Genes that regulate appetite

Wisse, BE. and Schwartz, MW. The skinny on neurotrophins. Commentary on: Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR, Tecott LH, Reichardt LF.Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor.

Energy homeostasis (food intake, energy consumption, weight control) Regulated in part by hormones such as insulin and leptin that are present in proportion to the amount of body fat. Insulin and leptin act on neurons in the hypothalamus to reduce food intake and body fat stores.

Among the hypothalamic systems, the melanocortin pathway is critical in the control of body fat. Melanocortins are anorexigenic (inhibiting food intake) neuropeptides. Drugs that activate the melanocortin receptor (Mcr) reduce food intake Drugs that block Mcr cause hyperphagia and weight gain.

Melanocortins are derived from the pro-opiomelanocortin (POMC) peptide. In the mammalian forebrain, POMC (the melanocortin precursor) is produced only in neurons located in the hypothalamus, specifically in the arcuate nucleus (ARC). The ARC is a key brain area for control of energy homeostasis, and is activated by leptin. Conversely, leptin inhibits neurons adjacent to the POMC-expressing ones, which co-express two molecules that potently stimulate food intake – neuropeptides Y (NPY) and agouti-related peptide (AgRP).

BDNF is known as a neurotrophin that governs brain development and neuronal plasticity. The idea that it also participates in energy homeostasis was triggered by experiments showing reduced food intake, body weight and blood glucose levels after obese mice were treated with BDNF.

Xu et al show that mice with reduced expression of the BDNF receptor TrkB suffer from hyperphagia and obesity. They also showed that, in rats, BDNF expression is reduced in the VMN region of the hypothalamus in response to fasting, but does not change in any other brain areas.

The effects of fasting on BDNF levels were partially reversed by administration of a melanocortin receptor agonist. These results suggest that reduced hypothalamic BDNF can be added to the list of potential mechanisms contributing to the hyperphagic response to fasting.

Are BDNF receptors good drug targets? Clinical use of a neuronal growth factor to control appetite raises obvious concerns about the potential for aberrant growth and neoplasia. Obesity drugs must be given over long periods to maintain efficacy, so exposure would be long term, and give greater opportunity for adverse effects. Weight loss medications have a mixed record of safety and efficacy, so further research is needed.