Interleukin-6 is important for regulation of core body temperature during long-term cold exposure in mice

Abstract

Interleukin-6 (IL6) is a cytokine important for inducing the fever response during infection and has been reported to uphold core body temperature during acute cold exposure. Recently it has also been indicated that IL6 in serum increases in cold-exposed mice. The aim of the present study was to investigate if IL6 is important for core body temperature regulation following a long-term cold exposure in mice. Experiments were performed with global IL6 deficient (-/-) mice, mice with conditional IL6 receptor α (IL6Rα) knockdown in the central nervous system (CNS; IL6Rα^NesCre) and appropriate wild-type (Wt) controls. All mice were placed in a cold environment (4°C) for 6 days. Core body temperature and oxygen consumption were measured by telemetry probes and indirect calorimetry at room temperature (20°C), and during the first and last day of cold exposure. Brain stem, hypothalamus and white and brown adipose tissues from the cold-exposed mice were subjected to gene expression analysis. After 6 days in 4°C, the IL6-/- mice exhibited significantly lower body temperature and oxygen consumption compared with Wt mice (P<0.05). The IL6Rα^NesCre mice also exhibited lower body temperature compared with Wt^NesCre controls during the last day of cold exposure (P<0.05). Furthermore, an increase in the mRNA level of brain-derived neurotrophic factor (Bdnf) was detected in the brain stem of both IL6-/- and IL6Rα^NesCre mice compared with the Wt groups (P<0.05). The finding that body temperature was decreased in IL6-/- and IL6Rα^NesCre mice indicates a decrease in thermogenesis in these animals. Bdnf has previously been indicated to increase body temperature and could in the present study be a mechanistic factor involved in counteracting the low body temperature in IL6-/- and IL6Rα^NesCre mice. These results suggest that IL6 is not only involved in body temperature regulation during infection, but also during long-term cold exposure, probably through mechanisms in the CNS.

Keywords: body temperature; brain stem; brown adipose tissue; cold exposure; energy expenditure; hypothalamus; interleukin-6; thermogenesis.

Figure 1.

Physiological parameters during cold exposure in IL6−/− mice. (A) Body weight, (B) food intake, (C) body temperature, (D) oxygen consumption (VO₂) and (E) locomotor activity in Wt (n=10) and IL6-deficient (IL6−/−; n=10) mice at baseline (20°C) and during cold exposure (4°C). Data are presented as mean ± standard error of the mean. *P<0.05. IL6, interleukin-6; Wt, wild-type.

Figure 2.

Physiological parameters during cold exposure in IL6Rα^NesCre mice. (A) Body weight, (B) food intake, (C) body temperature, (D) oxygen consumption (VO₂) and (E) locomotor activity in IL6Rα^+/+ Nestin-Cre (Wt^NesCre; n=10) and IL6Rα^loxP/loxP Nestin-Cre (IL6Rα^NesCre; n=6) mice at baseline (20°C) and during cold exposure (4°C). Data are presented as mean ± standard error of the mean. *P<0.05. IL6Rα, interleukin-6 receptor α; Wt, wild-type.

Figure 3.

mRNA expression in brain from mice exposed to 4°C for 6 days. mRNA expression in (A and B) brain stem and (C and D) hypothalamus from Wt (n=10) and IL6-deficient (IL6−/−; n=10) mice and from IL6Rα^+/+ Nestin-Cre (Wt^NesCre; n=10) and IL6Rα^loxP/loxP Nestin-Cre (IL6Rα^NesCre; n=6) mice. Data are presented as mean ± standard error of the mean. *P<0.05. IL6, interleukin-6; IL6Rα, interleukin-6 receptor α; Wt, wild-type; Bdnf, brain-derived neurotrophic factor; Gcg, preproglucagon; Th, tyrosine hydroxylase; Agrp, agouti related protein; Npy, neuropeptide Y; Cntf, ciliary neurotrophic factor; Ucp2, uncoupling protein 2.

Figure 4.

mRNA expression in adipose tissue from mice exposed to 4°C for 6 days. mRNA expression in (A and B) BAT and (C and D) WAT from Wt (n=10) and IL6-deficient (IL6−/−; n=10) mice and from IL6Rα^+/+ Nestin-Cre (Wt^NesCre; n=10) and IL6Rα^loxP/loxP Nestin-Cre (IL6Rα^NesCre; n=6) mice. Data are presented as mean ± standard error of the mean. *P<0.05. IL6, interleukin-6; IL6Rα, interleukin-6 receptor α; Wt, wild-type; BAT, brown adipose tissue; WAT, white adipose tissue; Ucp1, uncoupling protein 1; Pgc1a, peroxisome proliferative activated receptor γ, coactivator 1-α; Fgf21, fibroblast growth factor 21; Npy, neuropeptide Y; Th, tyrosine hydroxylase.