Journal Article

PSPC1-SMAD3 axis regulates iron-induced beiging of adipocytes in white adipose tissue

He, Rui, Wang, Wen-She, Kang, Qian-Qian, Pan, Ru-Ping, Deng, Hong-Yan, Gao, Rong-Hui, Zhu, Zeng-Zhe, Ge, Jing, Xie, Yu-Yu, Yang, Min, Peng, Xue-Min, Li, Dan-Pei, Wang, Huan-Yu, Wang, Zhi-Han, Liu, Yu-Lian, Chen, Yong, Liu, Jia-Dai

2025

Overview

Beige adipose tissue protects against obesity and related metabolic diseases by catabolizing stored energy to generate heat. While iron is essential for this process due to its role in mitochondrial function, the specific signaling mechanisms involved remain unclear. Here, we report that diet-induced obese mice exhibit a local iron deficiency in subcutaneous adipose tissue. Crucially, through integrated multi-omics approaches (RNA-seq and ATAC-seq), we identify that iron downregulates Paraspeckle component 1(PSPC1), which interacts with SMAD family member 3 (SMAD3) to promote its phosphorylation. The iron-induced reduction of PSPC1 alleviates the repressive signaling of SMAD3 on thermogenic gene expression, thereby inducing the beiging of white adipocytes. Furthermore, overexpression of Pspc1 in subcutaneous adipose tissue counteracted the iron-induced suppression of SMAD3 phosphorylation, effectively reversing iron-induced beiging of white adipocytes and its associated metabolic benefits. Collectively, our findings demonstrate that iron promotes the beiging of white adipocytes within subcutaneous adipose tissue and exerts anti-obesity effect by inhibiting PSPC1-SMAD3 axis, which may provide a potential therapeutic target for obesity and its related metabolic diseases. Graphical Abstract Iron protects against diet-induced obesity by promoting the beiging of adipocytes in white adipose tissue. This study identifies a novel regulatory mechanism where iron downregulates the expression of PSPC1. The reduction in PSPC1, which interacts with SMAD3, leads to decreased SMAD3 phosphorylation, thereby relieving its inhibition on thermogenic genes.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adipocytes / Adipose tissue / Adipose Tissue, White - cytology / Adipose Tissue, White - metabolism / Adipose tissues / Animals / Antibodies / Antigens / Beige adipocytes / Binding proteins / Biomedical and Life Sciences / Body fat / Cell Biology / Cellular signal transduction / Cytokines and Growth Factors / Diet / Down-regulation / Experiments / Fat cells / Fatty liver / Gene expression / Genetic aspects / Glucose / Health aspects / Insulin / Iron / Iron - metabolism / Iron - pharmacology / Iron deficiency / Iron in the body / Life Sciences / Male / Metabolic disorders / Metabolism / Mice / Mice, Inbred C57BL / Obesity / Obesity - metabolism / Obesity - pathology / Penicillin / Phosphorylation / Phosphorylation - drug effects / Prevention / Protein-Ligand Interactions / PSPC1-SMAD3 axis / Reagents / Receptors / RNA Splicing Factors - metabolism / Signal Transduction - drug effects / Smad protein / Smad proteins / Smad3 protein / Smad3 Protein - metabolism / Therapeutic targets / Thermogenesis