Abstract
The correlation between the Ngf/p75ntr-Ntrk1 and Bdnf, Osteocalcin-Ost/Gprc6a and Oxytocin-Oxt/Oxtr genes, was challenged investigating their mRNA levels in 3 months-old mice after cold-stress (CS). Uncoupling protein-1 (Ucp-1) was used as positive control. Control mice were maintained at room temperature T = 25°C, CS mice were maintained at T = 4°C for 6 h and 5-days (N = 15 mice). RT-PCR experiments showed that Ucp-1 and Ngf genes were up-regulated after 6 h CS in brown adipose tissues (BAT), respectively, by 2 and 1.5-folds; Ucp-1 was upregulated also after 5-days, while Ngfr (p75ntr) and Ntrk1 genes were downregulated after 6 h and 5-days CS in BAT. NGF and P75NTR were upregulated in bone and testis following 5-days, and P75NTR in testis after 6 h CS. Bdnf was instead up-regulated in bone following 5-days CS and down-regulated in testis. OST was upregulated by 16 and 3-fold in bone and BAT, respectively, following 5-days CS. Gprc6a was upregulated after 6 h in brain, while Bglap (Ost) gene was downregulated. Oxt gene was upregulated by 5-fold following 5-days CS in bone. Oxtr was upregulated by 0.5 and 0.3-fold, respectively, following 6 h and 5-days CS in brain. Oxtr and Oxt were downregulated in testis and in BAT. The changes in the expression levels of control genes vs. genes following 6 h and 5-days CS were correlated in all tissues, but not in BAT. Correlation in BAT was improved eliminating Ngfr (p75ntr) data. The correlation in brain was lost eliminating Oxtr data. In sum, Ucp-1 potentiation in BAT after cold stress is associated with early Ngf-response in the same tissue and trophic action in bone and testis. In contrast, BDNF exerts bone and neuroprotective effects. Similarly to Ucp-1, Bglap (Ost) signaling is enhanced in bone and BAT while it may exert local neuroprotective effects thought its receptor. Ngfr (p75ntr) regulates the adaptation to CS through a feed-back loop in BAT. Oxtr regulates the gene-response to CS through a feed-forward loop in brain. Overall these results expand the understanding of the physiology of these molecules under metabolic thermogenesis.
Highlights
Ucp-1 and Nerve Growth Factor (Ngf) mRNA levels were significantly enhanced after 6 h cold stress in Brown adipose tissue (BAT) respectively by 2 (p = 0.001) and 1.5-fold (p = 0.013) vs. controls, while Ngfr (p75ntr) and Ntrk1 genes were down-regulated by 0.95 and 0.92 folds, respectively (p = 0.001 and p = 0.0002) (Figure 1)
We show that the expression of Ngf/Bdnf, osteocalcin and oxytocin mRNA after cold stress is characterized by early response of these genes in brain and BAT and late response in bone consistent with a fast adaptation to challenges
During cold stress in mice Ucp-1 increase in BAT is associated with early Ngf gene response in the same tissue and down-regulation of Ngfr (p75ntr) and Ntrk1 receptors
Summary
Nerve Growth Factor (Ngf)/Brain-derived Neurotrophic Factor (Bdnf ), osteocalcin (Bglap) and oxytocin (Oxt) share common effects regulating energy, bone mass, reproduction and neuronal functions, suggesting a coordinated regulation (Fulzele et al, 2010; Oury et al, 2011; Camerino et al, 2012; Karsenty, 2012). The carboxylated osteocalcin has local effect leading to bone remodeling stimulating osteoblast, while the uncarboxylated form of osteocalcin acts as a hormone regulating insulin secretion and sensitivity (Ferron et al, 2010; Fulzele et al, 2010; Oury et al, 2011; Karsenty, 2012). NGF and BDNF levels are significantly altered in metabolic syndrome and in stress conditions (Unger et al, 2007; Sornelli et al, 2009)
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