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. 2018 Sep;596(18):4375-4391.
doi: 10.1113/JP276228. Epub 2018 Aug 14.

Prior exercise training improves cold tolerance independent of indices associated with non-shivering thermogenesis

Carly M Knuth  1 , Willem T Peppler  1 , Logan K Townsend  1 , Paula M Miotto  1 , Anders Gudiksen  2 , David C Wright  1
Affiliations

Prior exercise training improves cold tolerance independent of indices associated with non-shivering thermogenesis

Carly M Knuth et al. J Physiol. 2018 Sep.

Abstract

Key points: Mammals defend against cold-induced reductions in body temperature through both shivering and non-shivering thermogenesis. The activation of non-shivering thermogenesis is primarily driven by uncoupling protein-1 in brown adipose tissue and to a lesser degree by the browning of white adipose tissue. Endurance exercise has also been shown to increase markers of white adipose tissue browning. This study aimed to determine whether prior exercise training would alter the response to a cold challenge and if this would be associated with differences in indices of non-shivering thermogenesis. It is shown that exercise training protects against cold-induced weight loss by increasing food intake. Exercise-trained mice were better able to maintain their core temperature, independent of differences in markers of non-shivering thermogenesis.

Abstract: Shivering is one of the first defences against cold, and as skeletal muscle fatigues there is an increased reliance on non-shivering thermogenesis. Brown and beige adipose tissues are the primary thermogenic tissues regulating this process. Exercise has also been shown to increase the thermogenic capacity of subcutaneous white adipose tissue. Whether exercise has an effect on the adaptations to cold stress within adipose tissue and skeletal muscle remains to be shown. Male C57BL/6 mice were either subjected to voluntary wheel running or remained sedentary for 12 days. Exercise led to decreased body weight and increased glucose tolerance. Mice were then divided into groups kept at 25°C room temperature or a cold challenge of 4°C for 48 h. Exercised mice were protected against cold-induced reductions in weight and in parallel with increased food intake. Providing exercised mice with the same amount of food as sedentary mice eliminated the protection against cold-induced weight loss. Cold exposure led to greater reductions in rectal temperature in sedentary compared to exercised mice. This protective effect was not explained by differences in the browning of white adipose tissue or brown adipose tissue mass. Similarly, the ability of the β3 -adrenergic agonist CL 316,243 to increase energy expenditure was attenuated in previously exercised mice, suggesting that the activation of uncoupling protein-1 in brown and/or beige adipocytes is not the source of protective effects. We speculate that the protection against cold-induced reductions in rectal temperature could potentially be linked to exercise-induced alterations in skeletal muscle.

Keywords: cold exposure; exercise; thermogenesis.

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Figures

Figure 1
Figure 1. Twelve days of voluntary wheel running (VWR) produces beneficial effects
A, schematic design of the 12‐day exercise and 48‐h cold interventions. B–F, during the exercise intervention, distance (B; n = 30/group), time spent running (C; n = 14/group), body mass (D; n = 22/group) and food intake (E; n = 22/group) were measured every other day, while a GTT was conducted on the 8th day of VWR (F; n = 14/group). G–J, protein content (n = 4–9/group) and representative images of mitochondrial and thermogenic markers in iWAT (G), eWAT (H), BAT (I) and triceps (J), as well as an example representative image of a loading control via Ponceau S staining. Significant interactions denoted by * P < 0.05, ** P < 0.01, *** P < 0.001.
Figure 2
Figure 2. Prior exercise training alleviates cold‐induced decreases in body mass and mitigates cold‐induced drops in rectal temperature despite no change in blood glucose between exercise and sedentary mice
A–C, food intake was measured (A; n = 22/group) and the hypothalamus was collected following termination to determine the content of proteins involved in satiety (B; n = 8–9/group). Additionally, the change in body mass was calculated following cold exposure (C; n = 18–19/group). D and E, NEFA (D) and glycerol (E) concentrations in the plasma were also determined following termination (n = 5). F and G, rectal temperature was measured as an indication of core temperature over a period of 48 h, and the AUC was calculated to show overall changes. H and I, blood glucose was measured in a non‐fasted state at the same time points as rectal temperature (n = 18–19/group). Significant interactions denoted by *** P < 0.001. A main effect of cold exposure is denoted by C and a main effect of exercise is denoted by Ex, followed by the corresponding P‐value. ††a main effect of cold P < 0.05.
Figure 3
Figure 3. Exercise and cold‐induced effects in eWAT
A–C, tissue mass of eWAT was recorded (A; n = 18–19/group) and H&E histology was completed to characterize morphology (B; scale bar: 50 μm; n = 4 images/group) and to quantify mean cell size (C). D, representative images of western blots and an example loading control via Ponceau S staining. E, western blot protein content of various lipolytic, mitochondrial and thermogenic proteins (n = 8–9/group). Significant interactions denoted by ** P < 0.01, *** P < 0.001. A main effect of cold exposure is denoted by C and a main effect of exercise is denoted by Ex, followed by the corresponding P‐value. [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 4
Figure 4. Exercise and cold‐induced effects in iWAT
A, tissue mass of iWAT was recorded following termination (n = 18–19/group). B, H&E histology was completed to characterize morphology; the black arrows point to examples of multilocular adipocytes, a typical characteristic of beige adipose tissue (scale bar: 100 μm; n = 4 images/group). C, percentage of multilocular cells within the cold‐exposed groups was quantified to determine the degree of multilocularity. D, Representative images of western blots and an example loading control via Ponceau S staining. E, western blot protein content of select lipolytic, mitochondrial and thermogenic proteins (n = 8–9/group). Significant interactions denoted by ** P < 0.01, *** P < 0.001. A main effect of cold exposure is denoted by C and a main effect of exercise is denoted by Ex, followed by the corresponding P‐value. [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 5
Figure 5. Cold has more pronounced effects than exercise on BAT
A, tissue mass of BAT from trained and untrained mice subjected to either RT or cold stress (n = 17–19/group). B, representative H&E stained images of BAT morphology (scale bar: 100 μm; n = 4 images/group). C, representative images of western blots and an example loading control via Ponceau S staining. D, western blot protein content of select lipolytic, mitochondrial and thermogenic proteins (n = 16/group). A main effect of cold exposure is denoted by C and a main effect of exercise is denoted by Ex, followed by the corresponding P‐value. [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 6
Figure 6. The metabolic effects of CL 316,243 in previously exercised or sedentary mice under anaesthesia
A, schematic design of the intervention. Following sedation, SED and Ex mice were injected with either saline (sedentary, SS; exercise, ExS) or CL 316,243 (sedentary, SCL; exercise, ExCL) and oxygen consumption (D and E) and energy expenditure (F and G) were recorded and the AUC was calculated. Mice were then terminated and NEFA (B) and glycerol (C) plasma concentrations were measured. n = 6–7/group. A main effect of CL 316,243 is denoted by CL and a main effect of exercise is denoted by Ex, followed by the corresponding P‐value. [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 7
Figure 7. The effects of pair‐feeding exercised mice to sedentary controls in comparison to exercised mice given free access to food
A and B, total food consumption was measured during a 48‐h cold intervention for the pair‐feeding experiment (A) and the hypothalamus was collected following termination to determine the content of proteins involved in satiety (B). C, additionally, changes in body mass were measured. D, rectal temperature was recorded and the AUC was calculated. E, rectal temperature is also shown at specific time points during cold exposure. F and G, likewise, blood glucose AUC was calculated (F) and the time points are shown (G). H and I, NEFA (H) and glycerol (I) plasma concentrations were measured. n = 8/group. Significant differences denoted by * P < 0.05, *** P < 0.001.
Figure 8
Figure 8. Exercise and cold‐induced effects in triceps and soleus muscle
A and B, triceps glycogen content was measured (A) alongside the change in glycogen of triceps (B) between SED and Ex mice (n = 9–10/group). C and D, additionally, mitochondrial protein content was measured in triceps via western blotting (C), and representative images are shown with an example Ponceau S stain as a loading control (D). E and F, similarly, soleus glycogen content (E) was measured and the changes in glycogen (F) between SED and Ex groups was calculated (n = 5–6/group). G and H, the same proteins as measured in triceps were also measured via western blotting in soleus (G) and the representative images are shown (H). N.D., not detectable. A main effect of cold exposure is denoted by C and a main effect of exercise is denoted by Ex, followed by the corresponding P‐value.
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