Work

High-fat diet induces senescence in ADSCs via CDK4 ubiquitination-mediated cell cycle disruption, contributing to impaired glucose tolerance

Year: 2025

Type: article

Abstract: High-fat diet (HFD) promotes adipose tissue senescence, which in turn disrupts insulin-mediated glycemic homeostasis. The underlying mechanisms remain unclear. Through clinical survey data, animal models, and primary adipose-derived mesenchymal stem cells (ADSC), we investigated how dietary patterns influence adipocyte senescence. We found that elevated fatty acid levels enhance the interaction between the E3 ubiquitin ligase TRIP12 and Cyclin-dependent kinase 4 (CDK4) in ADSCs, triggering CDK4 ubiquitination and degradation. As a process associated with this disruption in cell cycle progression, cellular senescence may represent a key outcome. Consequently, senescent ADSC-derived mature adipocytes (ADSC-MA) exhibit impaired insulin-stimulated GLUT4 membrane translocation and reduced glucose uptake. In contrast, within an HFD setting, dietary fiber supplementation is associated with the reversal of cellular senescence. The gut microbiota–short-chain fatty acids (SCFAs) axis may be involved in the restoration of cell cycle progression and the amelioration of ADSC senescence, correlating with a partial recovery of glucose uptake capacity in ADSC-MAs. Our study highlights potential strategies to reverse cellular senescence and identifies promising therapeutic targets for impaired glucose tolerance. Our study shows that an HFD increases circulating NEFAs. In this context, we demonstrate that NEFAs promote the binding of TRIP12 to CDK4 in ADSCs, leading to ubiquitination and subsequent degradation of CDK4. The loss of CDK4 disrupts the cell cycle and induces cellular senescence in ADSCs. Senescent ADSCs differentiate into dysfunctional MAs, which exhibit impaired insulin sensitivity and defective insulin-mediated GLUT4 membrane translocation. Consequently, glucose uptake in MAs is significantly diminished. It is thus plausible that this reduction contributes to the manifestation of impaired glucose tolerance at the systemic level. Dietary fiber supplementation alters the gut microbiota composition, increasing SCFAs production. These SCFAs act directly on ADSCs to restore CDK4 protein levels, rescue cell cycle progression, and reverse cellular senescence. This functional recovery of ADSCs suggests that targeting CDK4 restoration could represent a novel therapeutic strategy for HFD-related metabolic disorders. • High-fat diet triggers ADSC senescence independently of obesity, a phenomenon that may be linked to elevated levels of non-esterified fatty acids • Senescent ADSCs differentiate into senescent adipocytes with disruption of GLUT4 membrane translocation and concurrent impaired glucose uptake capacity • TRIP12-mediated CDK4 ubiquitination bridges lipotoxicity to ADSC senescence through cell cycle arrest • In a high-fat diet setting, dietary fiber supplementation reverses cellular senescence, hinting the involvement of a gut microbiota-SCFAs-CDK4 axis

Source: Molecular Metabolism

DOI: 10.1016/j.molmet.2025.102293