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-15Ralpha and co-receptors IL-2Rbeta and IL-2Rgamma in neuronal cells. The functions of the cerebral IL-15 system, however, are not yet clear. To test the hypothesis that IL-15Ralpha regulates metabolic activity and body temperature, we quantified the specific metabolic phenotype of IL-15Ralpha 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-15Ralpha 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-15Ralpha 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.

Figure 1

Basic metabolic phenotype of IL15Rα KO mice. a There was no difference in body weight. b There was a significant reduction of fat composition and greater lean mass. *p<0.05. n=9/group

Figure 2

IL15Rα KO mice had higher body temperature. a The difference of resting temperature at 1100–1200 h was 0.8 C. **p<0.01. n=9/group. b The difference in body temperature was most pronounced around the transition from the dark phase to the light phase, occurring at 0600–0900 h

Figure 3

IL15Rα KO mice had higher locomotor activity both during the dark and light phase (a–b), with greater heat dissipation (c). Both variables showed a significant difference in the MESOR by cosinor analysis (p<0.05). Total horizontal plane activity was significantly higher in both the dark and light phases (***p<0.005)

Figure 4

IL15Rα KO mice had a trend toward a higher MESOR in both oxygen consumption (a VO₂, p=0.08) and carbon dioxide production (c VCO₂, p=0.06) (n=7/group). The difference in the light phase was significant for both VO₂ (b) and VCO₂ (d). *p<0.05

Figure 5

IL15Rα KO mice showed greater food intake in the light phase (a–b). n=7/group. ***p<0.005

Figure 6

IL15Rα KO mice showed a significantly higher mRNA for TRPV4 (a p<0.05) and a trend toward increased orexin mRNA (b p= 0.08) in the hypothalamus. n=5/group

Figure 7

The IL15-treated mice had a higher number of c-fos immunoreactive cells in the medial portion of the preoptic area 3 h after iv injection of IL15