A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding

Pablo Blanco Martinez de Morentin; J Antonio Gonzalez; Georgina K C Dowsett; Yuliia Martynova; Giles S. H. Yeo; Sergiy Sylantyev; Lora Heisler

doi:10.1016/j.cub.2024.02.074

A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding

Pablo Blanco Martinez de Morentin^* (Corresponding Author), J Antonio Gonzalez, Georgina K C Dowsett, Yuliia Martynova, Giles S. H. Yeo, Sergiy Sylantyev^* (Corresponding Author), Lora Heisler

^*Corresponding author for this work

University of Cambridge

Research output: Contribution to journal › Article › peer-review

Abstract

The obesity epidemic is principally driven by the consumption of more calories than the body requires. It is therefore essential that the mechanisms underpinning feeding behavior are defined. The brainstem nucleus of the solitary tract (NTS) receives direct information from the digestive system and projects to second order regions in the brain. Though γ-Aminobutyric acid is widely expressed in the NTS (GABANTS), its function has not been defined. Characterization of GABA cells using single nucleus RNA sequencing (Nuc-Seq) identified at least 19 clusters. Here we provide insight into the function of GABANTS cells, revealing that selective activation of GABANTS neurons significantly controls food intake and body weight. Optogenetic interrogation of GABANTS circuitry identified GABANTS→arcuate nucleus of the hypothalamus (ARC) projections as appetite suppressive without creating aversion. Electrophysiological analysis revealed GABANTS→ARC stimulation inhibits hunger promoting agouti-related protein/neuropeptide Y (AgRP/NPY) neurons via GABA release. Adopting an intersectional genetics strategy, we clarify that the GABANTS→ARC circuit induces satiety. These data identify GABANTS as a new modulator of feeding behavior, body weight and controller of orexigenic AgRP/NPY activity, thereby providing insight into the neural underpinnings of obesity.

Original language	English
Pages (from-to)	1646-1656.e4
Number of pages	16
Journal	Current Biology
Volume	34
Issue number	8
Early online date	21 Mar 2024
DOIs	https://doi.org/10.1016/j.cub.2024.02.074
Publication status	E-pub ahead of print - 21 Mar 2024

Bibliographical note

Open Access via the Elsevier Open Access Agreement.
We gratefully acknowledge Dr F. Naneix for advice on optogenetics and editorial advice, and staff within the University of Aberdeen Medical Research Facility and the Microscopy Facility for their technical assistance. This work was supported by the ERC (MSCA-IF-NeuroEE-660219) to PBM, Wellcome Trust Institutional Strategic Support Fund (204815/Z/16/Z) to PBM and LKH, and the Biotechnology and Biological Sciences Research Council (BB/V010557/1) to JAG and (BB/V016849/1) to LKH and SS. GKCD is funded by a BBSRC CASE 4-year PhD studentship, co-funded by Novo Nordisk. GSHY is funded by the UK Medical Research Council (MC_UU_00014/1).

Keywords

hunger
body weight
gamma-aminobutryic acid
neuropeptide Y
nucleus of the solitary tract
dorsal vagal complex
hypothalamus
food intake
obesity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cub.2024.02.074Licence: CC BY

Martinez_etal_CB_ABrainstem_To_VOR
ª 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 4.15 MBLicence: CC BY

Cite this

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title = "A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding",

abstract = "The obesity epidemic is principally driven by the consumption of more calories than the body requires. It is therefore essential that the mechanisms underpinning feeding behavior are defined. The brainstem nucleus of the solitary tract (NTS) receives direct information from the digestive system and projects to second order regions in the brain. Though γ-Aminobutyric acid is widely expressed in the NTS (GABANTS), its function has not been defined. Characterization of GABA cells using single nucleus RNA sequencing (Nuc-Seq) identified at least 19 clusters. Here we provide insight into the function of GABANTS cells, revealing that selective activation of GABANTS neurons significantly controls food intake and body weight. Optogenetic interrogation of GABANTS circuitry identified GABANTS→arcuate nucleus of the hypothalamus (ARC) projections as appetite suppressive without creating aversion. Electrophysiological analysis revealed GABANTS→ARC stimulation inhibits hunger promoting agouti-related protein/neuropeptide Y (AgRP/NPY) neurons via GABA release. Adopting an intersectional genetics strategy, we clarify that the GABANTS→ARC circuit induces satiety. These data identify GABANTS as a new modulator of feeding behavior, body weight and controller of orexigenic AgRP/NPY activity, thereby providing insight into the neural underpinnings of obesity.",

keywords = "hunger, body weight, gamma-aminobutryic acid, neuropeptide Y, nucleus of the solitary tract, dorsal vagal complex, hypothalamus, food intake, obesity",

author = "{Blanco Martinez de Morentin}, Pablo and Gonzalez, {J Antonio} and Dowsett, {Georgina K C} and Yuliia Martynova and Yeo, {Giles S. H.} and Sergiy Sylantyev and Lora Heisler",

note = "Open Access via the Elsevier Open Access Agreement. We gratefully acknowledge Dr F. Naneix for advice on optogenetics and editorial advice, and staff within the University of Aberdeen Medical Research Facility and the Microscopy Facility for their technical assistance. This work was supported by the ERC (MSCA-IF-NeuroEE-660219) to PBM, Wellcome Trust Institutional Strategic Support Fund (204815/Z/16/Z) to PBM and LKH, and the Biotechnology and Biological Sciences Research Council (BB/V010557/1) to JAG and (BB/V016849/1) to LKH and SS. GKCD is funded by a BBSRC CASE 4-year PhD studentship, co-funded by Novo Nordisk. GSHY is funded by the UK Medical Research Council (MC_UU_00014/1).",

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T1 - A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding

AU - Blanco Martinez de Morentin, Pablo

AU - Gonzalez, J Antonio

AU - Dowsett, Georgina K C

AU - Martynova, Yuliia

AU - Yeo, Giles S. H.

AU - Sylantyev, Sergiy

AU - Heisler, Lora

N1 - Open Access via the Elsevier Open Access Agreement. We gratefully acknowledge Dr F. Naneix for advice on optogenetics and editorial advice, and staff within the University of Aberdeen Medical Research Facility and the Microscopy Facility for their technical assistance. This work was supported by the ERC (MSCA-IF-NeuroEE-660219) to PBM, Wellcome Trust Institutional Strategic Support Fund (204815/Z/16/Z) to PBM and LKH, and the Biotechnology and Biological Sciences Research Council (BB/V010557/1) to JAG and (BB/V016849/1) to LKH and SS. GKCD is funded by a BBSRC CASE 4-year PhD studentship, co-funded by Novo Nordisk. GSHY is funded by the UK Medical Research Council (MC_UU_00014/1).

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N2 - The obesity epidemic is principally driven by the consumption of more calories than the body requires. It is therefore essential that the mechanisms underpinning feeding behavior are defined. The brainstem nucleus of the solitary tract (NTS) receives direct information from the digestive system and projects to second order regions in the brain. Though γ-Aminobutyric acid is widely expressed in the NTS (GABANTS), its function has not been defined. Characterization of GABA cells using single nucleus RNA sequencing (Nuc-Seq) identified at least 19 clusters. Here we provide insight into the function of GABANTS cells, revealing that selective activation of GABANTS neurons significantly controls food intake and body weight. Optogenetic interrogation of GABANTS circuitry identified GABANTS→arcuate nucleus of the hypothalamus (ARC) projections as appetite suppressive without creating aversion. Electrophysiological analysis revealed GABANTS→ARC stimulation inhibits hunger promoting agouti-related protein/neuropeptide Y (AgRP/NPY) neurons via GABA release. Adopting an intersectional genetics strategy, we clarify that the GABANTS→ARC circuit induces satiety. These data identify GABANTS as a new modulator of feeding behavior, body weight and controller of orexigenic AgRP/NPY activity, thereby providing insight into the neural underpinnings of obesity.

AB - The obesity epidemic is principally driven by the consumption of more calories than the body requires. It is therefore essential that the mechanisms underpinning feeding behavior are defined. The brainstem nucleus of the solitary tract (NTS) receives direct information from the digestive system and projects to second order regions in the brain. Though γ-Aminobutyric acid is widely expressed in the NTS (GABANTS), its function has not been defined. Characterization of GABA cells using single nucleus RNA sequencing (Nuc-Seq) identified at least 19 clusters. Here we provide insight into the function of GABANTS cells, revealing that selective activation of GABANTS neurons significantly controls food intake and body weight. Optogenetic interrogation of GABANTS circuitry identified GABANTS→arcuate nucleus of the hypothalamus (ARC) projections as appetite suppressive without creating aversion. Electrophysiological analysis revealed GABANTS→ARC stimulation inhibits hunger promoting agouti-related protein/neuropeptide Y (AgRP/NPY) neurons via GABA release. Adopting an intersectional genetics strategy, we clarify that the GABANTS→ARC circuit induces satiety. These data identify GABANTS as a new modulator of feeding behavior, body weight and controller of orexigenic AgRP/NPY activity, thereby providing insight into the neural underpinnings of obesity.

KW - hunger

KW - body weight

KW - gamma-aminobutryic acid

KW - neuropeptide Y

KW - nucleus of the solitary tract

KW - dorsal vagal complex

KW - hypothalamus

KW - food intake

KW - obesity

U2 - 10.1016/j.cub.2024.02.074

DO - 10.1016/j.cub.2024.02.074

M3 - Article

C2 - 38518777

SN - 0960-9822

VL - 34

SP - 1646-1656.e4

JO - Current Biology

JF - Current Biology

IS - 8

ER -

A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding

Abstract

Bibliographical note

Keywords

UN SDGs

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