Summary: Researchers have identified a female-specific neural mechanism in mice that can change estrogen’s role in glucose metabolism from protective to harmful.
Source: Tufts University
Researchers at Tufts University School of Medicine and Tufts Graduate School of Biomedical Sciences report a sex-specific neural mechanism in mice that can flip estrogen’s impact on glucose regulation. Published in the Proceedings of the National Academies of Sciences (PNAS), the study describes how the presence or absence of a receptor in a key hypothalamic region determines whether estrogen supports healthy glucose metabolism or contributes to insulin resistance and glucose intolerance. The authors propose that this estrogen-mediated “metabolic switch” could help explain the greater risk of insulin resistance and type 2 diabetes seen in women after menopause.
The team investigated the ventromedial hypothalamus (VMH), a brain region long implicated in controlling glucose production by the liver and glucose use by peripheral tissues. Within the VMH, a specific population of neurons identified by the expression of steroidogenic factor 1 (SF1) plays an important role in balancing glucose levels as well as lipid metabolism, including cholesterol and triglyceride regulation. Despite this recognized role, the precise molecular and neural mechanisms by which the VMH and its SF1 neurons influence systemic glucose homeostasis have been incompletely understood.
The receptor at the center of the study is metabotropic glutamate receptor 5 (mGluR5), known to influence neuronal activity in multiple brain regions and highly expressed in the VMH. Using targeted gene editing to remove mGluR5 specifically from VMH SF1 neurons, the researchers observed striking, sex-specific consequences. Female mice lacking mGluR5 in that region developed reduced SF1 neuronal activity and impairments in glucose regulation, including insulin resistance and poorer glucose tolerance. In contrast, male mice with the same receptor deletion showed no detectable change in glucose metabolism and maintained normal glycemic control.
To explore the underlying cause of these sex differences, the investigators examined interactions with sex hormones. They found that estrogen—generally regarded as protective for metabolic health in females—supports glycemic control only when mGluR5 is present in the VMH. When mGluR5 is removed, estrogen unexpectedly suppresses SF1 neuron activity, converting a normally beneficial hormone signal into one that undermines glucose regulation. In other words, the functional interaction between estrogen receptors and mGluR5 in VMH neurons determines whether estrogen exerts a metabolic benefit or a liability.
Electrophysiological and molecular analyses revealed that loss of mGluR5 reduced the intrinsic excitability and firing rate of SF1 neurons in females. The researchers also detected disrupted assembly of excitatory and inhibitory synapses and increased expression of GAD67, the enzyme involved in GABA synthesis, which together alter the balance of synaptic inputs onto mutant SF1 neurons. These cellular and synaptic changes align with the observed deficits in insulin sensitivity, glycemic control, lipid metabolism, and sympathetic nervous system output in female mice lacking VMH mGluR5.
Additional findings noted that mGluR5 expression in the VMH is sensitive to caloric status and is reduced in mice with mutations in brain-derived neurotrophic factor (BDNF), a model that exhibits severe obesity and impaired glucose balance. This supports the idea that mGluR5 acts downstream of metabolic signals to control VMH neuron function and whole-body glucose homeostasis, particularly in females.
“Our results demonstrate that mGluR5 is required for estrogen to promote proper glucose levels and utilization in females, while it appears dispensable for that regulation in males,” said senior author Maribel Rios, a neuroscience researcher at Tufts School of Medicine. The study’s sex-specific findings provide insight into how central nervous system mechanisms may contribute to differences in diabetes risk and disease progression between men and women across the lifespan, and may help explain why metabolic health declines for many women after menopause.
Co-first authors Micaella P. Fagan and Dominique Ameroso, both affiliated with the neuroscience program at Tufts Graduate School of Biomedical Sciences, led key portions of the experimental work.
About this neuroscience research article
Source: Tufts University
Contacts: Angelina Sutin – Tufts University
Image source: public domain.
Abstract
Essential and sex-specific effects of mGluR5 in ventromedial hypothalamus regulating estrogen signaling and glucose balance
The ventromedial hypothalamus (VMH) plays major roles in regulating energy and glucose balance and shows sexual dimorphism. The authors report that mGluR5 expression in the VMH is regulated by caloric status and reduced in BDNF mutants that have severe obesity and impaired glucose control. This led to the hypothesis that mGluR5 acts downstream of BDNF to regulate VMH neuronal firing and metabolic function. The study found that mGluR5 depletion in VMH SF1 neurons left energy balance intact but produced significant impairments in insulin sensitivity, glycemic control, lipid metabolism, and sympathetic output in females but not in males. These sex-specific deficits were associated with lower intrinsic excitability and firing rates of SF1 neurons, abnormal synaptic assembly, and elevated expression of the GABAergic enzyme GAD67. Critically, disrupted interactions between mGluR5 and estrogen receptors switched estrogen’s normally positive effects on SF1 neuronal activity and glucose balance to paradoxical, detrimental effects. Together, these data identify an essential central mechanism that regulates metabolic function in females and mediates estrogen’s protective effects against metabolic disease.