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. 2025 May;68(5):1057-1075.
doi: 10.1007/s00125-025-06385-8. Epub 2025 Feb 27.

Brown adipose tissue alleviates podocyte apoptosis through NRG4 in a male mouse model of diabetic kidney disease

Sheng Ding  1   2   3 , Jin-Ling Xu  1   4 , Jia-Yue Tong  1   2 , Yang-Yang Cheng  1   2 , Ling-Feng Shi  1   2 , Wei Wei  1   2   4 , Li-Ming Zhang  1   2 , Jia-Jia Zhang  1 , Bi-Ying Meng  1 , Xiang-Yan Peng  1   2 , Lin Xiang  1 , Shu-Guang Li  1 , Ling Yue  1 , Zhong-Jing Wang  5 , Guang-da Xiang  6   7
Affiliations

Brown adipose tissue alleviates podocyte apoptosis through NRG4 in a male mouse model of diabetic kidney disease

Sheng Ding et al. Diabetologia. 2025 May.

Abstract

Aims/hypothesis: Brown adipose tissue (BAT) consumes excess energy through heat production by uncoupling protein 1 (UCP1) to regulate the metabolic profile, but the UCP1-independent mechanisms of BAT, such as in endocrine function, are largely unknown. Our previous study showed that BAT-derived neuregulin 4 (NRG4) displays anti-atherosclerotic properties. Thus, we hypothesised that BAT could regulate diabetic nephropathy, a diabetic microvascular complication, via NRG4.

Methods: To investigate the influence of NRG4 from BAT on podocyte apoptosis, both loss- and gain-of-function approaches were used in in vivo experiments. Diabetic nephropathy models were created using BAT-specific Nrg4-knockout (BKO) mice, global Nrg4-knockout (KO) mice and wild-type (WT) mice. In in vitro studies, podocytes (MPC5) were exposed to glucose and recombinant NRG4 (rNrg4). Additionally, brown adipocytes were co-cultured with MPC5 podocytes using a transwell system. The expression levels of proteins associated with podocyte apoptosis and signalling pathways were measured.

Results: BAT-specific NRG4 deficiency aggravated podocyte apoptosis (increased by 47.46%) and increased the urinary albumin/creatinine ratio (increased by 41.71%), decreased nephrin expression and increased desmin expression. As expected, these changes were reversed by NRG4 replenishment using adeno-associated virus-NRG4 interscapular BAT injection and BAT transplantation assays in KO mice. Additionally, co-culture experiments demonstrated that brown adipocytes from WT mice could alleviate high-glucose-induced podocyte apoptosis. In in vitro experiments, recombinant NRG4 inhibited high-glucose-induced podocyte apoptosis. Mechanistically, the Akt-glycogen synthase kinase 3 β (GSK-3β) pathway is crucial for the protection that BAT-derived NRG4 provides to podocytes in diabetic nephropathy.

Conclusions/interpretation: Our data show that BAT had a protective effect on podocyte apoptosis in diabetic nephropathy through BAT-derived NRG4, and the Akt-GSK‑3β signalling pathway may mediate the inhibition of BAT-derived NRG4 on podocyte apoptosis in diabetic nephropathy.

Keywords: Apoptosis; Brown adipocytes; Diabetic nephropathy; Neuregulin 4; Podocytes.

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Conflict of interest statement

Acknowledgements: The authors thank X. Gong and Y. Zhu from Chronic Disease Management Center, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China for their help with statistics and graphs. Data availability: All data generated or analysed during this study are included in this published article and ESM files. Funding: This work was funded by grants from the National Natural Science Foundation of China (no. 82170857, 81870573), Natural Science Foundation of Project of Hubei Province (no. 2022CFC022), Research Project of Hubei Administration of Traditional Chinese Medicine (no. ZY2023F060), Wuhan Medical Science Research Project (no. WX23A56) and policy supported by Wuhan Municipal Health Youth Talent Training Program. Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: SD, JLX, JYT, YYC, LFS, WW, LMZ, JJZ, BYM, XYP, LX and SGL were responsible for data acquisition and interpretation. SD, JLX and JYT conducted the experiments. SD, LY, ZJW and GDX focused on the conception and design of the study and analysis of data. SD drafted the manuscript. All authors contributed to its revision and approved the final manuscript for submission. GDX is the guarantor of this work.

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