NPY derived from AGRP neurons controls feeding via Y1 and energy expenditure and food foraging behaviour via Y2 signalling

Feb 15, 2022Molecular metabolism

Neuropeptide from hunger neurons controls eating through Y1 signals and controls energy use and food searching through Y2 signals

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Abstract

The deletion of NPY in AGRP neurons results in a mild obese phenotype with increased feeding and reduced locomotion.

Specific deletion of NPY in AGRP neurons leads to reduced energy expenditure and higher Respiratory Quotient (RQ).
Activation of NPY-deficient AGRP neurons can still promote feeding but with a delayed response.
Clozapine-N-oxide treatment decreases locomotion without affecting overall energy expenditure.
Rescue experiments indicate that increased feeding and RQ are primarily driven by NPY receptor 1 (Npy1r), while energy expenditure and locomotion are regulated by NPY receptor 2 (Npy2r).
These findings clarify the distinct roles of NPY and its receptors in feeding behavior and energy homeostasis.

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OBJECTIVE: Aguti-related protein (AGRP) neurons in the arcuate nucleus of the hypothalamus (ARC), which co-express neuropeptide Y (NPY), are key regulators of feeding and energy homeostasis. However, the precise role NPY has within these neurons and the specific pathways that it control are still unclear. In this article, we aimed to determine what aspects of feeding behaviour and energy homeostasis are controlled by NPY originating from AGRP neurons and which Y-receptor pathways are utilised to fulfil this function.

METHODS: Novel conditional Agrp;Npyknockout mice were generated and comprehensively phenotyped, both under standard chow as well as high-fat-diet conditions. Designer receptor exclusively activated by designer drugs (DREADD) technology was used to assess the altered responses on feeding and energy homeostasis control in the absence of NPY in these neurons. Rescue experiments utilising Npy1r- and Npy2r-selective NPY ligands were performed to assess which component of the energy homeostasis control is dependent by which specific Y-receptor pathway. cre/+ lox/lox

RESULTS: We show that the specific deletion of Npy only in AGRP neurons leads to a paradoxical mild obese phenotype associated with reduced locomotion and energy expenditure and increased feeding and Respiratory Quotient (RQ) that remain elevated under a positive energy balance. The activation of Npy-deficient AGRP neurons via DREADD's is still able to drive feeding, yet with a delayed onset. Additionally, Clozapine-N-oxide (CNO) treatment reduces locomotion without impacting on energy expenditure. Rescue experiments re-introducing Npy1r- and Npy2r-selective NPY ligands revealed that the increased feeding and RQ are mostly driven by Npy1r, whereas energy expenditure and locomotion are controlled by Npy2r signalling.

CONCLUSION: Together, these results demonstrate that NPY originating from AGRP neurons is not only critical to initiate but also for continuously driving feeding, and we for the first time identify which Y-receptor controls which pathway.

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NPY derived from AGRP neurons controls feeding via Y1 and energy expenditure and food foraging behaviour via Y2 signalling

Abstract

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