# Sex-Specific Role of NPVF Signalling in Homeostatic Control

## TL;DR

NPVF signaling affects energy and glucose control differently in male and female mice, depending on diet and environment.

## Contribution

This study reveals sex-specific roles of NPVF in regulating metabolism under varying environmental and dietary conditions.

## Key findings

- Female Npvf−/− mice show altered water intake, bone mineral content, and adiposity compared to males.
- Npvf deletion leads to hyperphagia and weight gain in both sexes under high-fat diet conditions.
- Sex differences in insulin and glucose tolerance depend on diet and temperature conditions.

## Abstract

Neuropeptide VF (NPVF) is a member of the RFamide family of peptides and is suggested to be involved in homeostatic regulations. However, direct evidence is sparse. Here, we generated a NPVF knockout mouse model to comprehensively investigate its role in energy and glucose homeostasis controls. We show that while male Npvf−/− mice on chow were WT-like at both room temperature (RT 22 °C) and thermoneutrality (TN 28 °C) with regards to body weight, body composition, and the parameters involved in energy homeostasis, female Npvf−/− mice exhibit significantly reduced water intake at RT and TN regardless of food access, significantly increased the femur bone mineral content at RT and reduced the adiposity at TN. Strikingly, sex differences are absent under high-fat diet (HFD) conditions, with Npvf deletion leading to hyperphagia and increased weight gain in both sexes. Furthermore, Npvf−/− mice on chow at RT exhibit normal glucose tolerance and insulin action for both sexes. On a HFD or at TN, Npvf−/− mice display improved and impaired insulin action in females and males, respectively, with female Npvf−/− mice at TN further showing an improved glucose tolerance. Collectively, these findings establish NPVF as a key regulator of energy and glucose metabolism with sex dimorphism, and are critically dependent on environmental and nutritional factors.