Adipocyte CLDN5 promotes thermogenesis and energy expenditure through regulation of IL10 expression

Ke Feng, Wenqin Wang, Xianlong Gao, Hejie Yan, Mengyuan Xu, Baozhen Fan, Qianfeng Jia, Chao Wang, Jian Yu, Yi Li, Qinfeng Xu, Yanan An, Peng Jiao, Mingxia Wang, Hui Sun, Feng Kong (), Yongfeng Gong () and Shengtian Zhao ()
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Ke Feng: Binzhou Medical University
Wenqin Wang: Binzhou Medical University
Xianlong Gao: Binzhou Medical University
Hejie Yan: Binzhou Medical University
Mengyuan Xu: Binzhou Medical University
Baozhen Fan: Binzhou Medical University
Qianfeng Jia: Binzhou Medical University
Chao Wang: Shandong University
Jian Yu: Yantai Nursing School
Yi Li: Shandong Provincial Engineering Laboratory of Urologic Tissue Reconstruction
Qinfeng Xu: Shandong Provincial Engineering Laboratory of Urologic Tissue Reconstruction
Yanan An: Binzhou Medical University
Peng Jiao: Binzhou Medical University Hospital
Mingxia Wang: Binzhou Medical University
Hui Sun: Binzhou Medical University
Feng Kong: Shandong Provincial Engineering Laboratory of Urologic Tissue Reconstruction
Yongfeng Gong: Binzhou Medical University
Shengtian Zhao: Shandong University

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract The claudin protein family plays key roles in maintaining normal structure and function of epithelial and endothelial tight junctions. While several prior studies have addressed the expression of claudin in adipocytes that do not form tight junctions, here we demonstrate that CLDN5 is selectively expressed in non-thermogenic adipocytes within adipose tissue. Ablation of CLDN5 in adipocyte impairs thermogenesis and energy expenditure. CLDN5 deficiency also significantly increases diet-induced fat mass in mice, accompanied with glucose intolerance and insulin resistance. Mechanistically, CLDN5 affects the subcellular localization of Y-box protein 3, which directly regulates IL10 expression via binding to its promoter and specific sites in 3′-untranslated region, thereby acts in a paracrine manner to signal through IL10R in neighbouring thermogenic adipocytes. These findings expand our understanding about location and function of the extra-tight junction claudin proteins and provide molecular insights into signaling mechanisms underlying adipose thermogenesis that could inform future therapy.

Date: 2025
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DOI: 10.1038/s41467-025-61371-3

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