Paracrine role of endothelial IGF-1 receptor in depot-specific adipose tissue adaptation in male mice

Abstract

During recent decades, changes in lifestyle have led to widespread nutritional obesity and its related complications. Remodelling adipose tissue as a therapeutic goal for obesity and its complications has attracted much attention and continues to be actively explored. The endothelium lines all blood vessels and is close to all cells, including adipocytes. The endothelium has been suggested to act as a paracrine organ. We explore the role of endothelial insulin-like growth factor-1 receptor (IGF-1R), as a paracrine modulator of white adipose phenotype. We show that a reduction in endothelial IGF-1R expression in the presence of high-fat feeding in male mice leads to depot-specific beneficial white adipose tissue remodelling, increases whole-body energy expenditure and enhances insulin sensitivity via a non-cell-autonomous paracrine mechanism. We demonstrate that increased endothelial malonate may be contributory and that malonate prodrugs have potentially therapeutically relevant properties in the treatment of obesity-related metabolic disease.

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Item Type:	Article
Authors/Creators:	Luk, C. Bridge, K.I. Warmke, N. Simmons, K.J. Drozd, M. Moran, A. MacCannell, A.D.V. Cheng, C.W. Straw, S. Scragg, J.L. Smith, J. Ozber, C.H. Wilkinson, C.G. Skromna, A. Makava, N. Prag, H.A. Futers, T.S. Brown, O.I. Bruns, A.-F. Walker, A.M.N. Watt, N.T. Mughal, R. Griffin, K.J. Yuldasheva, N.Y. Limumpornpetch, S. Viswambharan, H. Sukumar, P. Beech, D.J. Vidal-Puig, A. Witte, K.K. Murphy, M.P. Hartley, R.C. Wheatcroft, S.B. Cubbon, R.M. Roberts, L.D. Kearney, M.T. Haywood, N.J. https://orcid.org/0000-0002-8762-7257
Copyright, Publisher and Additional Information:	© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/.
Dates:	Published: 2 January 2025 Published (online): 2 January 2025 Accepted: 18 November 2024
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds)
Funding Information:	Funder Grant number Society for Endocrinology No Ext Ref
Depositing User:	Symplectic Publications
Date Deposited:	04 Dec 2024 16:59
Last Modified:	13 Jan 2025 08:49
Published Version:	https://www.nature.com/articles/s41467-024-54669-1
Status:	Published
Publisher:	Nature Research
Identification Number:	10.1038/s41467-024-54669-1
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:220223

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Paracrine role of endothelial IGF-1 receptor in depot-specific adipose tissue adaptation in male mice

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