Cold stress in mice requires Nerve Growth Factor activity in brown fat and increases Osteocalcin expression in bone

Brown adipose tissue (BAT) is controlled by the sympathetic nervous system (SNS) and has the ability to dissipate energy through uncoupling protein-1 (UCP-1), influencing energy expenditure. Besides BAT, the SNS influences bone, and recent studies have demonstrated a positive correlation between BAT activity and bone. Nerve Growth Factor (NGF) genes are expressed in brain, white adipose tissue (WAT), BAT and bone where it coordinates brain and body reactions to challenges. Similarly Osteocalcin besides its role in bone metabolism acts as an hormone regulating glucose metabolism and brain. We previously showed that NGF and its receptor p75NTR genes are highly expressed in BAT versus brain in mice, suggesting that NGF may act as a regulator of energy. To further investigate the role of NGF and osteocalcin in bone and energy regulation we analyzed NGF and its receptor p75NTR and Osteocalcin mRNA from 3 months old mice after cold exposure. UCP-1 was used as positive control. Mice were divided into three groups: room temperature (RT), cold stress for 6h and 5 days (n = 5 for each group). Mice as control group were all placed at RT (23 °C) for 5 days, while the cold groups were placed at 4 °C for the abovementioned times. The mice were subsequently sacrificed and the interscapular BAT, bone and brain were analyzed for mRNA extraction. The exposure of 6 h to cold stress enhanced mRNA levels of UCP-1 and NGF genes by 3 and 2.5 fold vs controls, respectively, reducing mRNA of p75NTR by 19 fold. The UCP-1 gene was still up-regulated after 5 days of cold stress, the NGF gene was not affected and mRNA of the p75NTR gene was reduced by 7 fold vs controls. The mRNA NGF/NGFR genes were not affected in bone or brain following cold stress. The mRNA levels of osteocalcin in bone were upregulated following 6h and 5 days cold exposure vs controls. Osteocalcin gene in brain was downregulated following cold stress. Our study shows that NGF mRNA expression significantly increases after 6 hours of cold stress however with minor extent with respect to UCP-1. The enhanced mRNA level of NGF is observed in parallel with the decrease of NGF receptor gene expression. We found no change in NGF and p75NTR expression in brain or bone, but osteocalcin genes were upregulated in bone following cold stress. These results suggest that during cold stress when BAT-dependent thermogenesis is required, NGF activity is required, and osteocalcin may exert a local protective effect on bone mass.