Age-dependent changes in amino acid phenotype and the role of glutamate release from hypothalamic proopiomelanocortin neurons

J Comp Neurol. 2016 Apr 15;524(6):1222-35. doi: 10.1002/cne.23900. Epub 2015 Sep 28.


Hypothalamic proopiomelanocortin (POMC) neurons are important regulators of energy balance. Recent studies indicate that in addition to their peptides, POMC neurons can release either the amino acid (AA) transmitter gamma-aminobutyric acid (GABA) or glutamate. A small subset of POMC neurons appears to have a dual AA phenotype based on coexpression of mRNA for the vesicular glutamate transporter (vGlut2) and the GABA synthetic enzyme Gad67. To determine whether the colocalization of GABAergic and glutamatergic markers may be indicative of a switch in AA transmitter phenotype, fluorescent in situ hybridization was used to detect vGlut2 and Gad mRNA in POMC neurons during early postnatal development. The percentage of POMC neurons expressing vGlut2 mRNA in POMC neurons progressively decreased from ∼40% at day 1 to less than 10% by 8 weeks of age, whereas Gad67 was only expressed in ∼10% of POMC neurons at day 1 and increased until ∼45% of POMC neurons coexpressed Gad67 at 8 weeks of age. To determine whether the expression of vGlut2 may play a role in energy balance regulation, genetic deletion of vGlut2 in POMC neurons was accomplished using Cre-lox technology. Male, but not female, mice lacking vGlut2 in POMC neurons were unable to maintain energy balance to the same extent as control mice when fed a high-fat diet. Altogether, the results indicate that POMC neurons are largely glutamatergic early in life and that the release of glutamate from these cells is involved in sex- and diet-specific regulation of energy balance.

Keywords: AB_2307336; AB_2314332; AB_300798; AB_5145000; AB_840257; GABA; Gad; POMC; in situ hybridization; plasticity; vGlut2 knockout.

Publication types

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

MeSH terms

  • Age Factors
  • Amino Acids / biosynthesis
  • Animals
  • Animals, Newborn
  • Diet, High-Fat
  • Female
  • Glutamic Acid / metabolism*
  • Hypothalamus / growth & development
  • Hypothalamus / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / metabolism*
  • Phenotype*
  • Pro-Opiomelanocortin / biosynthesis*
  • Sex Factors
  • Vesicular Glutamate Transport Protein 2 / biosynthesis*


  • Amino Acids
  • Slc17a6 protein, mouse
  • Vesicular Glutamate Transport Protein 2
  • Glutamic Acid
  • Pro-Opiomelanocortin