Sirtuin-1 prevents perivascular adipose tissue inflammation via adiponectin/adiponectin receptor-2 axis

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Abstract Background Inflammation of perivascular adipose tissue (PVAT) in central obesity elevates the risk of cardiovascular complications. Research indicates that the secretome of inflamed PVAT, known as "adipocytokines," affects nearby vascular regions, contributing to oxidative stress, endothelial dysfunction, systemic insulin resistance, and cardiovascular complications linked to type 2 diabetes (T2D). However, the mechanisms regulating adipocytokine secretion from PVAT remain largely unclear. Additionally, the effectiveness of medications prescribed for managing T2D-related cardiovascular complications in reducing PVAT inflammation remains uncertain. Purpose Sirtuin-1 (SIRT1), an NAD+-dependent deacetylase, plays a protective role against weight gain and hyperglycemia. However, its systemic levels are reduced in obese T2D mice, potentially exacerbating PVAT inflammation and vascular dysfunction. This study aims to evaluate whether restoring circulating SIRT1 levels can mitigate PVAT inflammation and metabolic imbalance in obese and diabetic mice. Methods and Results Circulating SIRT1 levels were lower in obese diabetic (db/db) mice compared to age-matched non-diabetic db/+ controls. Restoring plasma SIRT1 levels using recombinant murine SIRT1 (SIRT1) for four weeks prevented weight gain, enhanced glucose metabolism, and improved vascular function in obesity and T2D mouse models. Histological analysis of PVAT from SIRT1-treated db/db mice revealed a significant reduction in adipocyte hypertrophy. Targeted adipocytokine measurements indicated that SIRT1 alleviated PVAT inflammation by promoting adiponectin synthesis and secretion. At the molecular level, SIRT1 directly bound and deacetylated adiponectin receptor 2 (AdipoR2) in cultured adipocytes, protecting against mitochondrial dysfunction, reducing cellular inflammation, and thereby inducing a beige adipocyte response via adiponectin/AdipoR2 axis. Additionally, SIRT1 treatment of isolated PVAT adipocytes from coronary artery disease patients undergoing CABG demonstrated reduced inflammation and promoted beige/browning response. Conclusion Acetylation of AdipoR2 contributes to PVAT inflammation by inducing mitochondrial dysfunction in obesity, but this effect is alleviated by systemic SIRT1 replenishment. Therefore, restoring systemic SIRT1 could serve as a potential therapeutic approach to maintaining PVAT health and reducing cardiovascular complications associated with obesity-T2D.Summary

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