Sex-Specific Role of NPVF Signalling in Homeostatic Control

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 <i>Npvf</i>^-^/- 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 <i>Npvf</i>^-/- 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, <i>Npvf</i>^-^/- mice on chow at RT exhibit normal glucose tolerance and insulin action for both sexes. On a HFD or at TN, <i>Npvf</i>^-/- mice display improved and impaired insulin action in females and males, respectively, with female <i>Npvf</i>^-^/- 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.