Direct effects of ciliary neurotrophic factor on brown adipocytes: evidence for a role in peripheral regulation of energy homeostasis

Abstract

Ciliary neurotrophic factor (CNTF) plays an important role in regulating neuronal growth. Recently, central anorexigenic effects of this cytokine have been characterized. However, peripheral effects on tissues that actively contribute to the regulation of energy homeostasis have not been described. Here, we report direct potent and selective effects of CNTF on growth factor and metabolic signalling intermediates in mouse brown adipocytes. CNTF stimulates STAT3, MAP kinase, Akt, and p70 S6 kinase. We find that, next to mediating Akt and p70 S6 kinase activation, both phosphatidylinositol 3-kinase and protein kinase C are separately acting, main intermediates for inducing mitogen-activated protein (MAP) kinase activation. On a functional level, CNTF enhances 3-adrenergic induction of uncoupling protein-1. Thus, these results demonstrate direct effects of CNTF on adipose tissue signalling and metabolism and suggest a novel role for this cytokine in the peripheral regulation of energy homeostasis.

JAK2 promotes brown adipose tissue function and is required for diet- and cold-induced thermogenesis in mice

“…In addition to crosstalk with adrenergic signalling, several hormones and growth factors could directly regulate BAT function via JAK2-STAT signalling. CNTF, leptin and GH all activate JAK2 and are known to regulate the expression of thermogenic genes [17,20,21,24,41]. The observed reduction in UCP1 expression in Jak2-deficient BAT could therefore be due to the concerted action of all these hormones.…”

“…JAK2 is activated in response to a number of cytokines and hormones that regulate brown and beige adipocytes such as growth hormone (GH) [17,18], prolactin [19], leptin [20,21], IL-6 [22,23] and ciliary neurotrophic factor (CNTF) [24]. In this study, we investigated the role of JAK2 in thermogenesis, particularly in response to metabolic and thermal stress.…”

gp130 receptor ligands as potential therapeutic targets for obesity

“…Two subsequent in vitro studies supported the concept that CNTF may act on peripheral target tissues in a manner independent of central mediation. CNTF was shown to increase the mRNA expression and/or phosphorylate several proteins in brown adipocytes (94) as well as in 3T3-L1 preadipocytes and mature adipocytes (95). In the latter study, the authors noted that this effect occurred in spite of the fact that adipocytes do not express CNTFRa, suggesting that the IL-6Ra may serve as an a receptor for CNTF in adipocytes (51).…”

Cold tolerance, cold-induced hyperphagia, and nonshivering thermogenesis are normal in α1-AMPK−/−mice

“…A common factor in these five genes is that they have established effects on nonshivering thermogenesis. Specifically, Cntfr, Trh, and Lepr (via leptin signaling) are "prothermogenic" in brown adipocytes, either directly increasing nonshivering thermogenesis or facilitating sympathetically induced nonshivering thermogenesis (1,14,22,31). In contrast, Tnf has been reported to inhibit nonshivering thermogenesis, and Nmb inhibits the prothermogenic action of Trh (23,26).…”