Adipocyte-specific ablation of Gadd45b exacerbates obesity-associated cellular senescence and metabolic disorders via Fgf1b promoter hypermethylation.

Fan Hu, Yafen Ye, Ningning Bai, Jun Xu, Yikai Wang, Yingying Su, Jingjing Sun, Xuhong Lu, Wenfei Li, Rongrong Xu, Tingting Hu, Miriayi Alimujiang, Junfeng Han, Ling Wu, Xiaojing Ma, Ying Yang

Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. · pubmed

Paper

Abstract

Cellular senescence contributes to obesity-associated adipose dysfunction, yet the upstream regulators of this process remain poorly understood. Here, we identified growth arrest and DNA damage-inducible protein 45 beta (Gadd45b) as an adaptive regulator of adipocyte senescence and systemic metabolic homeostasis. GADD45B expression was elevated in adipose tissue from obese human subjects and positively correlated with senescence-related markers. Adipocyte-specific Gadd45b deletion in mice caused depot-selective remodeling under high-fat diet, with inguinal fat hypertrophy but epididymal white adipose tissue (eWAT) atrophy, accompanied by enhanced DNA damage and pronounced senescence. These alterations thereby contributed to impaired lipolytic response, hepatic steatosis and insulin resistance, underscoring the vital role of Gadd45b in maintaining eWAT expandability during nutritional overload. Mechanistically, Gadd45b deficiency led to hypermethylation of fibroblast growth factor 1b (Fgf1b) promoter and reduced Fgf1 expression in eWAT, thereby exacerbating adipose senescence and metabolic abnormalities, while recombinant FGF1 treatment partially reversed these defects. Collectively, our findings establish Gadd45b as a depot-specific epigenetic regulator that sustains adipose tissue plasticity and links DNA damage responses to adipocyte senescence and metabolic homeostasis in obesity.

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Research summary

Adipocyte-specific deletion of Gadd45b exacerbates obesity-induced metabolic dysfunction and cellular senescence in white adipose tissue by promoting Fgf1b promoter hypermethylation. This study provides incremental mechanistic insight into the role of Gadd45b in adipose tissue plasticity and senescence, which is relevant to understanding age-related metabolic decline, but represents a specific molecular pathway rather than a broad breakthrough in longevity science.

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