BDNF and the central control of feeding: accidental bystander or essential player?

Abstract

A considerable body of evidence links diminished brain-derived neurotrophic factor (BDNF) signaling to energy balance dysregulation and severe obesity in humans and rodents. Because BDNF exhibits broad neurotrophic properties, the underpinnings of these effects and its true role in the central regulation of food intake remain topics of debate in the field. Here, I discuss recent evidence supporting a critical role for this neurotrophin in physiological mechanisms regulating nutrient intake and body weight in the mature brain. They include reports of functional interactions of BDNF with central anorexigenic and orexigenic signaling pathways and evidence of recognized appetite hormones exerting neurotrophic effects similar to those of BDNF.

Figure 1. Interactions of BDNF and TrkB signaling with known anorexigenic pathways

(a) Representative brain sections containing arcuate nucleus (ARC) or dorsomedial hypothalamus (DMH) from wild type (+/+) and knock-in mice (k/k) with depletion of dendritically-targeted BDNF mRNA. They show decreased neuronal activity as marked by c-fos immunoreactivity in k/k compared to WT mice following systemic vehicle and leptin treatment. Scale bar, 100 μM. (b) Food intake following systemic vehicle or leptin administration in wild type (+/+) and young non-obese knock-in mice (k/k) with depletion of dendritically-targeted BDNF transcripts. *, p < 0.05. (c) Cumulative food intake was measured in fasted TrkB^F616A mice after various pharmacological treatments. These mice harbor a knock-in mutation in TrkB that results in the receptor being fully functional, but its kinase activity can be blocked by use of pharmacological agents such as the analog-sensitive kinase allele (ASKA) inhibitor 1NaPP1. The anorexigenic effects of CCK were reversed in the presence of 1NaPP1 in TrkB^F616A mice. These findings demonstrate that CCK-induced suppression of feeding requires TrkB activation. *, p < 0.0001; **, p < 0.05. Adapted, with permission, from [47] (a and b) and [60] (c).

Figure 2. BDNF and TrkB expression and signaling in the feeding neurocircuitry

Diagram depicts BDNF and TrkB expression in brain regions involved in the regulation of homeostatic and hedonic food intake. BDNF is shown in black font in regions where it is expressed and in red font in areas where it is synthesized and has been demonstrated to induce appetite suppression. Peripheral and central factors regulating expression of BDNF and TrkB in homeostatic and reward feeding pathways are also shown. Dashed arrow represents a previously proposed positive effect of POMC neurons in the Arc on BDNF expression in the VMN. Finally, putative mechanisms downstream of BDNF facilitating its satiety effects are shown in the VTA, PVN and the Arc, where the question mark reflects that the endogenous source of BDNF for this negative effect on NPY expression is unknown. Abbreviations: Arc, arcuate nucleus; CCK, cholecystokinin; CRH, corticotropin releasing hormone; DA, dopamine; DMH, dorsomedial hypothalamus; DVC, dorsal vagal complex; LH, lateral hypothalamus; MC4-R, melanocortin 4 receptor; NAc, nucleus accumbens; PP, pancreatic polypeptide; PVN, paraventricular nucleus; SF-1, steroidogenic factor 1; Uro, urocortin; VMN, ventromedial nucleus; VTA, ventral tegmental area; 3V, third ventricle.