Poster only 3rd Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity 2022

Targeted stimulation of brainstem NPFF neurons induces a torpor-like state and reduces glucose tolerance in mice (#54)

Julia Koller 1 2 , Herbert Herzog 1 3 , Lei Zhang 1 2
  1. Neuroscience Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. St. Vincent’s Clinical School, University of NSW, Sydney, NSW, Australia
  3. School of Medical Sciences, University of NSW, Sydney, NSW, Australia

Neuropeptide FF (NPFF) belongs to the evolutionary conserved RF-amide peptides family that has been implicated in a variety of biological functions. Here we used transgenic mouse models and DREADD technology to investigate the involvement of the NPFF system in energy- and glucose homeostasis control.

NPFF neurons, which can be found in the solitary nucleus (NTS) of the brainstem are largely glutamatergic and co-express receptors for peripheral factors involved in glucose metabolism including insulin and GLP1. NPFFR2 - the cognate receptor of NPFF, has also dense expression in cholinergic neurons of the dorsal motor nucleus of the vagus, indicating an involvement of vagal pathways in NPFF’s action in glucose homeostasis control. We observed that lack of NPFF signalling in mice improves glucose tolerance and insulin action, and alleviates diet-induced glucose intolerance. Consistent with that, chemogenetic stimulation of NPFF neurons via DREADD technology in the NTS impairs glucose tolerance, whereas chemogenetic inhibition improves it.

We further show that chemogenetic stimulation of NPFF neurons induces a torpor-like state in mice characterized by a significant reduction in body/core temperature of approximately 8oC. This is accompanied by reduced energy expenditure and thermogenesis, food and water intake, locomotion, and a shift to lipids as oxidative fuel. Interestingly, this torpor-like state occurs within minutes upon NPFF neuronal stimulation and remains stable for 8-10 hours. Importantly, the reduced core temperature induced by NPFF stimulation varies among ambient temperatures (28oC, 22oC, 4oC), indicating a functional thermo-sensory and -regulatory system in the torpor-like state to achieve regulated hypothermia and hypometabolism.

Overall, our results reveal an unrecognized physiological function of the NPFF system in glucose homeostasis and the control of hypothermic and hypometabolic states. Targeting the NPFF system may therefore provide an attractive therapeutic approach to treat type 2 diabetes and could be useful for the induction of surgical hypothermia.