Autocrine effect of vascular endothelial growth factor-A is essential for mitochondrial function in brown adipocytes

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• 作者：Kiana Mahdaviani^a ; David Chess^a ; Yuanyuan Wu^a ; Orian Shirihai^a ; Tamar R. Aprahamian^b ; ^{aprahami@bu.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：BAT ; brown adipose tissue ; NE ; norepinephrine ; OCR ; oxygen consumption rate ; VEGF-A ; vascular endothelial growth factor-A ; WAT ; white adipose tissue
• 刊名：Metabolism
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：65
• 期：1
• 页码：26-35
• 全文大小：1223 K

文摘

The obesity epidemic in the United States, as well as the accompanying condition of type 2 diabetes, puts a majority of the population at an increased risk of developing cardiovascular diseases including coronary artery disease, stroke, and myocardial infarction. In contrast to white adipose tissue (WAT), brown adipose tissue (BAT) is well vascularized, rich in mitochondria, and highly oxidative. While it is known that the angiogenic factor VEGF-A is required for brown adipocyte development, the functional consequences and exact mechanism remain to be elucidated. Here, we show that VEGF-A plays an essential autocrine role in the function of BAT.

Materials and methods

Mouse models were generated with an adipose-specific and macrophage-specific ablation of VEGF-A. Adipose tissue characteristics and thermogenic response were analyzed in vivo, and mitochondrial morphology and oxidative respiration were analyzed in vitro to assess effects of endogenous VEGF-A ablation.

Results

VEGF-A expression levels are highest in adipocyte precursors compared to immune or endothelial cell populations within both WAT and BAT. Loss of VEGF-A in adipocytes, but not macrophages, results in decreased adipose tissue vascularization, with remarkably diminished thermogenic capacity in vivo. Complete ablation of endogenous VEGF-A decreases oxidative capacity of mitochondria in brown adipocytes. Further, acute ablation of VEGF-A in brown adipocytes in vitro impairs mitochondrial respiration, despite similar mitochondrial mass compared to controls.

Conclusion

These data demonstrate that VEGF-A serves to orchestrate the acquisition of thermogenic capacity of brown adipocytes through mitochondrial function in conjunction with the recruitment of blood vessels.