SLC35D3 promotes white adipose tissue browning to ameliorate obesity by NOTCH signaling

Hongrui Wang, Liang Yu, Jin’e Wang, Yaqing Zhang, Mengchen Xu, Cheng Lv, Bing Cui, Mengmeng Yuan, Yu Zhang, Yupeng Yan, Rutai Hui and Yibo Wang ()
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Hongrui Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Liang Yu: Chinese Academy of Medical Sciences and Peking Union Medical College
Jin’e Wang: China Three Gorges University
Yaqing Zhang: China Three Gorges University
Mengchen Xu: Chinese Academy of Medical Sciences and Peking Union Medical College
Cheng Lv: Chinese Academy of Medical Sciences and Peking Union Medical College
Bing Cui: Chinese Academy of Medical Sciences and Peking Union Medical College
Mengmeng Yuan: Chinese Academy of Medical Sciences and Peking Union Medical College
Yu Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Yupeng Yan: Chinese Academy of Medical Sciences and Peking Union Medical College
Rutai Hui: Chinese Academy of Medical Sciences and Peking Union Medical College
Yibo Wang: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract White adipose tissue browning can promote lipid burning to increase energy expenditure and improve adiposity. Here, we show that Slc35d3 expression is significantly lower in adipose tissues of obese mice. While adipocyte-specific Slc35d3 knockin is protected against diet-induced obesity, adipocyte-specific Slc35d3 knockout inhibits white adipose tissue browning and causes decreased energy expenditure and impaired insulin sensitivity in mice. Mechanistically, we confirm that SLC35D3 interacts with the NOTCH1 extracellular domain, which leads to the accumulation of NOTCH1 in the endoplasmic reticulum and thus inhibits the NOTCH1 signaling pathway. In addition, knockdown of Notch1 in mouse inguinal white adipose tissue mediated by orthotopic injection of AAV8-adiponectin-shNotch1 shows considerable improvement in obesity and glucolipid metabolism, which is more pronounced in adipocyte-specific Slc35d3 knockout mice than in knockin mice. Overall, in this study, we reveal that SLC35D3 is involved in obesity via NOTCH1 signaling, and low adipose SLC35D3 expression in obesity might be a therapeutic target for obesity and associated metabolic disorders.

Date: 2023
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DOI: 10.1038/s41467-023-43418-5

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