Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.
Institute of Food Nutrition and Health, Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich (ETH), Schwerzenbach, Switzerland.
Nat Commun. 2024 Feb 15;15(1):1391. doi: 10.1038/s41467-024-45724-y.
In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, the impact of fasting regimens on the regulation of AT immune infiltration is still elusive. Here we show that intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, this increase in LAM abundance is strongly p53 dependent and partly mediated by p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation during IF, increases the catabolic state of adipocytes, and enhances systemic metabolic flexibility and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to efficacy of a fasting-mimicking diet and that the expression of p53 and TREM2 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signalling in adipocytes dictates LAM accumulation in AT under IF and modulates fasting effectiveness in mice and humans.
在肥胖症中，持续的脂肪组织（AT）炎症构成了一种细胞记忆，限制了减肥干预措施的有效性。然而，禁食方案对调节 AT 免疫浸润的影响仍不清楚。在这里，我们表明间歇性禁食（IF）会加剧肥胖小鼠内脏 AT 中与脂质相关的巨噬细胞（LAM）的炎症表型。重要的是，这种 LAM 丰度的增加强烈依赖于 p53，部分是由 p53 驱动的脂肪细胞凋亡介导的。脂肪细胞特异性敲除 p53 可防止 IF 期间 LAM 的积累，增加脂肪细胞的分解代谢状态，并增强全身代谢灵活性和胰岛素敏感性。最后，在肥胖/糖尿病患者队列中，我们描述了一种 p53 多态性，它与禁食模拟饮食的疗效相关，并且 AT 中 p53 和 TREM2 的表达与减重手术后保持体重减轻呈负相关。总的来说，我们的研究结果表明，脂肪细胞中的 p53 信号在 IF 下调节 AT 中 LAM 的积累，并调节小鼠和人类的禁食效果。
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