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

Autor: Jamie Maguire, Anna Rock, Maribel Rios, Dominique Ameroso, Micaella P Fagan, Alice Meng
Rok vydání: 2020
Předmět:
Blood Glucose
Male
0301 basic medicine
medicine.medical_specialty
Sympathetic Nervous System
Receptor
Metabotropic Glutamate 5
Inhibitory synapse assembly
Estrogen receptor
Biology
Steroidogenic Factor 1
Synaptic Transmission
Mice
03 medical and health sciences
Sex Factors
0302 clinical medicine
Neurotrophic factors
Internal medicine
medicine
Animals
Homeostasis
Glucose homeostasis
Neurons
Multidisciplinary
Glutamate Decarboxylase
Metabotropic glutamate receptor 5
Brain-Derived Neurotrophic Factor
Glutamate receptor
Estrogens
Neural Inhibition
Biological Sciences
Lipid Metabolism
Mice
Mutant Strains
030104 developmental biology
Endocrinology
Receptors
Estrogen
nervous system
Ventromedial Hypothalamic Nucleus
Hypothalamus
Metabotropic glutamate receptor
Female
Nerve Net
Energy Metabolism
030217 neurology & neurosurgery
Signal Transduction
Zdroj: Proc Natl Acad Sci U S A
ISSN: 1091-6490
0027-8424
Popis: 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.
Databáze: OpenAIRE
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