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A The endothelium as a paracrine modulator of adipose function: a role for endothelial IGF-1R in the setting of nutritional obesity
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  1. Natalie J Haywood,
  2. Katherine I Bridge,
  3. Cheuk Luk,
  4. Amy Moran,
  5. Nadira Y Yuldasheva,
  6. Lee D Roberts,
  7. Richard M Cubbon,
  8. Mark T Kearney
  1. Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, UK

Abstract

In obesity the relationship between white adipose tissue expansion and neovascularisation becomes uncoupled leading to inadequate perfusion of adipose tissue. Under these circumstances the secretory profile of adipocytes becomes unfavourable and pro-atherosclerotic.

We hypothesised that reducing endothelial insulin like growth factor 1 receptor (IGF-1R) expression affects adipose tissue remodelling as a result of communication between endothelial cells and adipocytes.

To study the effect of endothelial IGF-1R deficiency, we developed a mouse with inducible endothelial specific IGF-1R deficiency (ECIGF-1RKD). In the context of diet induced obesity, ECIGF-1RKD mice were more insulin sensitive and had increased energy expenditure compared to littermate controls. ECIGF-1RKD mice also had favourable changes specific to the white adipose tissue, including; increased uncoupling protein-1 and vascular endothelial growth factor expression, enhanced endothelial sprouting and greater vascularisation.

The mechanisms underpinning the specific effect of endothelial specific IGF-1R deficiency on white adipose tissue were then explored in more detail. Lineage tracing experiments eliminated the possibility that ECIGF-1RKD endothelial cells were directly differentiating into brown/brite adipocytes. In vitro treatment of primary human white adipocytes with conditioned media from isolated ECIGF-1RKD endothelial cells revealed an altered secretome which caused browning of human white adipocytes in culture.

The favourable metabolic profile seen in ECIGF-1RKD mice are the result of an altered endothelial secretome. The endothelial secretome, its production in the context of IGF-1R depletion, and its action on white adipose tissue provide a potential novel therapeutic strategy to combat the negative metabolic consequences of diet-induced obesity.

  • Endothelium
  • adipose tissue
  • secretome

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