"Turning up the heat": Role of neurotrophic batokines in the postnatal maturation and remodelling of brown adipose tissue in deer mice.

Abstract

Activation of brown adipose tissue (BAT) thermogenesis impacts energy balance and must be tightly regulated. Several neurotrophic factors, expressed in BAT of adult laboratory rodents, have been implicated in remodelling the sympathetic neural network to enhance thermogenesis (e.g., NGF, NRG4 and S100b). Here, we compare for the first time the relative roles of three neurotropic 'batokines' in establishing/remodelling innervation during postnatal development and adult cold stress. We used lab-reared P. maniculatus, which rely heavily on BAT-based thermogenesis for survival in the wild, beginning between postnatal days (P) 8 and 10. BAT sympathetic innervation was enhanced from P6-10, and exogenous NGF, NRG4, and S100b stimulated neurite outgrowth from P6 sympathetic neurons. Endogenous BAT protein stores and/or gene expression of NRG4, S100b, and calsyntenin-3ß (which regulates S100b secretion), remained high and constant during development. However, endogenous NGF was low and ngf mRNA was undetectable. Conditioned media (CM) from cultured P10 BAT slices stimulated neurite outgrowth from sympathetic neurons in vitro that was inhibited by antibodies against all three growth factors. P10 CM had significant amounts of secreted NRG4 and S100b protein, but not NGF. By contrast, BAT slices from cold-acclimated adults released significant amounts of all three factors relative to thermoneutral controls. These data suggest that while neurotrophic batokines regulate sympathetic innervation in vivo, their relative contributions differ depending on life stage. They also provide novel insight into the regulation of BAT remodelling and BAT's secretory role, which are both critical to our understanding of mammalian energy homeostasis.