# Lack of glutamate neurotransmission in melanin-concentrating hormone neurons alters mouse reproduction and metabolism in a sex-specific manner

## TL;DR

Deleting glutamate in MCH neurons affects mouse reproduction and metabolism differently in males and females.

## Contribution

A new transgenic mouse model reveals sex-specific roles of glutamate in MCH neurons for reproduction and metabolism.

## Key findings

- Female mice with deleted VGLUT2 in MCH neurons showed delayed puberty and disrupted estrous cycles.
- Male mice on a high-fat diet had improved insulin resistance when VGLUT2 was deleted in MCH neurons.
- Both sexes showed improved daily food intake patterns when VGLUT2 was deleted in MCH neurons.

## Abstract

Melanin-concentrating hormone (MCH) is a neuropeptide important for the regulation of metabolism, sleep, circadian rhythms, and other body functions. MCH neurons contain the excitatory neurotransmitter glutamate, which is released via vesicular glutamate transporter 2 (VGLUT2). The release of glutamate from MCH neurons is known to play a role in metabolism in males, but its action in female physiology has not been determined. Furthermore, little is known about the role of glutamate release from MCH neurons in reproductive function. We developed a new transgenic mouse model that expresses Cre recombinase driven by the MCH gene (Pmch) and deleted Vglut2 from the MCH neurons. We then assessed reproductive and metabolic function in both sexes. Females exhibited late-onset leanness, delayed sexual maturation, and increased latency to pregnancy. On a high-fat diet, males showed improved insulin resistance, and both sexes displayed an improved daily pattern of food intake. These findings highlight the importance of considering sex as a relevant biological variable in MCH neuronal function.

The online version contains supplementary material available at 10.1186/s13293-025-00742-3.

PmchΔVglut2 female, but not male, mice showed a delay in puberty onset and completion.PmchΔVglut2 female mice were (HFD)-induced disruption of estrous cycles.PmchΔVglut2 female mice exhibited late-onset reduced total body mass whereas males showed late-onset reduced fat mass.PmchΔVglut2 male, but not female, mice on HFD showed reduced insulin resistance compared to controls.HFD disrupted the daily pattern of food consumption in control Vglut2flox male and female mice. This disruption was not observed in PmchΔVglut2 mice.

PmchΔVglut2 female, but not male, mice showed a delay in puberty onset and completion.

PmchΔVglut2 female mice were (HFD)-induced disruption of estrous cycles.

PmchΔVglut2 female mice exhibited late-onset reduced total body mass whereas males showed late-onset reduced fat mass.

PmchΔVglut2 male, but not female, mice on HFD showed reduced insulin resistance compared to controls.

HFD disrupted the daily pattern of food consumption in control Vglut2flox male and female mice. This disruption was not observed in PmchΔVglut2 mice.

The online version contains supplementary material available at 10.1186/s13293-025-00742-3.

Melanin-concentrating hormone (MCH) neurons contribute to the regulation of a diverse array of physiological functions including glucose and energy homeostasis. MCH neurons express genes involved in the synthesis, packaging, and release of glutamate, the brain’s predominant excitatory neurotransmitter. Deletion of vesicular glutamate transporter 2 (VGLUT2, Slc17a6 gene) in MCH neurons of male mice results in a hypophagic, hyperactive, lean phenotype. However, the metabolic and reproductive effects of VGLUT2 deletion in females have not been fully addressed.

Previous studies have utilized Pmch-Cre mice generated using a bacterial artificial chromosome (BAC). The loci of insertion for the BAC are random and may fail to recapitulate epigenetic regulation at the native gene locus. Here, we generated a novel knock-in Pmch-iCre mouse model and investigated the effects of deleting Slc17a6 from MCH neurons in both male and female mice. Assessment of sexual maturation, fertility, glucose homeostasis and energy balance (food intake, body composition, energy expenditure, locomotion, glucose and fat oxidation) on regular chow and high fat diet (HFD) were performed in both sexes.

Lack of glutamate neurotransmission in MCH neurons (PmchΔVglut2 mice) delays puberty onset and completion in female, but not male mice. PmchΔVglut2 females were also protected against (HFD)-induced disruption of estrous cycles. On a regular chow diet, neither male nor female PmchΔVglut2 mice showed differences in body weight, food intake, or lean and fat masses compared to littermate controls until 20 weeks of age. At 24 weeks of age, PmchΔVglut2 females exhibited reduced total body mass, and males had lower fat mass. PmchΔVglut2 female mice also gained less weight on HFD than littermate controls. An attenuation of HFD-induced disruption of daily feeding pattern was observed in PmchΔVglut2 mice of both sexes, while only males were protected against insulin resistance on HFD.

Glutamate neurotransmission from MCH neurons has a sex-specific role in sexual maturation, fertility, typical weight gain trajectory, and HFD-induced weight gain and insulin resistance. In addition, a sex-independent role in daily feeding pattern was observed.

The online version contains supplementary material available at 10.1186/s13293-025-00742-3.