Essential and sex-specific effects of mGluR5 in ventromedial hypothalamus regulating estrogen signaling and glucose balance

Proc Natl Acad Sci U S A. 2020 Aug 11;117(32):19566-19577. doi: 10.1073/pnas.2011228117. Epub 2020 Jul 27.

Abstract

The ventromedial hypothalamus (VMH) plays chief roles regulating energy and glucose homeostasis and is sexually dimorphic. We discovered that expression of metabotropic glutamate receptor subtype 5 (mGluR5) in the VMH is regulated by caloric status in normal mice and reduced in brain-derived neurotrophic factor (BDNF) mutants, which are severely obese and have diminished glucose balance control. These findings led us to investigate whether mGluR5 might act downstream of BDNF to critically regulate VMH neuronal activity and metabolic function. We found that mGluR5 depletion in VMH SF1 neurons did not affect energy balance regulation. However, it significantly impaired insulin sensitivity, glycemic control, lipid metabolism, and sympathetic output in females but not in males. These sex-specific deficits are linked to reductions in intrinsic excitability and firing rate of SF1 neurons. Abnormal excitatory and inhibitory synapse assembly and elevated expression of the GABAergic synthetic enzyme GAD67 also cooperate to decrease and potentiate the synaptic excitatory and inhibitory tone onto mutant SF1 neurons, respectively. Notably, these alterations arise from disrupted functional interactions of mGluR5 with estrogen receptors that switch the normally positive effects of estrogen on SF1 neuronal activity and glucose balance control to paradoxical and detrimental. The collective data inform an essential central mechanism regulating metabolic function in females and underlying the protective effects of estrogen against metabolic disease.

Keywords: estrogen; glucose; glutamate; synapses; ventromedial hypothalamus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Glucose / metabolism*
  • Brain-Derived Neurotrophic Factor / genetics
  • Energy Metabolism
  • Estrogens / metabolism*
  • Female
  • Glutamate Decarboxylase / metabolism
  • Homeostasis
  • Lipid Metabolism
  • Male
  • Mice
  • Mice, Mutant Strains
  • Nerve Net
  • Neural Inhibition
  • Neurons / metabolism
  • Neurons / physiology
  • Receptor, Metabotropic Glutamate 5 / genetics
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • Receptors, Estrogen / metabolism
  • Sex Factors
  • Signal Transduction
  • Steroidogenic Factor 1 / metabolism
  • Sympathetic Nervous System / metabolism
  • Synaptic Transmission
  • Ventromedial Hypothalamic Nucleus / cytology
  • Ventromedial Hypothalamic Nucleus / metabolism
  • Ventromedial Hypothalamic Nucleus / physiology*

Substances

  • Bdnf protein, mouse
  • Blood Glucose
  • Brain-Derived Neurotrophic Factor
  • Estrogens
  • Grm5 protein, mouse
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Estrogen
  • Steroidogenic Factor 1
  • steroidogenic factor 1, mouse
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1