insulation is offset by the inevitable increase in surface area (and therefore increased heat loss) as fat mass increases. .
In normal weight mice, fasting plasma concentrations of TG, 3-HB, cholesterol, HDL, ALT, and AST did not change at various temperatures for almost 5 weeks, probably because the mice were in the same state of energy balance. were the same in weight and body composition as at the end of the study. Consistent with the similarity in fat mass, there were also no differences in plasma leptin levels, nor in fasting insulin, C-peptide, and glucagon. More signals were found in DIO mice. Although mice at 22°C also did not have an overall negative energy balance in this state (as they gained weight), at the end of the study they were relatively more energy deficient compared to mice reared at 30°C, in conditions such as high ketones. production by the body (3-GB) and a decrease in the concentration of glycerol and TG in plasma. However, temperature-dependent differences in lipolysis do not appear to be the result of intrinsic changes in epididymal or inguinal fat, such as changes in the expression of adipohormone-responsive lipase, since FFA and glycerol released from fat extracted from these depots are between Temperature groups are similar to each other. Although we did not investigate sympathetic tone in the current study, others have found that it (based on heart rate and mean arterial pressure) is linearly related to ambient temperature in mice and is approximately lower at 30°C than at 22°C 20% C Thus, temperature-dependent differences in sympathetic tone may play a role in lipolysis in our study, but since an increase in sympathetic tone stimulates rather than inhibits lipolysis, other mechanisms may counteract this decrease in cultured mice. Potential role in the breakdown of body fat. Room temperature. Furthermore, part of the stimulatory effect of sympathetic tone on lipolysis is indirectly mediated by strong inhibition of insulin secretion, highlighting the effect of insulin interrupting supplementation on lipolysis30, but in our study, fasting plasma insulin and C-peptide sympathetic tone at different temperatures were not enough to alter lipolysis. Instead, we found that differences in energy status were most likely the main contributor to these differences in DIO mice. The underlying reasons that lead to better regulation of food intake with EE in normal weight mice require further study. In general, however, food intake is controlled by homeostatic and hedonic cues31,32,33. Although there is debate as to which of the two signals is quantitatively more important,31,32,33 it is well known that long-term consumption of high-fat foods leads to more pleasure-based eating behavior that is to some extent unrelated to homeostasis. . – regulated food intake34,35,36. Therefore, the increased hedonic feeding behavior of DIO mice treated with 45% HFD may be one of the reasons why these mice did not balance food intake with EE. Interestingly, differences in appetite and blood glucose-regulating hormones were also observed in the temperature-controlled DIO mice, but not in normal-weight mice. In DIO mice, plasma leptin levels increased with temperature and glucagon levels decreased with temperature. The extent to which temperature can directly influence these differences deserves further study, but in the case of leptin, the relative negative energy balance and thus lower fat mass in mice at 22°C certainly played an important role, as fat mass and plasma leptin is highly correlated37. However, the interpretation of the glucagon signal is more puzzling. As with insulin, glucagon secretion was strongly inhibited by an increase in sympathetic tone, but the highest sympathetic tone was predicted to be in the 22°C group, which had the highest plasma glucagon concentrations. Insulin is another strong regulator of plasma glucagon, and insulin resistance and type 2 diabetes are strongly associated with fasting and postprandial hyperglucagonemia 38,39 . However, the DIO mice in our study were also insulin insensitive, so this also could not be the main factor in the increase in glucagon signaling in the 22°C group. Liver fat content is also positively associated with an increase in plasma glucagon concentration, the mechanisms of which, in turn, may include hepatic glucagon resistance, decreased urea production, increased circulating amino acid concentrations, and increased amino acid-stimulated glucagon secretion40,41,42. However, since extractable concentrations of glycerol and TG did not differ between temperature groups in our study, this also could not be a potential factor in the increase in plasma concentrations in the 22°C group. Triiodothyronine (T3) plays a critical role in overall metabolic rate and initiation of metabolic defense against hypothermia43,44. Thus, plasma T3 concentration, possibly controlled by centrally mediated mechanisms,45,46 increases in both mice and humans under less than thermoneutral conditions47, although the increase in humans is smaller, which is more predisposed to mice. This is consistent with heat loss to the environment. We did not measure plasma T3 concentrations in the current study, but concentrations may have been lower in the 30°C group, which may explain the effect of this group on plasma glucagon levels, as we (updated Figure 5a) and others have shown that T3 increases plasma glucagon in a dose-dependent manner. Thyroid hormones have been reported to induce FGF21 expression in the liver. Like glucagon, plasma FGF21 concentrations also increased with plasma T3 concentrations (Supplementary Fig. 5b and ref. 48), but compared to glucagon, FGF21 plasma concentrations in our study were not affected by temperature. The underlying reasons for this discrepancy require further study, but T3-driven FGF21 induction should occur at higher levels of T3 exposure compared to the observed T3-driven glucagon response (Supplementary Fig. 5b).
HFD has been shown to be strongly associated with impaired glucose tolerance and insulin resistance (markers) in mice reared at 22°C. However, HFD was not associated with either impaired glucose tolerance or insulin resistance when grown in a thermoneutral environment (defined here as 28 °C) 19 . In our study, this relationship was not replicated in DIO mice, but normal weight mice maintained at 30°C significantly improved glucose tolerance. The reason for this difference requires further study, but may be influenced by the fact that the DIO mice in our study were insulin resistant, with fasting plasma C-peptide concentrations and insulin concentrations 12-20 times higher than normal weight mice. and in the blood on an empty stomach. glucose concentrations of about 10 mM (about 6 mM at normal body weight), which seems to leave a small window for any potential beneficial effects of exposure to thermoneutral conditions to improve glucose tolerance. A possible confusing factor is that, for practical reasons, OGTT is carried out at room temperature. Thus, mice housed at higher temperatures experienced mild cold shock, which may affect glucose absorption/clearance. However, based on similar fasting blood glucose concentrations in different temperature groups, changes in ambient temperature may not have significantly affected the results.
As mentioned earlier, it has recently been highlighted that increasing the room temperature may attenuate some reactions to cold stress, which may call into question the transferability of mouse data to humans. However, it is not clear what is the optimal temperature for keeping mice to mimic human physiology. The answer to this question can also be influenced by the field of study and the endpoint being studied. An example of this is the effect of diet on liver fat accumulation, glucose tolerance and insulin resistance19. In terms of energy expenditure, some researchers believe that thermoneutrality is the optimum temperature for rearing, as humans require little extra energy to maintain their core body temperature, and they define a single lap temperature for adult mice as 30°C7,10. Other researchers believe that a temperature comparable to that humans typically experience with adult mice on one knee is 23-25°C, as they found thermoneutrality to be 26-28°C and based on humans being lower about 3°C. their lower critical temperature, defined here as 23°C, is slightly 8.12. Our study is consistent with several other studies that state that thermal neutrality is not achieved at 26-28°C4, 7, 10, 11, 24, 25, indicating that 23-25°C is too low. Another important factor to consider regarding room temperature and thermoneutrality in mice is single or group housing. When mice were housed in groups rather than individually, as in our study, temperature sensitivity was reduced, possibly due to crowding of the animals. However, room temperature was still below the LTL of 25 when three groups were used. Perhaps the most important interspecies difference in this regard is the quantitative significance of BAT activity as a defense against hypothermia. Thus, while mice largely compensated for their higher calorie loss by increasing BAT activity, which is over 60% EE at 5°C alone,51,52 the contribution of human BAT activity to EE was significantly higher, much smaller. Therefore, reducing BAT activity may be an important way to increase human translation. The regulation of BAT activity is complex but is often mediated by the combined effects of adrenergic stimulation, thyroid hormones and UCP114,54,55,56,57 expression. Our data indicate that the temperature needs to be raised above 27.5°C compared to mice at 22°C in order to detect differences in the expression of BAT genes responsible for function/activation. However, the differences found between groups at 30 and 22°C did not always indicate an increase in BAT activity in the 22°C group because Ucp1, Adrb2 and Vegf-a were downregulated in the 22°C group. The root cause of these unexpected results remains to be determined. One possibility is that their increased expression may not reflect a signal of elevated room temperature, but rather an acute effect of moving them from 30°C to 22°C on the day of removal (the mice experienced this 5-10 minutes before takeoff). ).
A general limitation of our study is that we only studied male mice. Other research suggests that gender may be an important consideration in our primary indications, as single-knee female mice are more temperature sensitive due to higher thermal conductivity and maintaining more tightly controlled core temperatures. In addition, female mice (on HFD) showed a greater association of energy intake with EE at 30 °C compared to male mice that consumed more mice of the same sex (20 °C in this case) 20 . Thus, in female mice, the effect subthermonetral content is higher, but has the same pattern as in male mice. In our study, we focused on single-knee male mice, as these are the conditions under which most of the metabolic studies examining EE are conducted. Another limitation of our study was that the mice were on the same diet throughout the study, which precluded studying the importance of room temperature for metabolic flexibility (as measured by RER changes for dietary changes in various macronutrient compositions). in female and male mice kept at 20°C compared to corresponding mice kept at 30°C.
In conclusion, our study shows that, as in other studies, lap 1 normal weight mice are thermoneutral above the predicted 27.5°C. In addition, our study shows that obesity is not a major insulating factor in mice with normal weight or DIO, resulting in similar temperature:EE ratios in DIO and normal weight mice. While the food intake of normal weight mice was consistent with the EE and thus maintained a stable body weight over the entire temperature range, the food intake of DIO mice was the same at different temperatures, resulting in a higher ratio of mice at 30°C. at 22°C gained more body weight. Overall, systematic studies examining the potential importance of living below thermoneutral temperatures are warranted because of the often observed poor tolerability between mouse and human studies. For example, in obesity studies, a partial explanation for the generally poorer translatability may be due to the fact that murine weight loss studies are usually performed on moderately cold stressed animals kept at room temperature due to their increased EE. Exaggerated weight loss compared to the expected body weight of a person, in particular if the mechanism of action depends on increasing EE by increasing the activity of BAP, which is more active and activated at room temperature than at 30°C.
In accordance with the Danish Animal Experimental Law (1987) and the National Institutes of Health (Publication No. 85-23) and the European Convention for the Protection of Vertebrate used for Experimental and Other Scientific Purposes (Council of Europe No. 123, Strasbourg, 1985) .
Twenty-week-old male C57BL/6J mice were obtained from Janvier Saint Berthevin Cedex, France, and were given ad libitum standard chow (Altromin 1324) and water (~22°C) after a 12:12 hour light:dark cycle. room temperature. Male DIO mice (20 weeks) were obtained from the same supplier and were given ad libitum access to a 45% high fat diet (Cat. No. D12451, Research Diet Inc., NJ, USA) and water under rearing conditions. Mice were adapted to the environment a week before the start of the study. Two days prior to transfer to the indirect calorimetry system, mice were weighed, subjected to MRI scanning (EchoMRITM, TX, USA) and divided into four groups corresponding to body weight, fat and normal body weight.
A graphical diagram of the study design is shown in Figure 8. Mice were transferred to a closed and temperature-controlled indirect calorimetry system at Sable Systems Internationals (Nevada, USA), which included food and water quality monitors and a Promethion BZ1 frame that recorded activity levels by measuring beam breaks. XYZ. Mice (n = 8) were housed individually at 22, 25, 27.5, or 30°C using bedding but no shelter and nesting material on a 12:12-hour light:dark cycle (light: 06:00– 18:00). 2500ml/min. Mice were acclimatized for 7 days prior to registration. Recordings were collected four days in a row. Thereafter, mice were kept at the respective temperatures at 25, 27.5, and 30°C for an additional 12 days, after which the cell concentrates were added as described below. Meanwhile, groups of mice kept at 22°C were kept at this temperature for two more days (to collect new baseline data), and then the temperature was increased in steps of 2°C every other day at the beginning of the light phase (06:00) until reaching 30 °C After that, the temperature was lowered to 22°C and data was collected for another two days. After two additional days of recording at 22°C, skins were added to all cells at all temperatures, and data collection began on the second day (day 17) and for three days. After that (day 20), nesting material (8-10 g) was added to all cells at the beginning of the light cycle (06:00) and data were collected for another three days. Thus, at the end of the study, mice kept at 22°C were kept at this temperature for 21/33 days and at 22°C for the last 8 days, while mice at other temperatures were kept at this temperature for 33 days . /33 days. Mice were fed during the study period.
Normal weight and DIO mice followed the same study procedures. At day -9, mice were weighed, MRI scanned, and divided into groups comparable in body weight and body composition. On day -7, mice were transferred to a closed temperature controlled indirect calorimetry system manufactured by SABLE Systems International (Nevada, USA). Mice were housed individually with bedding but without nesting or shelter materials. The temperature is set to 22, 25, 27.5 or 30 °C. After one week of acclimatization (days -7 to 0, animals were not disturbed), data were collected on four consecutive days (days 0-4, data shown in FIGS. 1, 2, 5). Thereafter, mice kept at 25, 27.5 and 30°C were kept under constant conditions until the 17th day. At the same time, the temperature in the 22°C group was increased at intervals of 2°C every other day by adjusting the temperature cycle (06:00 h) at the beginning of light exposure (data are shown in Fig. 1). On day 15, the temperature dropped to 22°C and two days of data were collected to provide baseline data for subsequent treatments. Skins were added to all mice on day 17, and nesting material was added on day 20 (Fig. 5). On the 23rd day, the mice were weighed and subjected to MRI scanning, and then left alone for 24 hours. On day 24, mice were fasted from the beginning of the photoperiod (06:00) and received OGTT (2 g/kg) at 12:00 (6-7 hours of fasting). Thereafter, the mice were returned to their respective SABLE conditions and euthanized on the second day (day 25).
DIO mice (n = 8) followed the same protocol as normal weight mice (as described above and in Figure 8). Mice maintained 45% HFD throughout the energy expenditure experiment.
VO2 and VCO2, as well as water vapor pressure, were recorded at a frequency of 1 Hz with a cell time constant of 2.5 min. Food and water intake was collected by continuous recording (1 Hz) of the weight of the food and water pails. The quality monitor used reported a resolution of 0.002 g. Activity levels were recorded using a 3D XYZ beam array monitor, data was collected at an internal resolution of 240 Hz and reported every second to quantify total distance traveled (m) with an effective spatial resolution of 0.25 cm. The data was processed with Sable Systems Macro Interpreter v.2.41, calculating EE and RER and filtering out outliers (eg, false meal events). The macro interpreter is configured to output data for all parameters every five minutes.
In addition to regulating EE, ambient temperature may also regulate other aspects of metabolism, including postprandial glucose metabolism, by regulating the secretion of glucose-metabolizing hormones. To test this hypothesis, we finally completed a body temperature study by provoking normal weight mice with a DIO oral glucose load (2 g/kg). Methods are described in detail in additional materials.
At the end of the study (day 25), mice were fasted for 2-3 hours (starting at 06:00), anesthetized with isoflurane, and completely bled by retroorbital venipuncture. Quantification of plasma lipids and hormones and lipids in the liver is described in Supplementary Materials.
To investigate whether shell temperature causes intrinsic changes in adipose tissue affecting lipolysis, inguinal and epididymal adipose tissue was excised directly from mice after the last stage of bleeding. Tissues were processed using the newly developed ex vivo lipolysis assay described in Supplementary Methods.
Brown adipose tissue (BAT) was collected on the day of the end of the study and processed as described in the supplementary methods.
Data are presented as mean ± SEM. Graphs were created in GraphPad Prism 9 (La Jolla, CA) and graphics were edited in Adobe Illustrator (Adobe Systems Incorporated, San Jose, CA). Statistical significance was assessed in GraphPad Prism and tested by paired t-test, repeated measures one-way/two-way ANOVA followed by Tukey’s multiple comparisons test, or unpaired one-way ANOVA followed by Tukey’s multiple comparisons test as needed. The Gaussian distribution of the data was validated by the D’Agostino-Pearson normality test before testing. The sample size is indicated in the corresponding section of the “Results” section, as well as in the legend. Repetition is defined as any measurement taken on the same animal (in vivo or on a tissue sample). In terms of data reproducibility, an association between energy expenditure and case temperature was demonstrated in four independent studies using different mice with a similar study design.
Detailed experimental protocols, materials, and raw data are available upon reasonable request from lead author Rune E. Kuhre. This study did not generate new unique reagents, transgenic animal/cell lines, or sequencing data.
For more information on study design, see the Nature Research Report abstract linked to this article.
All data form a graph. 1-7 were deposited in the Science database repository, accession number: 1253.11.sciencedb.02284 or https://doi.org/10.57760/sciencedb.02284. The data shown in ESM may be sent to Rune E Kuhre after reasonable testing.
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Post time: Oct-28-2022
