Elsevier

Molecular Metabolism

Volume 4, Issue 11, November 2015, Pages 857-866
Molecular Metabolism

Original article
Sex-dependent changes in metabolism and behavior, as well as reduced anxiety after eliminating ventromedial hypothalamus excitatory output

https://doi.org/10.1016/j.molmet.2015.09.001Get rights and content
Under a Creative Commons license
open access

Highlights

  • Excitatory VMH output controls sex-dependent metabolic and behavioral phenotypes.

  • Vglut2Sf1-Cre mice are not prone to diet-induced obesity or glucose misregulation.

  • Loss of VMH glutamatergic signaling leads to negative energy state in females.

  • Aggression and learned fear are lower in males lacking VMH excitatory output.

  • VMH glutamatergic signaling drives normal anxiety responses in both sexes.

Abstract

Objectives

The ventromedial hypothalamic nucleus (VMH) regulates energy homeostasis as well as social and emotional behaviors. Nearly all VMH neurons, including those in the sexually dimorphic ventrolateral VMH (VMHvl) subregion, release the excitatory neurotransmitter glutamate and use the vesicular glutamate transporter 2 (Vglut2). Here, we asked how glutamatergic signaling contributes to the collective metabolic and behavioral responses attributed to the VMH and VMHvl.

Methods

Using Sf1-Cre and a Vglut2 floxed allele, Vglut2 was knocked-out in SF-1 VMH neurons (Vglut2Sf1-Cre). Metabolic and neurobehavioral assays were carried out initially on Vglut2fl/fl and Vglut2Sf1-Cre mice in a mixed, and then in the C57BL/6 genetic background, which is prone to hyperglycemia and diet induced obesity (DIO).

Results

Several phenotypes observed in Vglut2Sf1-Cre mice were largely unexpected based on prior studies that have perturbed VMH development or VMH glutamate signaling. In our hands, Vglut2Sf1-Cre mice failed to exhibit the anticipated increase in body weight after high fat diet (HFD) or the impaired glucose homeostasis after fasting. Instead, there was a significant sex-dependent attenuation of DIO in Vglut2Sf1-Cre females. Vglut2Sf1-Cre males also display a sex-specific loss of conditioned-fear responses and aggression accompanied by more novelty-associated locomotion. Finally, unlike the higher anxiety noted in Sf1Nestin-Cre mice that lack a fully formed VMH, both male and female Vglut2Sf1-Cre mice were less anxious.

Conclusions

Loss of VMH glutamatergic signaling sharply decreased DIO in females, attenuated aggression and learned fear in males, and was anxiolytic in males and females. Collectively, our findings demonstrate that while glutamatergic output from the VMH appears largely dispensable for counter regulatory responses to hypoglycemia, it drives sex-dependent differences in metabolism and social behaviors and is essential for adaptive responses to anxiety-provoking stimuli in both sexes.

Keywords

VMH
VGlut2
Sex-dependent obesity
Excitatory output
Anxiety
Male aggression

Cited by (0)

4

Clement C. Cheung and William C. Krause contributed equally to this work.

5

Present address: Department of Pediatrics, Center for Endocrinology, Diabetes, and Metabolism, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, United States.

6

Present address: University of California, San Diego, Department of Neurosciences, 9500 Gilman Drive, La Jolla, CA 92093, United States.