Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue

Chih-Hao Wang (), Tadataka Tsuji, Li-Hong Wu, Cheng-Ying Yang, Tian Lian Huang, Mari Sato, Farnaz Shamsi and Yu-Hua Tseng ()
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Chih-Hao Wang: China Medical University
Tadataka Tsuji: Harvard Medical School
Li-Hong Wu: China Medical University
Cheng-Ying Yang: China Medical University
Tian Lian Huang: Harvard Medical School
Mari Sato: Harvard Medical School
Farnaz Shamsi: Harvard Medical School
Yu-Hua Tseng: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.

Date: 2024
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DOI: 10.1038/s41467-024-51579-0

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