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.

Regulation of Energy Expenditure and Brown/Beige Thermogenic Activity by Interleukins: New Roles for Old Actors

“…Thus, IL6 deficient mice exhibited decreased NE levels after stress challenge but similar increases in EE to those found in control mice after peripheral NE treatment. In line with these findings, lower rectal or core body temperatures than controls have been reported in other mouse models with tissue specific IL6 [ 195 ] or IL6RA deletion [ 196 ] (muscle and CNS) when maintained at warm or cold environments.…”

Interleukin-6 released from differentiating human beige adipocytes improves browning

“…IL-6 -/mice develop obesity during aging mostly because of the missing effects of the cytokine on the central nervous system [43]. Recently, it was shown that these mice have reduced core body temperature and energy expenditure during long-term cold exposure [44]. Mice overexpressing IL-6 and the soluble IL-6R are significantly smaller and have a decreased body weight including markedly reduced body fat in all regions as compared to wild type mice [45].…”

Inflammatory Signaling and Brown Fat Activity

“…Interleukin 6 (IL-6) is secreted by brown adipocytes upon β-adrenergic activation (62). Chronic elevation of IL-6 in the CNS leads to increased UCP1 in BAT, but not in denervated BAT tissue which suggest a central role in IL-6-dependent promotion of thermogenesis (174). Signaling by IL-6 promotes M2 macrophage polarization in BAT (175).…”