Low levels of physical activity increase metabolic responsiveness to cold in a rat (Rattus fuscipes)

Abstract

Background: Physical activity modulates expression of metabolic genes and may therefore be a prerequisite for metabolic responses to environmental stimuli. However, the extent to which exercise interacts with environmental conditions to modulate metabolism is unresolved. Hence, we tested the hypothesis that even low levels of physical activity are beneficial by improving metabolic responsiveness to temperatures below the thermal neutral zone, thereby increasing the capacity for substrate oxidation and energy expenditure.

Methodology/principal findings: We used wild rats (Rattus fuscipes) to avoid potential effects of breeding on physiological phenotypes. Exercise acclimation (for 30 min/day on 5 days/week for 30 days at 60% of maximal performance) at 22°C increased mRNA concentrations of PGC1α, PPARδ, and NRF-1 in skeletal muscle and brown adipose tissue compared to sedentary animals. Lowering ambient temperature to 12°C caused further increases in relative expression of NRF-1 in skeletal muscle, and of PPARδ of brown adipose tissue. Surprisingly, relative expression of UCP1 increased only when both exercise and cold stimuli were present. Importantly, in sedentary animals cold acclimation (12°C) alone did not change any of the above variables. Similarly, cold alone did not increase maximum capacity for substrate oxidation in mitochondria (cytochrome c oxidase and citrate synthase activities) of either muscle or brown adipose tissue. Animals that exercised regularly had higher exercise induced metabolic rates in colder environments than sedentary rats, and temperature induced metabolic scope was greater in exercised rats.

Conclusions/significance: Physical activity is a necessary prerequisite for the expression of transcriptional regulators that influence a broad range of physiological functions from energy metabolism to cardiovascular function and nutrient uptake. A sedentary lifestyle leads to decreased daily energy expenditure because of a lack of direct use of energy and a muted metabolic response to ambient temperature, which can be reversed even by low levels of physical activity.

Figure 1. Relative expression of transcription factors and UCP1.

Relative expression (mean ± s.e.m) of transcriptional regulators PGC-1α, NRF-1, and PPARδ in skeletal muscle (A) and BAT (B), and UCP1 in BAT (B) from cold exercised (blue bars), warm exercised (red bars), cold sedentary (blue striped bars) and warm sedentary (red striped bars) rats. The relative expression of all genes increased with exercise in both skeletal muscle and BAT. There were significant interactions between thermal acclimation and exercise for NRF-1 relative expression in muscle, and for PPARδ expression in BAT. UCP1 relative expression did not increase in response to either cold or exercise alone, but only when those two stimuli coincided. Significant differences are indicated by different letters above each column.

Figure 2. PGC-1α co-varies with PPARδ, NRF-1 and UCP1.

There were significant associations between PGC-1α and PPARδ (a), NRF-1 (b) and UCP1 (c) relative expression in BAT, and between PGC-1α and PPARδ (d), NRF-1 (e) in skeletal muscle. Results form regression analyses are shown in each panel, and the axes are on a logarithmic scale.

Figure 3. Enzyme activities in skeletal muscle and BAT from cold and warm acclimated sedentary and exercised rats.

Activity (µmol substrate converted g⁻¹ wet tissue; mean ± s.e.m) of cytochrome c oxidase (COX; A and B), citrate synthase (CS; C and D) and lactate dehydrogenase (LDH; E and F) of cold exercised (blue bars), warm exercised (red bars), cold sedentary (blue hatched bars) and warm sedentary (red hatched bars) rat skeletal muscle and brown adipose tissue (BAT). Exercise had a significant effect on all enzyme activities, but the effect of cold exposure alone was limited. Letters above each column indicate significant differences.

Figure 4. Oxygen consumption and metabolic scopes of cold and warm acclimated sedentary and exercised rats.

Resting (RMR; A) and exercise induced (EIMR; C) metabolic rates (ml O₂.g⁻¹.hr⁻¹) in cold exercised (blue bars), warm exercised (red bars), cold sedentary (blue hatched bars) and warm sedentary (red hatched bars) rats (mean ± s.e.m) measured at different ambient test temperatures (12°C and 22°C). Resting metabolic rates (A) were lowest in exercised animals at 22°C, and exercised induced metabolic rates (C) were highest in cold acclimated exercised rats. Temperature induced metabolic scope (RMR at 12°C/RMR at 22°C; B) was greatest in exercised rats, and exercise induced metabolic scope (EIMR/RMR; D) was greatest in cold acclimated exercised rats at 12°C. Letters above columns indicate significant differences; please note however that there were also significant interactions which are difficult to represent graphically.

Figure 5. Critical sustained running speed of cold and warm acclimated sedentary and exercised rats.

Critical sustained running speed (U_crit) of cold exercised (blue bars), warm exercised (red bars), cold sedentary (blue hatched bars) and warm sedentary (red hatched bars) rats at 12°C and 22°C (mean ± s.e.m). There was a three-way interaction between exercise, thermal acclimation, and test temperature. Cold acclimated animals performed best, and warm acclimated animal performed worst at 12°C. Cold acclimated and exercised rats performed worst at 22°C.