Genes that regulate appetite

1
Genes that regulate appetite
2

• 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.

3

• 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.

4

• 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.
• ltFigure 1 from Wissegt

5

• 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).

6

• 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.

7

• 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.

8

• 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.

9

• 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.