Cover Story Current Issue
Glucose is a ubiquitous and essential source of energy for all living organisms. Although mammals have evolved ways to convert other nutritional molecules to ATP, the preference for dietary glucose appears to be preserved. In rodents, the immediate detection of ingested glucose potently reinforces intake, hierarchically organizing behaviors towards glucose-yielding substances, and away from other types of food including other sugars. Taste is the primary sense linked to nutrient selection. Until recently, it was thought that most mammalian species utilize a single broadly tuned receptor to detect all simple sugars. Indeed, this “sweet” receptor, which comprises a heterodimer of the T1R2 and T1R3 proteins, binds multiple natural sugars (e.g., glucose, fructose, sucrose, maltose), as well as various other chemicals that yield little to no energy (e.g., low calorie sweeteners, sugar alcohols) and some d-amino acids. The neural signal originating from the sweet receptor is hardwired into brain circuits that drive eating and drinking behaviors, but it is an unreliable indicator of nutrient quality and quantity.
Current Issue
High-fat diet induces senescence in ADSCs via CDK4 ubiquitination-mediated cell cycle disruption, contributing to impaired glucose tolerance
High-fat diet induces senescence in ADSCs via CDK4 ubiquitination-mediated cell cycle disruption, contributing to impaired glucose tolerance
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.
Graphical abstract
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.
Articles in Press
High-fat diet induces senescence in ADSCs via CDK4 ubiquitination-mediated cell cycle disruption, contributing to impaired glucose tolerance
High-fat diet induces senescence in ADSCs via CDK4 ubiquitination-mediated cell cycle disruption, contributing to impaired glucose tolerance
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.
Graphical abstract
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.
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13th
Helmholtz Diabetes Conference
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You are what you eat
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