Gender-specific roles of Neuropeptide VF signalling in homeostatic control

Background: Neuropeptide VF (NPVF), a member of the evolutionarily conserved RF-amide peptide family is predominantly expressed in the dorsal-medial hypothalamus. Initially identified as the gonadotropic inhibitory hormone, NPVF and its cognate receptor, NPFFR1, have mostly been investigated for their roles in reproduction. Interestingly, however, the expression of Npvf is also impacted by ambient temperature and energy status, indicating a role of NPVF in the regulation of energy homeostasis, which has not been fully explored. Aims and hypothesis: In this study, we aimed to investigate the role of NPVF signalling in homeostatic control and hypothesized that lack of NPVF signalling results in alterations in energy and glucose homeostasis and stress-related behaviours. Methods: We generated a Npvf knockout mouse model ( Npvf −/− ) and comprehensively examined energy and glucose homeostasis in wild-type (WT) and Npvf −/− mice of both genders under either standard chow or high-fat diet (HFD) conditions at room temperature (RT, 22°C) as well as at the mouse thermoneutral temperature (TN, 28°C). We further examined stress-related behaviours using the open field (OF) test and elevated plus maze (EPM). Results: Male Npvf −/− mice fed on chow were WT-like under both RT and TN conditions, with regards to body weight, body composition and parameters involved in energy homeostasis. In contrast, chow-fed female Npvf −/− mice exhibit a significant increase in food intake and a decrease in water intake at RT, as well as reduced fat mass and increased energy expenditure at TN compared to controls. Interestingly, when fed on HFD, lack of NPVF signalling led to significantly greater weight gain in both males and female mice. This greater HFD-induced weight gain was attributable to an increased food intake in both genders, and an additional decrease in energy expenditure in female. Furthermore, lack of NPVF signalling at basal chow condition in male mice has a negative effect on glucose metabolism, i.e. impaired glucose tolerance at RT and reduced insulin responsiveness at TN. By contrast, during a HFD exposure, lack of NPVF signalling in male mice leads to an improved glucose tolerance and insulin responsiveness at RT. On the other hand, lack of NPVF signalling in female mice, whilst not affecting glucose metabolism on chow at RT, enhances glucose tolerance and insulin responsiveness at TN, and also improves insulin responsiveness when challenged with a HFD. Finally, lack of NPVF signalling in female, but not male mice, leads to reduced anxiety-like and an increased explorative behaviour, evidenced by increased time spent in the center and center entries during the OF test. In addition, they also show a trend towards increasing in time spent in the open arms and significant increases in open arm entries relative to total arm entries during the EPM test. Conclusion: Taken together, these data show that NPVF signalling is a novel and important player in the control of energy and glucose homeostasis, as well as anxiety-related behaviours. Importantly, NPVF signalling exerts these regulations in a gender-specific manner which is also influenced by ambient temperature and diet conditions. National Health and Medical Research Council This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.