Nuclear Fetuin-A Drives Adipocyte Senescence via HIF-1α During Obesity

Abstract Fetuin-A (FetA), a liver derived glycoprotein, has emerged from genome-wide association studies and epidemiological surveillance as a serum biomarker linked to obesity-driven type 2 diabetes mellitus (T2D), primarily due to its contribution to adipose tissue dysfunction. Here, we uncovered an eccentric role of nuclear FetA in visceral white adipocytes of obese T2D conditions. Hypoxia-inducible factor-1α (HIF-1α) facilitates the nuclear translocation of FetA via direct interaction, a process that promotes the emergence of a senescence-associated secretory phenotype (SASP). While nuclear co-localization of FetA and HIF-1α strongly promotes adipocyte senescence, silencing FetA alone is sufficient to prevent senescence, even in conditions of HIF-1α overexpression or lipid-rich hypoxic stress. Although nuclear FetA does not directly bind to DNA, it enhances HIF-1α transcriptional activity, potentiating the activation of senescence markers such as β-galactosidase and p53. Selective knockdown of FetA in obese mice notably reduced adipocyte senescence in visceral white adipose tissue (vWAT) and improved fasting glycemic control. Collectively, our findings reveal a previously unrecognized nuclear function for FetA in orchestrating adipocyte senescence in obesity, establishing nuclear FetA as a potential therapeutic target for obesity related metabolic diseases.