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Suppression of Endothelial AGO1 Promotes Adipose Tissue Browning and Improves Metabolic Dysfunction.

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

Circulation · 2020 · Vol. 142 (4) · pp. 365-379

PubMed ↗ DOI ↗ PMC full text ↗

Abstract

Metabolic disorders such as obesity and diabetes mellitus 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 vascular endothelial growth factor-vascular endothelial growth factor receptor-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. We generated and subjected mice with EC-AGO1 deletion (EC-AGO1-knockout [KO]) and their wild-type littermates to a fast food-mimicking, high-fat high-sucrose diet and profiled the metabolic phenotypes. We used crosslinking immunoprecipitation- 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 donors and donors with obesity/type 2 diabetes mellitus. We identified an antiobesity 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 (<i>THBS1</i>/TSP1), an antiangiogenic and proinflammatory cytokine that promotes insulin resistance. In EC-AGO1-KO mice, overexpression of TSP1 substantially attenuated the beneficial phenotype. In human endothelium isolated from donors with obesity or type 2 diabetes mellitus, AGO1 and THBS1 are expressed at higher levels than the healthy controls, supporting a pathological role of this pathway. Our study suggests a novel mechanism by which ECs, through the AGO1-TSP1 pathway, control vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state.

Linked datasets 5

GSE136907 GSE · via ncbi_elink
GEO ↗

Individual nucleotide resolution Crosslinking Immunoprecipitation (iCLIP)-seq

Homo sapiens

16 data files
FileTypeSize
SRR10071151_GSM4061740 RIP-Seq 310.0 MB
SRR10071152_GSM4061740 RIP-Seq 1.9 GB
SRR10071153_GSM4061741 RIP-Seq 804.0 MB
SRR10071154_GSM4061741 RIP-Seq 378.0 MB
SRR10071155_GSM4061742 RIP-Seq 1.9 GB
SRR10071156_GSM4061742 RIP-Seq 1.1 GB
SRR10071157_GSM4061743 RIP-Seq 3.5 GB
SRR10071158_GSM4061743 RIP-Seq 2.4 GB
ZNH_NoIndex_L008_R1.R09_AGO1_normoxia_LowRNAse_H.fastq.gz RIP-Seq 3.5 GB
ZNH_NoIndex_L008_R1.R10_AGO1_normoxia_HighRNAse_H.fastq.gz RIP-Seq 1.9 GB
ZNH_NoIndex_L008_R1.R11_AGO1_hypoxia_LowRNAse_H.fastq.gz RIP-Seq 804.4 MB
ZNH_NoIndex_L008_R1.R12_AGO1_hypoxia_HighRNase_H.fastq.gz RIP-Seq 310.5 MB
ZNL_NoIndex_L007_R1.R09_AGO1_normoxia_LowRNAse_L.fastq.gz RIP-Seq 2.4 GB
ZNL_NoIndex_L007_R1.R10_AGO1_normoxia_HighRNAse_L.fastq.gz RIP-Seq 1.1 GB
ZNL_NoIndex_L007_R1.R11_AGO1_hypoxia_LowRNAse_L.fastq.gz RIP-Seq 378.5 MB
ZNL_NoIndex_L007_R1.R12_AGO1_hypoxia_HighRNase_L.fastq.gz RIP-Seq 1.9 GB
GSE136908 GSE · via ncbi_elink
GEO ↗

RNA Seq of HMVEC under hypoxia

Homo sapiens

16 data files
FileTypeSize
JK_A1_R1_merged.fastq.gz RNA-Seq 957.3 MB
JK_A2_R1_merged.fastq.gz RNA-Seq 1.0 GB
JK_A3_R1_merged.fastq.gz RNA-Seq 1.1 GB
JK_A4_R1_merged.fastq.gz RNA-Seq 1.2 GB
JK_N1_R1_merged.fastq.gz RNA-Seq 1.1 GB
JK_N2_R1_merged.fastq.gz RNA-Seq 995.2 MB
JK_N3_R1_merged.fastq.gz RNA-Seq 1.2 GB
JK_N4_R1_merged.fastq.gz RNA-Seq 1.1 GB
SRR10071159_GSM4061744 RNA-Seq 957.0 MB
SRR10071160_GSM4061745 RNA-Seq 1.0 GB
SRR10071161_GSM4061746 RNA-Seq 1.1 GB
SRR10071162_GSM4061747 RNA-Seq 1.2 GB
SRR10071163_GSM4061748 RNA-Seq 1.1 GB
SRR10071164_GSM4061749 RNA-Seq 995.0 MB
SRR10071165_GSM4061750 RNA-Seq 1.2 GB
SRR10071166_GSM4061751 RNA-Seq 1.1 GB
GSE136912 GSE · via ncbi_elink
GEO ↗

Endothelial-AGO1-knockout (EC-AGO1-KO) mice and wild-type (WT) littermates

Mus musculus

GSE136910 GSE · via ncbi_elink
GEO ↗

RNA Seq of Subcutaneous adipose tissue from endothelial-AGO1-knockout (EC-AGO1-KO) mice and wild-type (WT) littermates

Mus musculus

19 data files
FileTypeSize
AGO_1_Hete_SAT_S21_R1_001.fastq.gz RNA-Seq 5.8 GB
AGO_1_Homo_SAT_S19_R1_001.fastq.gz RNA-Seq 4.8 GB
AGO_2_Hete_SAT_S24_R1_001.fastq.gz RNA-Seq 5.6 GB
AGO_2_Homo_SAT_S25_R1_001.fastq.gz RNA-Seq 5.2 GB
AGO_3_Hete_SAT_S27_R1_001.fastq.gz RNA-Seq 4.7 GB
AGO_3_Homo_SAT_S22_R1_001.fastq.gz RNA-Seq 5.3 GB
SRR10071341_GSM4061752 RNA-Seq 5.0 GB
SRR10071342_GSM4061753 RNA-Seq 5.4 GB
SRR10071343_GSM4061754 RNA-Seq 6.0 GB
SRR10071344_GSM4061755 RNA-Seq 5.8 GB
SRR10071345_GSM4061756 RNA-Seq 5.6 GB
SRR10071346 RNA-Seq 4.7 GB
SRR10071346_GSM4061757 RNA-Seq 4.7 GB
SRR10071347_GSM4061758 RNA-Seq 4.8 GB
SRR10071348_GSM4061759 RNA-Seq 5.2 GB
SRR10071349_GSM4061760 RNA-Seq 5.3 GB
WT_1_SAT_S26_R1_001.fastq.gz RNA-Seq 5.0 GB
WT_2_SAT_S23_R1_001.fastq.gz RNA-Seq 5.4 GB
WT_3_SAT_S20_R1_001.fastq.gz RNA-Seq 6.0 GB
GSE136911 GSE · via ncbi_elink
GEO ↗

small RNA Seq of Subcutaneous adipose tissue from endothelial-AGO1-knockout (EC-AGO1-KO) mice and wild-type (WT) littermates fed 16 week of high fat high sucrose diet

Mus musculus

18 data files
FileTypeSize
AGO_1_Hete_SAT_S54_R1_001.fastq.gz miRNA-Seq 851.9 MB
AGO_1_Homo_SAT_S59_R1_001.fastq.gz miRNA-Seq 591.8 MB
AGO_2_Hete_SAT_S56_R1_001.fastq.gz miRNA-Seq 356.6 MB
AGO_2_Homo_SAT_S57_R1_001.fastq.gz miRNA-Seq 508.8 MB
AGO_3_Hete_SAT_S55_R1_001.fastq.gz miRNA-Seq 638.7 MB
AGO_3_Homo_SAT_S58_R1_001.fastq.gz miRNA-Seq 723.1 MB
SRR10071167_GSM4061761 miRNA-Seq 552.0 MB
SRR10071168_GSM4061762 miRNA-Seq 458.0 MB
SRR10071169_GSM4061763 miRNA-Seq 625.0 MB
SRR10071170_GSM4061764 miRNA-Seq 851.0 MB
SRR10071171_GSM4061765 miRNA-Seq 356.0 MB
SRR10071172_GSM4061766 miRNA-Seq 638.0 MB
SRR10071173_GSM4061767 miRNA-Seq 591.0 MB
SRR10071174_GSM4061768 miRNA-Seq 508.0 MB
SRR10071175_GSM4061769 miRNA-Seq 723.0 MB
WT_1_SAT_S52_R1_001.fastq.gz miRNA-Seq 552.5 MB
WT_2_SAT_S51_R1_001.fastq.gz miRNA-Seq 458.5 MB
WT_3_SAT_S74_R1_001.fastq.gz miRNA-Seq 626.0 MB

Potentially related datasets 1

These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.

Accession Source Title
GSE136912 GSE · GEO GEO ↗ Endothelial-AGO1-knockout (EC-AGO1-KO) mice and wild-type (WT) littermates

Analysis pipelines 5

Pipeline Assay Steps Dataset
GSE136907 iCLIP Data Processing geo_data_processing iCLIP 2 GSE136907
GSE136908 Data Processing geo_data_processing — 2 GSE136908
GSE136910 Data Processing geo_data_processing — 2 GSE136910
GSE136911 Data Processing geo_data_processing — 2 GSE136911
GSE136912 Data Processing geo_data_processing — 2 GSE136912
Funding 10 grants
Grant Funder
U24 HG009889 NHGRI NIH HHS (United States)
R01 HG004659 NHGRI NIH HHS (United States)
U41 HG009889 NHGRI NIH HHS (United States)
U54 HG007005 NHGRI NIH HHS (United States)
R01 HL145170 NHLBI NIH HHS (United States)
R01 DK081705 NIDDK NIH HHS (United States)
P30 CA033572 NCI NIH HHS (United States)
R00 HL122368 NHLBI NIH HHS (United States)
DP1 HD087990 NICHD NIH HHS (United States)
K99 HL122368 NHLBI NIH HHS (United States)