Smad4-mediated angiogenesis facilitates the beiging of white adipose tissue in mice

Chenguang Wang; Yalan Wu; Yangxian Li; Yang Zhang; Yee Lok Fung; Ka Kui Tong; Chi Wai Lau; Li Xiang; Kin Ming Kwan; Li-Ru You; Yu Huang; Xiao Yu Tian

doi:10.1016/j.isci.2023.106272

Smad4-mediated angiogenesis facilitates the beiging of white adipose tissue in mice

iScience. 2023 Feb 25;26(3):106272. doi: 10.1016/j.isci.2023.106272. eCollection 2023 Mar 17.

Authors

Chenguang Wang¹, Yalan Wu¹, Yangxian Li¹, Yang Zhang², Yee Lok Fung¹, Ka Kui Tong¹, Chi Wai Lau¹, Li Xiang¹, Kin Ming Kwan³, Li-Ru You⁴, Yu Huang^{1

5

6}, Xiao Yu Tian^{1

6}

Affiliations

¹ School of Biomedical Sciences, Heart and Vascular Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
² School of Public Health (Shenzhen), Sun Yat-Sen University, Shenzhen, Guangdong 518107, China.
³ School of Life Science, State Key Laboratory of Agrobiotechnology (CUHK), Center for Cell and Developmental Biology, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁴ Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan.
⁵ Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China.
⁶ CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong 518057, China.

Abstract

Beige adipocytes are thermogenic with high expression of uncoupling protein 1 in the white adipose tissue (WAT), accompanied by angiogenesis. Previous studies showed that Smad4 is important for angiogenesis. Here we studied whether endothelial Smad4-mediated angiogenesis is involved in WAT beiging. Inducible knockout of endothelial cell (EC) selective Smad4 (Smad4 ^iEC-KO) was achieved by using the Smad4 ^Floxp/floxp and Tie2 ^CreERT2 mice. Beige fat induction achieved by cold or adrenergic agonist, and angiogenesis were attenuated in WAT of Smad4 ^iEC-KO mice, with the less proliferation of ECs and adipogenic precursors. RNA sequencing of human ECs showed that Smad4 is involved in angiogenesis-related pathways. Knockdown of SMAD4 attenuated the upregulation of VEGFA, PDGFA, and angiogenesis in vitro. Treatment of human ECs with palmitic acid-induced Smad1/5 phosphorylation and the upregulation of core endothelial genes. Our study shows that endothelial Smad4 is involved in WAT beiging through angiogenesis and the expansion of adipose precursors into beige adipocytes.

Keywords: Biological sciences; Cell biology; Molecular biology; Physiology.