Circulation. 2020 May 12.
Xiaofang Tang,
Yifei Miao,
Yingjun Luo,
Kiran Sriram,
Zhijie Qi,
Feng-Mao Lin,
Yusu Gu,
Chih-Hung Lai,
Chien-Yi Hsu,
Kirk L Peterson,
Kendall Van Keuren-Jensen,
Patrick T Fueger,
Gene W Yeo,
Rama Natarajan,
Sheng Zhong,
Zhen Bouman Chen.
Background: Metabolic disorders such as obesity and diabetes can cause dysfunction of endothelial cells (ECs) and vascular rarefaction in adipose tissues. However, the modulatory role of ECs in adipose tissue function is not fully understood. Other than VEGF-VEGFR-mediated angiogenic signaling, little is known about the EC-derived signals in adipose tissue regulation. We previously identified Argonaute 1 (AGO1; a key component of microRNA-induced silencing complex) as a crucial regulator in hypoxia-induced angiogenesis. In this study, we intend to determine the AGO1-mediated EC transcriptome, the functional importance of AGO1-regulated endothelial function in vivo, and the relevance to adipose tissue function and obesity. Methods: We generated and subjected mice with EC-AGO1 deletion (EC-AGO1-KO) and their wild-type littermates (WT) to a fast-food-mimicking, high-fat high-sucrose diet and profiled the metabolic phenotypes. We employed crosslinking immunoprecipitation (iCLIP)- and RNA-sequencing to identify the AGO1-mediated mechanisms underlying the observed metabolic phenotype of EC-AGO1-KO. We further leveraged cell cultures and mouse models to validate the functional importance of the identified molecular pathway, for which the translational relevance was explored using human endothelium isolated from healthy and obese/Type 2 diabetic donors. Results: We identified an anti-obesity phenotype of EC-AGO1-KO, evident by lower body weight and body fat, improved insulin sensitivity, and enhanced energy expenditure. At the organ level, we observed the most significant phenotype in the subcutaneous and brown adipose tissues of KO mice, with greater vascularity and enhanced browning and thermogenesis. Mechanistically, EC-AGO1 suppression results in inhibition of thrombospondin-1 (THBS1/TSP1), an anti-angiogenic and pro-inflammatory cytokine that promotes insulin resistance. In EC-AGO1-KO mice, overexpression of TSP1 substantially attenuated the beneficial phenotype. In human endothelium isolated from obese and/or type 2 diabetic donors, AGO1 and THBS1 are expressed at higher levels than the healthy controls, supporting a pathological role of this pathway. Conclusions: Our study suggests a novel mechanism by which ECs, through AGO1-TSP1 pathway, control vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state.
Keywords: Argonaute; Thrombspondin; browning; diabetes; metabolic syndrome