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

Luk, Cheukyau; Bridge, Katherine I.; Warmke, Nele; Simmons, Katie J.; Drozd, Michael; Moran, Amy; MacCannell, Amanda D. V.; Cheng, Chew W.; Straw, Sam; Scragg, Jason L.; Smith, Jessica; Ozber, Claire H.; Wilkinson, Chloe G.; Skromna, Anna; Makava, Natallia; Prag, Hiran A.; Futers, T. Simon; Brown, Oliver I.; Bruns, Alexander-Francisco; Walker, Andrew MN; Watt, Nicole T.; Mughal, Romana; Griffin, Kathryn J.; Yuldasheva, Nadira Y.; Limumpornpetch, Sunti; Viswambharan, Hema; Sukumar, Piruthivi; Beech, David J.; Vidal-Puig, Antonio; Witte, Klaus K.; Murphy, Michael P.; Hartley, Richard C.; Wheatcroft, Stephen B.; Cubbon, Richard M.; Roberts, Lee D.; Kearney, Mark T.; Haywood, Natalie J.

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

Cheukyau Luk, Katherine I. Bridge, Nele Warmke, Katie J. Simmons, Michael Drozd, Amy Moran, Amanda D. V. MacCannell, Chew W. Cheng, Sam Straw, Jason L. Scragg, Jessica Smith, Claire H. Ozber, Chloe G. Wilkinson, Anna Skromna, Natallia Makava, Hiran A. Prag, T. Simon Futers, Oliver I. Brown, Alexander-Francisco Bruns, Andrew MN Walker, Nicole T. Watt, Romana Mughal, Kathryn J. Griffin, Nadira Y. Yuldasheva, Sunti Limumpornpetch, Hema Viswambharan, Piruthivi Sukumar, David J. Beech, Antonio Vidal-Puig, Klaus K. Witte, Michael P. Murphy, Richard C. Hartley, Stephen B. Wheatcroft, Richard M. Cubbon, Lee D. Roberts, Mark T. Kearney () and Natalie J. Haywood
Additional contact information
Cheukyau Luk: University of Leeds
Katherine I. Bridge: University of Leeds
Nele Warmke: University of Leeds
Katie J. Simmons: University of Leeds
Michael Drozd: University of Leeds
Amy Moran: University of Leeds
Amanda D. V. MacCannell: University of Leeds
Chew W. Cheng: University of Leeds
Sam Straw: University of Leeds
Jason L. Scragg: University of Leeds
Jessica Smith: University of Leeds
Claire H. Ozber: University of Leeds
Chloe G. Wilkinson: University of Leeds
Anna Skromna: University of Leeds
Natallia Makava: University of Leeds
Hiran A. Prag: University of Cambridge, Cambridge Biomedical Campus
T. Simon Futers: University of Leeds
Oliver I. Brown: University of Leeds
Alexander-Francisco Bruns: University of Leeds
Andrew MN Walker: University of Leeds
Nicole T. Watt: University of Leeds
Romana Mughal: University of Leeds
Kathryn J. Griffin: University of Leeds
Nadira Y. Yuldasheva: University of Leeds
Sunti Limumpornpetch: University of Leeds
Hema Viswambharan: University of Leeds
Piruthivi Sukumar: University of Leeds
David J. Beech: University of Leeds
Antonio Vidal-Puig: University of Cambridge Metabolic Research Laboratories
Klaus K. Witte: University of Leeds
Michael P. Murphy: University of Cambridge, Cambridge Biomedical Campus
Richard C. Hartley: University of Glasgow
Stephen B. Wheatcroft: University of Leeds
Richard M. Cubbon: University of Leeds
Lee D. Roberts: University of Leeds
Mark T. Kearney: University of Leeds
Natalie J. Haywood: University of Leeds

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-54669-1

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