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.

• <Figure 1 from Wisse>

• 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.