Neuropeptide FF and Neuropeptide VF and their control in the regulation of energy homeostasis and glucose metabolism

Despite the growing obesity epidemic and its adverse health effects, such as diabetes and cardiovascular diseases, effective treatments are still missing. This is partly due to our insufficient understanding of the regulatory mechanisms underlying energy homeostasis. This work used transgenic and knockout mouse models combined with neuronal manipulation and pathway tracing to investigate the role of the Neuropeptide FF (NPFF) and Neuropeptide VF (NPVF) in the regulation of energy balance and glucose homeostasis. This study reveals that NPFF signalling plays important roles in fluid and glucose homeostasis, since Npff-/- mice exhibit an increased water intake and improved glucose tolerance, the latter being due to higher insulin responsiveness. Coherently, chemogenetic activation of brainstem NPFF neurons via DREADD technology impaired glucose tolerance, whereas inhibition improved it. In addition, the lack of NPFF signalling leads to a rise in energy expenditure and brown adipose tissue thermogenesis, however, shows impaired high fat diet-induced thermogenesis at thermoneutrality. Together this indicates a critical role of NPFF signalling in the thermos-sensory and dietary regulation of thermogenesis. Consistent with a role of NPFF in the control of energy metabolism, targeted stimulation of NPFF neurons induces a torpor-like state, characterized by strong hypothermia and hypometabolic reactions. Lack of NPVF shows strong gender-specific effects on glucose homeostasis and energy metabolism, such as providing protection against HFD-induced glucose intolerance in male mice. An exacerbated diet-induced obesity in Npvf-/- mice, attributable to reduced energy expenditure observed in females only, and/or higher food intake observed in both genders, suggests a role of NPVF signalling in the regulation of feeding and energy metabolism under positive energy balance. Furthermore, this work reveals important roles of both NPFF and NPVF signalling in the regulation of anxiety-r