TY - JOUR

T1 - NPFF Decreases Activity of Human Arcuate NPY Neurons

T2 - A Study in Embryonic-Stem-Cell-Derived Model

AU - Torz, Lola

AU - Niss, Kristoffer

AU - Lundh, Sofia

AU - Rekling, Jens C.

AU - Quintana, Carlos Damian

AU - Frazier, Signe Emilie Dannulat

AU - Mercer, Aaron J.

AU - Cornea, Anda

AU - Bertelsen, Charlotte Vinther

AU - Gerstenberg, Marina Kjærgaard

AU - Hansen, Ann Maria Kruse

AU - Guldbrandt, Mette

AU - Lykkesfeldt, Jens

AU - John, Linu Mary

AU - Villaescusa, J. Carlos

AU - Petersen, Natalia

N1 - Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022

Y1 - 2022

N2 - Restoring the control of food intake is the key to obesity management and prevention. The arcuate nucleus (ARC) of the hypothalamus is extensively being studied as a potential anti-obesity target. Animal studies showed that neuropeptide FF (NPFF) reduces food intake by its action in neuropeptide Y (NPY) neurons of the hypothalamic ARC, but the detailed mode of action observed in human neurons is missing, due to the lack of a human-neuron-based model for pharmacology testing. Here, we validated and utilized a human-neural-stem-cell-based (hNSC) model of ARC to test the effects of NPFF on cellular pathways and neuronal activity. We found that in the human neurons, decreased cAMP levels by NPFF resulted in a reduced rate of cytoplasmic calcium oscillations, indicating an inhibition of ARC NPY neurons. This suggests the therapeutic potential of NPFFR2 in obesity. In addition, we demonstrate the use of human-stem-cell-derived neurons in pharmacological applications and the potential of this model to address functional aspects of human hypothalamic neurons.

AB - Restoring the control of food intake is the key to obesity management and prevention. The arcuate nucleus (ARC) of the hypothalamus is extensively being studied as a potential anti-obesity target. Animal studies showed that neuropeptide FF (NPFF) reduces food intake by its action in neuropeptide Y (NPY) neurons of the hypothalamic ARC, but the detailed mode of action observed in human neurons is missing, due to the lack of a human-neuron-based model for pharmacology testing. Here, we validated and utilized a human-neural-stem-cell-based (hNSC) model of ARC to test the effects of NPFF on cellular pathways and neuronal activity. We found that in the human neurons, decreased cAMP levels by NPFF resulted in a reduced rate of cytoplasmic calcium oscillations, indicating an inhibition of ARC NPY neurons. This suggests the therapeutic potential of NPFFR2 in obesity. In addition, we demonstrate the use of human-stem-cell-derived neurons in pharmacological applications and the potential of this model to address functional aspects of human hypothalamic neurons.

KW - Appetite control

KW - Human-arcuate-like neurons

KW - Neuropeptide FF

KW - Neuropeptide FF receptor 2

KW - Obesity

KW - Screening platform

U2 - 10.3390/ijms23063260

DO - 10.3390/ijms23063260

M3 - Journal article

C2 - 35328681

AN - SCOPUS:85126675323

VL - 23

JO - International Journal of Molecular Sciences (Online)

JF - International Journal of Molecular Sciences (Online)

SN - 1661-6596

IS - 6

M1 - 3260

ER -