Estrogen receptor-α in medial amygdala neurons regulates body weight

J Clin Invest. 2015 Jul 1;125(7):2861-76. doi: 10.1172/JCI80941. Epub 2015 Jun 22.


Estrogen receptor-α (ERα) activity in the brain prevents obesity in both males and females. However, the ERα-expressing neural populations that regulate body weight remain to be fully elucidated. Here we showed that single-minded-1 (SIM1) neurons in the medial amygdala (MeA) express abundant levels of ERα. Specific deletion of the gene encoding ERα (Esr1) from SIM1 neurons, which are mostly within the MeA, caused hypoactivity and obesity in both male and female mice fed with regular chow, increased susceptibility to diet-induced obesity (DIO) in males but not in females, and blunted the body weight-lowering effects of a glucagon-like peptide-1-estrogen (GLP-1-estrogen) conjugate. Furthermore, selective adeno-associated virus-mediated deletion of Esr1 in the MeA of adult male mice produced a rapid body weight gain that was associated with remarkable reductions in physical activity but did not alter food intake. Conversely, overexpression of ERα in the MeA markedly reduced the severity of DIO in male mice. Finally, an ERα agonist depolarized MeA SIM1 neurons and increased their firing rate, and designer receptors exclusively activated by designer drug-mediated (DREADD-mediated) activation of these neurons increased physical activity in mice. Collectively, our results support a model where ERα signals activate MeA neurons to stimulate physical activity, which in turn prevents body weight gain.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Body Weight / physiology*
  • Corticomedial Nuclear Complex / cytology
  • Corticomedial Nuclear Complex / drug effects
  • Corticomedial Nuclear Complex / metabolism*
  • Energy Metabolism
  • Estrogen Receptor alpha / deficiency
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Estrogens / administration & dosage
  • Female
  • Glucagon-Like Peptide 1 / administration & dosage
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Motor Activity / physiology
  • Neurons / metabolism
  • Obesity / etiology
  • Obesity / metabolism
  • Obesity / pathology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Sex Characteristics
  • Signal Transduction
  • Weight Gain / physiology


  • Basic Helix-Loop-Helix Transcription Factors
  • Estrogen Receptor alpha
  • Estrogens
  • Repressor Proteins
  • Sim1 protein, mouse
  • Glucagon-Like Peptide 1