# Lack of receptor for advanced glycation end products attenuates obesity-induced adipose tissue senescence in mice

## TL;DR

This study shows that mice lacking the RAGE receptor have less fat tissue aging and inflammation when on a high-fat diet, thanks to improved antioxidant defenses.

## Contribution

The study reveals that RAGE deficiency prevents obesity-induced adipose tissue senescence via SIRT1 signaling.

## Key findings

- RAGE-deficient mice showed reduced body weight and adipocyte hypertrophy on a high-fat diet.
- Lack of RAGE increased antioxidant gene expression and reduced senescence markers in adipose tissue.
- SIRT1 upregulation in RAGE−/− mice was crucial for the anti-senescent effects.

## Abstract

The receptor for advanced glycation end products (RAGE) and its ligands are critical drivers of adipose tissue inflammation. While RAGE expression increases in ageing cells and pathological conditions, its specific role in high-fat diet (HFD)-induced adipose tissue senescence remains to be fully elucidated. In this study, we investigated the function of RAGE in the development of adipose tissue senescence associated with obesity. We observed that HFD-fed RAGE-deficient (RAGE−/−) mice exhibited significantly reduced body weight and adipocyte hypertrophy compared to wild-type (WT) controls. At the molecular level, RAGE−/− mice displayed lower mRNA expression of cell cycle regulators and markers of the senescence-associated secretory phenotype. This anti-senescent phenotype was accompanied by decreased reactive oxygen species (ROS) production and elevated expression of anti-oxidant genes. Mechanistically, the lack of RAGE resulted in the upregulation of silent information regulator type 1 (SIRT1) in adipose tissues. Notably, the inhibition of SIRT1 reversed these anti-senescent effects and attenuated anti-oxidant gene expression in RAGE-deficient mice. Furthermore, while antioxidant treatment with N-acetylcysteine (NAC) reduced p53 in WT mice, it failed to fully suppress p16 and p21, whereas NAC treatment in RAGE−/− mice significantly downregulated all senescence markers, suggesting a synergistic protective effect. In conclusion, our results demonstrated that RAGE deficiency improved anti-oxidant properties and prevents adipocyte senescence via the SIRT1 signalling pathway, highlighting a potential therapeutic target for obesity-associated tissue dysfunction.