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Aims/hypothesis <p>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&#xa0;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.</p> Methods <p>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 <i>Nrg4</i>-knockout (BKO) mice, global <i>Nrg4</i>-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.</p> Results <p>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.</p> Conclusions/interpretation <p>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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 发表日期：

    2025年2月27日

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  • Sheng Ding,
  • Jin-ling Xu,
  • Jia-yue Tong,
  • Yang-yang Cheng,
  • Ling-feng Shi,
  • Wei Wei,
  • Li-ming Zhang,
  • Jia-jia Zhang,
  • Bi-ying Meng,
  • Xiang-yan Peng,
  • Lin Xiang,
  • Shu-guang Li,
  • Ling Yue,
  • Zhong-jing Wang,
  • Guang-da Xiang

摘要

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.

Graphical Abstract