Endle, Heiko ORCID: 0000-0002-1012-4563, Horta, Guilherme, Stutz, Bernardo, Muthuraman, Muthuraman, Tegeder, Irmgard ORCID: 0000-0001-7524-8025, Schreiber, Yannick, Snodgrass, Isabel Faria, Gurke, Robert, Liu, Zhong-Wu, Sestan-Pesa, Matija ORCID: 0000-0002-9873-6387, Radyushkin, Konstantin, Streu, Nora, Fan, Wei, Baumgart, Jan, Li, Yan, Kloss, Florian, Groppa, Sergiu, Opel, Nils, Dannlowski, Udo, Grabe, Hans J., Zipp, Frauke, Racz, Bence, Horvath, Tamas L., Nitsch, Robert and Vogt, Johannes (2022). AgRP neurons control feeding behaviour at cortical synapses via peripherally derived lysophospholipids. Nat. Metab., 4 (6). S. 683 - 702. BERLIN: NATURE PORTFOLIO. ISSN 2522-5812

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Abstract

Hypothalamic AgRP neurons are shown to control peripheral and central levels of lysophospholipids in association with food deprivation, which leads to cortical excitability, hyperphagia and body weight gain. Phospholipid levels are influenced by peripheral metabolism. Within the central nervous system, synaptic phospholipids regulate glutamatergic transmission and cortical excitability. Whether changes in peripheral metabolism affect brain lipid levels and cortical excitability remains unknown. Here, we show that levels of lysophosphatidic acid (LPA) species in the blood and cerebrospinal fluid are elevated after overnight fasting and lead to higher cortical excitability. LPA-related cortical excitability increases fasting-induced hyperphagia, and is decreased following inhibition of LPA synthesis. Mice expressing a human mutation (Prg-1(R346T)) leading to higher synaptic lipid-mediated cortical excitability display increased fasting-induced hyperphagia. Accordingly, human subjects with this mutation have higher body mass index and prevalence of type 2 diabetes. We further show that the effects of LPA following fasting are under the control of hypothalamic agouti-related peptide (AgRP) neurons. Depletion of AgRP-expressing cells in adult mice decreases fasting-induced elevation of circulating LPAs, as well as cortical excitability, while blunting hyperphagia. These findings reveal a direct influence of circulating LPAs under the control of hypothalamic AgRP neurons on cortical excitability, unmasking an alternative non-neuronal route by which the hypothalamus can exert a robust impact on the cortex and thereby affect food intake.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Endle, HeikoUNSPECIFIEDorcid.org/0000-0002-1012-4563UNSPECIFIED
Horta, GuilhermeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stutz, BernardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muthuraman, MuthuramanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tegeder, IrmgardUNSPECIFIEDorcid.org/0000-0001-7524-8025UNSPECIFIED
Schreiber, YannickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Snodgrass, Isabel FariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gurke, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, Zhong-WuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sestan-Pesa, MatijaUNSPECIFIEDorcid.org/0000-0002-9873-6387UNSPECIFIED
Radyushkin, KonstantinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Streu, NoraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fan, WeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumgart, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloss, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Groppa, SergiuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Opel, NilsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dannlowski, UdoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grabe, Hans J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zipp, FraukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Racz, BenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horvath, Tamas L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nitsch, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogt, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-690636
DOI: 10.1038/s42255-022-00589-7
Journal or Publication Title: Nat. Metab.
Volume: 4
Number: 6
Page Range: S. 683 - 702
Date: 2022
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 2522-5812
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CEREBROSPINAL-FLUID; HEPATIC SECRETION; AUTOTAXIN; IDENTIFICATION; PLASTICITY; PLASMA; IMPACT; MICEMultiple languages
Endocrinology & MetabolismMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69063

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