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, Simon Futers T, 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
Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK.
Integrative Vascular Biology Laboratory, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Nat Commun. 2025 Jan 2;16(1):170. doi: 10.1038/s41467-024-54669-1.
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.
在最近几十年里，生活方式的改变导致了广泛的营养性肥胖及其相关并发症。将脂肪组织重塑作为肥胖及其并发症的治疗目标已引起广泛关注，并仍在积极探索中。内皮细胞衬于所有血管内，且与包括脂肪细胞在内的所有细胞相邻。内皮细胞被认为是一种旁分泌器官。我们探讨内皮胰岛素样生长因子-1受体（IGF-1R）作为白色脂肪表型旁分泌调节剂的作用。我们发现，在雄性小鼠高脂喂养条件下，内皮IGF-1R表达降低会导致特定部位有益的白色脂肪组织重塑，增加全身能量消耗，并通过非细胞自主旁分泌机制增强胰岛素敏感性。我们证明，内皮丙二酸水平升高可能起作用，且丙二酸前药在治疗肥胖相关代谢疾病方面具有潜在的治疗相关特性。
