Regulatory changes contribute to the adaptive enhancement of thermogenic capacity in high-altitude deer mice

Abstract

In response to hypoxic stress, many animals compensate for a reduced cellular O(2) supply by suppressing total metabolism, thereby reducing O(2) demand. For small endotherms that are native to high-altitude environments, this is not always a viable strategy, as the capacity for sustained aerobic thermogenesis is critical for survival during periods of prolonged cold stress. For example, survivorship studies of deer mice (Peromyscus maniculatus) have demonstrated that thermogenic capacity is under strong directional selection at high altitude. Here, we integrate measures of whole-organism thermogenic performance with measures of metabolic enzyme activities and genomic transcriptional profiles to examine the mechanistic underpinnings of adaptive variation in this complex trait in deer mice that are native to different elevations. We demonstrate that highland deer mice have an enhanced thermogenic capacity under hypoxia compared with lowland conspecifics and a closely related lowland species, Peromyscus leucopus. Our findings suggest that the enhanced thermogenic performance of highland deer mice is largely attributable to an increased capacity to oxidize lipids as a primary metabolic fuel source. This enhanced capacity for aerobic thermogenesis is associated with elevated activities of muscle metabolic enzymes that influence flux through fatty-acid oxidation and oxidative phosphorylation pathways in high-altitude deer mice and by concomitant changes in the expression of genes in these same pathways. Contrary to predictions derived from studies of humans at high altitude, our results suggest that selection to sustain prolonged thermogenesis under hypoxia promotes a shift in metabolic fuel use in favor of lipids over carbohydrates.

Fig. 1.

Mass-specific maximum rates oxygen consumption (VO_2max) for highland deer mice (HA), lowland deer mice (LA), and a lowland outgroup species, Peromyscus leucopus (PL). Data are presented as means ±1 SEM.

Fig. 2.

Respiratory exchange ratios (A) and mass-specific rates of O₂ consumption (B) during combined cold and hypoxia challenge. Data are presented as 1-min averages ±1 SEM.

Fig. 3.

Proportion of genes in the fatty-acid oxidation (Upper) and OXPHOS (Lower) pathways that are differentially expressed (>20% difference in transcript abundance) in pairwise comparisons among high-altitude deer mice (HA), low-altitude deer mice (LA) and P. leucopus (PL). The black bars indicate genes that are up-regulated in HA (HA vs. LA and HA vs. PL comparisons) and LA (LA vs. PL comparison), whereas gray bars indicate those that are down-regulated in the focal group. Asterisks indicate significant differences in the proportion of up- and down-regulated genes (exact bionomical test; *P < 0.05, **P < 0.01, ***P < 0.001).