IL-15 Receptor Deletion Results in Circadian Changes of Locomotor and Metabolic Activity

Abstract

Interleukin-15 (IL-15) is a cytokine produced in the normal brain that acts on its specific receptor IL-15Rα and co-receptors IL-2Rβ and IL-2Rγ in neuronal cells. The functions of the cerebral IL-15 system, however, are not yet clear. To test the hypothesis that IL-15Rα regulates metabolic activity and body temperature, we quantified the specific metabolic phenotype of IL-15Rα knockout mice. These normal-appearing mice were leaner with lower fat composition. During the entire circadian cycle, the knockout mice had a significantly higher acrophase in locomotor activity and heat dissipation. During the light phase, there was significantly greater food intake, oxygen consumption, and carbon dioxide production. The difference in the dark and light phases suggests that IL-15Rα participates in circadian rhythm regulation. The higher oxygen consumption in the light phase indicates adaptive thermogenesis in the knockout mice. The body temperature of the receptor knockout mice was significantly higher than the control in the light phase, and this was mainly caused by a large difference occurring between 0600 and 0900 h. In addition to the metabolic chamber studies and circadian rhythm analyses, qPCR of hypothalamic homogenates indicated higher mRNA expression of orexin and transient receptor potential vanilloid 4 cation channels. Consistent with a direct role of IL-15Rα in the hypothalamus, IL-15 treatment of the wild-type mice induced c-Fos expression in the preoptic area. We conclude that activation of hypothalamic neurons by IL-15 in mice contributes to thermoregulation and modifies the metabolic phenotype.

Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles

“…This is interesting, given that muscle/lean muscle mass ratios of non-skeletal muscle organs from IL-15Rα-KO mice, such as the heart, spleen, and kidneys, were not significantly different from those of B6129 controls. These data demonstrate a preferential effect of loss of IL-15Rα on normalized skeletal muscle weight, which may reflect alterations in overall body metabolism, as previously suggested (14). He et al (14) measured horizontal and vertical beam breaks in a metabolic chamber and reported a significant increase in activity levels of female IL-15Rα-KO compared with control mice.…”

“…These data demonstrate a preferential effect of loss of IL-15Rα on normalized skeletal muscle weight, which may reflect alterations in overall body metabolism, as previously suggested (14). He et al (14) measured horizontal and vertical beam breaks in a metabolic chamber and reported a significant increase in activity levels of female IL-15Rα-KO compared with control mice. Similarly, we observed that male IL-15Rα-KO mice produced 6.3-fold more wheel revolutions compared with B1629 control mice in cage wheel running experiments and had a larger number of ambulatory photobeam breaks in the light and dark cycles.…”

“…However, this result has not been replicated in vivo, as increasing IL-15 levels in wild-type experimental animals has not resulted in muscle hypertrophy, suggesting that IL-15 and IL-15Rα interactions in vivo may be more complex than simple ligand-receptor binding (11)(12)(13). Recently, studies have revealed differing neurological and locomotor activities when comparing IL-15Rα-KO, IL-15-KO, and IL-2Rβ-KO mice (14,15). The data demonstrate that unique roles for IL-15Rα and IL-15 in vivo exist, since interruption of IL-15 signaling by deletion of either IL-15 or IL-15Rα resulted in differing mouse phenotypes.…”

“…Indeed, IL-15/IL-15Rα complex formation leads to an increase in biological activity and half-life of IL-15, and this complex has been hypothesized to be the predominant form of the molecule (21,(24)(25)(26). Mice that lack either IL-15 or IL-15Rα have unique phenotypes (14,15,27,28), and multiple isoforms of IL-15Rα exist that can either potentiate or inhibit the effects of IL-15 (29)(30)(31)(32)(33). Thus, IL-15/IL-15Rα interactions and associated signaling are extremely complex, and IL-15Rα likely represents a mechanism for controlling IL-15 signaling capacity.…”

Functional Genomic Architecture of Predisposition to Voluntary Exercise in Mice: Expression QTL in the Brain

“…Interleukin (IL)-15a (cytokine-specific receptor) knockout mice have been shown to exhibit a leaner phenotype with lower fat composition, elevated home-cage activity and heat dissipation (light and dark phases), greater food intake (light phase only), and raised oxygen consumption (light phase only) (He et al 2010). In the present study, an eQTL for IL15 was mapped to Chr.…”