Glutamate mediates the function of melanocortin receptor 4 on Sim1 neurons in body weight regulation

Cell Metab. 2013 Dec 3;18(6):860-70. doi: 10.1016/j.cmet.2013.11.003.

Abstract

The melanocortin receptor 4 (MC4R) is a well-established mediator of body weight homeostasis. However, the neurotransmitter(s) that mediate MC4R function remain largely unknown; as a result, little is known about the second-order neurons of the MC4R neural pathway. Single-minded 1 (Sim1)-expressing brain regions, which include the paraventricular nucleus of hypothalamus (PVH), represent key brain sites that mediate melanocortin action. We conditionally restored MC4R expression in Sim1 neurons in the background of Mc4r-null mice. The restoration dramatically reduced obesity in Mc4r-null mice. The anti-obesity effect was completely reversed by selective disruption of glutamate release from those same Sim1 neurons. The reversal was caused by lower energy expenditure and hyperphagia. Corroboratively, selective disruption of glutamate release from adult PVH neurons led to rapid obesity development via reduced energy expenditure and hyperphagia. Thus, this study establishes glutamate as the primary neurotransmitter that mediates MC4Rs on Sim1 neurons in body weight regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Body Weight* / drug effects
  • Energy Metabolism / drug effects
  • Female
  • Glutamic Acid / metabolism*
  • Hyperphagia
  • Male
  • Mice
  • Mice, Knockout
  • Neurons / metabolism*
  • Obesity / etiology
  • Obesity / metabolism
  • Paraventricular Hypothalamic Nucleus / drug effects
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Peptides, Cyclic / pharmacology
  • Potassium Chloride / pharmacology
  • RNA, Messenger / metabolism
  • Receptor, Melanocortin, Type 4 / deficiency
  • Receptor, Melanocortin, Type 4 / genetics
  • Receptor, Melanocortin, Type 4 / metabolism*
  • Repressor Proteins / metabolism*
  • Vesicular Glutamate Transport Protein 2 / genetics
  • Vesicular Glutamate Transport Protein 2 / metabolism
  • alpha-MSH / analogs & derivatives
  • alpha-MSH / pharmacology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Peptides, Cyclic
  • RNA, Messenger
  • Receptor, Melanocortin, Type 4
  • Repressor Proteins
  • Sim1 protein, mouse
  • Slc17a6 protein, mouse
  • Vesicular Glutamate Transport Protein 2
  • melanotan-II
  • Glutamic Acid
  • alpha-MSH
  • Potassium Chloride