Cargando…
A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite
The endocrine control of food intake remains incompletely understood, and whether the leptin receptor-mediated anorexigenic pathway in the hypothalamus is negatively regulated by a humoral factor is unknown. Here we identify an appetite-stimulating factor - ASRA - that acts as a leptin receptor anta...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10515849/ https://www.ncbi.nlm.nih.gov/pubmed/37745491 http://dx.doi.org/10.1101/2023.09.12.557454 |
_version_ | 1785109031758594048 |
---|---|
author | Huang, Lei Liu, Pengpeng Du, Yong Pan, Dongning Lee, Alexandra Wolfe, Scot A. Wang, Yong-Xu |
author_facet | Huang, Lei Liu, Pengpeng Du, Yong Pan, Dongning Lee, Alexandra Wolfe, Scot A. Wang, Yong-Xu |
author_sort | Huang, Lei |
collection | PubMed |
description | The endocrine control of food intake remains incompletely understood, and whether the leptin receptor-mediated anorexigenic pathway in the hypothalamus is negatively regulated by a humoral factor is unknown. Here we identify an appetite-stimulating factor - ASRA - that acts as a leptin receptor antagonist. ASRA encodes an 8 kD protein that is abundantly and selectively expressed in adipose tissue and to a lesser extent, in liver, and is upregulated during fasting and cold. ASRA protein associates with autophagosomes and its secretion is induced by energy deficiency. Overexpression of ASRA in mice attenuates leptin receptor signaling leading to elevated blood glucose and development of severe hyperphagic obesity, whereas either adipose- or liver-specific ASRA knockout mice display increased leptin sensitivity, improved glucose homeostasis, reduced food intake, and resistance to high fat diet-induced obesity. Furthermore, ASRA is indispensable for cold-evoked feeding response. Recombinant ASRA (rASRA) protein binds to leptin receptor and suppresses leptin receptor signaling in cultured cells. In vivo, rASRA promotes food intake and increases blood glucose in a leptin receptor signaling-dependent manner. Our studies collectively show that ASRA, acting as a peripheral signal of energy deficit, stimulates appetite and regulates glucose metabolism by antagonizing leptin receptor signaling, thus revealing a previously unknown endocrine mechanism that has important implications for our understanding of leptin resistance. |
format | Online Article Text |
id | pubmed-10515849 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-105158492023-09-23 A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite Huang, Lei Liu, Pengpeng Du, Yong Pan, Dongning Lee, Alexandra Wolfe, Scot A. Wang, Yong-Xu bioRxiv Article The endocrine control of food intake remains incompletely understood, and whether the leptin receptor-mediated anorexigenic pathway in the hypothalamus is negatively regulated by a humoral factor is unknown. Here we identify an appetite-stimulating factor - ASRA - that acts as a leptin receptor antagonist. ASRA encodes an 8 kD protein that is abundantly and selectively expressed in adipose tissue and to a lesser extent, in liver, and is upregulated during fasting and cold. ASRA protein associates with autophagosomes and its secretion is induced by energy deficiency. Overexpression of ASRA in mice attenuates leptin receptor signaling leading to elevated blood glucose and development of severe hyperphagic obesity, whereas either adipose- or liver-specific ASRA knockout mice display increased leptin sensitivity, improved glucose homeostasis, reduced food intake, and resistance to high fat diet-induced obesity. Furthermore, ASRA is indispensable for cold-evoked feeding response. Recombinant ASRA (rASRA) protein binds to leptin receptor and suppresses leptin receptor signaling in cultured cells. In vivo, rASRA promotes food intake and increases blood glucose in a leptin receptor signaling-dependent manner. Our studies collectively show that ASRA, acting as a peripheral signal of energy deficit, stimulates appetite and regulates glucose metabolism by antagonizing leptin receptor signaling, thus revealing a previously unknown endocrine mechanism that has important implications for our understanding of leptin resistance. Cold Spring Harbor Laboratory 2023-09-12 /pmc/articles/PMC10515849/ /pubmed/37745491 http://dx.doi.org/10.1101/2023.09.12.557454 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Huang, Lei Liu, Pengpeng Du, Yong Pan, Dongning Lee, Alexandra Wolfe, Scot A. Wang, Yong-Xu A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite |
title | A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite |
title_full | A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite |
title_fullStr | A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite |
title_full_unstemmed | A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite |
title_short | A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite |
title_sort | brown fat-enriched adipokine, asra, is a leptin receptor antagonist that stimulates appetite |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10515849/ https://www.ncbi.nlm.nih.gov/pubmed/37745491 http://dx.doi.org/10.1101/2023.09.12.557454 |
work_keys_str_mv | AT huanglei abrownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite AT liupengpeng abrownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite AT duyong abrownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite AT pandongning abrownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite AT leealexandra abrownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite AT wolfescota abrownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite AT wangyongxu abrownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite AT huanglei brownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite AT liupengpeng brownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite AT duyong brownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite AT pandongning brownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite AT leealexandra brownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite AT wolfescota brownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite AT wangyongxu brownfatenrichedadipokineasraisaleptinreceptorantagonistthatstimulatesappetite |