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

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.

New Insights of SF1 Neurons in Hypothalamic Regulation of Obesity and Diabetes

“…The sex-specific impairment of insulin sensitivity and glucose tolerance was associated with a reduction in intrinsic excitability and the firing rate of SF1 neurons. This suggests a functional indirect interaction of mGluR5 with estrogen receptors to control the effects of estradiol on SF1 neurons activity and glycemic control, which switch from facilitatory to detrimental in the absence of the glutamate receptor in these neurons [54]. These results are in line with the previously described study reporting that ERα depletion in SF1 neurons drives metabolic disturbances only in females [52].…”

“…Importantly, this study was the first demonstration of the importance of glutamate release in VMH neurocircuitry to prevent hypoglycemia. The relevant role of glutamatergic neurotransmission in SF1 neurons to regulate energy homeostasis was also recently established by the development of mice lacking the metabotropic glutamate receptor mGluR5 in these neurons [54]. The most remarkable finding of this study was that mGluR5 depletion in SF1 neurons did not affect energy balance, but it significantly impaired glucose balance control (Figure 4), as this dysfunction was only observed in female but not in male mice.…”

“…Ablation of the ERα led to abdominal obesity with adipocyte hypertrophy in females, but not in male mice [53]. Despite the fact that most of the studies on SF1 neurons until now were performed only in male mice, these last results described, and others discussed later [40,54], reinforce the notion that SF1 neurons may have a sex-specific effect on energy balance and glucose metabolism.…”

“…As has been already specified, there are other genetic deletions that presented different outputs in a sex-specific manner. Expression of mGluR5 in SF1 neurons was necessary for estradiol protective effects in glucose balance in female but not in male mice, and mGluR5 deletion resulted in reduced electrical activity only in female mice [54]. Deletion of α2δ-1 expression in SF1 neurons also presented sexually dimorphic effects depending on diet conditions.…”

Pentobarbital Anesthesia Suppresses the Glucose Response to Acute Intermittent Hypoxia in Rat

“…The VMH contains glucose excited (GE) neurons that are primarily responsible for glucose utilization and regulating insulin sensitivity, as well as glucose-inhibited (GI) neurons that activate the counterregulatory reflex to raise glucose in response to falling glucose levels ( Shimazu and Minokoshi, 2017 ). Female mice lacking glutamate receptors in the VMH have impaired insulin sensitivity and glucose regulation but without any deficit in responding to a hypoglycemia challenge ( Fagan et al, 2020 ) suggesting that glutamate input is not the primary driver of GI neuron activation within the VMH. Inhibition of synaptic glutamate release ( Tong et al, 2007 ) or optogenetic inhibition of neuronal firing ( Meek et al, 2016 ) in the VMH does impair the counterregulatory reflex to hypoglycemia suggesting that the GI neurons are glutamatergic and tonically inhibited.…”