The Role of BDNF in the Regulation of Body Weight and Energy Homeostasis

Brain-derived neurotrophic factor (BDNF) has been shown to play a crucial role in the regulation of neuronal development including survival, differentiation, and growth of existing and new neurons [1]. However, BDNF has also been identified as a key component of the hypothalamic pathway that controls body weight and energy homeostasis [2]. 

In the hypothalamus, BDNF mRNA is found in most of its functional units, i.e. paraventricular, arcuate, ventromedial and dorsomedial nuclei as well as the lateral hypothalamic area and the median eminence. Together with the hippocampus, the hypothalamus is the brain structure that contains the highest BDNF mRNA and protein levels. BDNF is largely coexpressed with its tyrosine kinase receptor trkB, suggesting that autocrine or paracrine mechanisms account for the general modality of BDNF action in the CNS (reviewed in [3]).
It has been shown that BDNF levels are low in obese people [4]. Interestingly, on the contrary, it has been found that serum levels of BDNF are significantly increased in obese women and significantly reduced in female patients with anorexia nervosa or bulimia nervosa compared to age-matched normal control subjects. Since BDNF has been described to exert a satiating effect, this may represent a long-term adaptation to counteract decreased caloric ingestion in anorexic and bulimic individuals or the increased one in obese subjects [5-7]. In humans, obesity and obesity-related symptoms have been associated with functional loss of one copy of the BDNF gene [8] and with a de novo mutation in the BDNF receptor Ntrk2 gene [9].
In animal studies, obese phenotypes are found in Bdnf-heterzygous mice associated with hyperphagia, hyperactivity, hyperleptinemia, hyperinsulinemia, and hyperglycemia [10, 11]. Both central and peripheral administration of BDNF decreases food intake, increases energy expenditure, and leads to weight loss [12, 13]. A recent study suggests that gene transfer of BDNF has a therapeutic efficacy in a mouse model of obesity and diabetes, leading to marked weight loss and alleviation of obesity-associated insulin resistance [14]. Knowledge of the exact molecular mechanisms of how BDNF regulates body weight and energy homeostasis is sparse and must be further elucidated.
 
[1] Hofer and Barde, Nature, 1988
[2] Wisse and Schwartz, Nat Neurosci, 2003
[3] Tapia-Arancibia et al., Front Neuroendocrinol, 2004
[4] Krabbe et al., Diabetologia, 2007
[5] Nakazato et al., Biol Psychiatry, 2003
[6] Montelone et al., Psychosom Med, 2004
[7] Montelone et al., Psychol Med, 2005
[8] Gray et al., Diabetes, 2006
[9] Yeo et al., Nat Neurosci, 2004
[10] Kernie et al., EMBO J, 2000
[11] Rios et al., Mol Endocrinol, 2001
[12] Pelleymounter et al., Exp Neurol, 1995
[13] Bariohay et al., Endocrinology, 2005
[14] Cao et al., Nat Med, 2009

By Charlotte Klein, PhD Student Medical Neurosciences, AG Neural Regeneration and Plasticity  

This article originally appeared December 2012 in "Fat Gut or Fat Brain"