肥胖期间肝脏X受体对脂肪组织炎症的调节与巨噬细胞功能失调有关。

LXR regulation of adipose tissue inflammation during obesity is associated with dysregulated macrophage function.

作者信息

da Silva Pereira Jessica Aparecida, de Souza Gerson Profeta, Virgilio-da-Silva João V, Prodonoff Juliana S, de Castro Gisele, Pimentel Leonardo F, Mousovich-Neto Felippe, Davanzo Gustavo G, Aguiar Cristhiane F, Breda Cristiane N S, Guereschi Marcia G, Araújo Ronaldo C, Mori Marcelo A, Câmara Niels O S, Souza Diorge P, Basso Alexandre S, Moraes-Vieira Pedro M

机构信息

Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, State University of Campinas Institute of Biology, Campinas, Brazil.

Graduate Program in Immunology, University of São Paulo Institute of Biomedical Sciences, São Paulo, Brazil.

出版信息

Obesity (Silver Spring). 2025 Jan;33(1):78-90. doi: 10.1002/oby.24158. Epub 2024 Dec 4.

DOI:10.1002/oby.24158

PMID:39632389

Abstract

OBJECTIVE

Liver X receptors (LXRs) play essential roles in cholesterol homeostasis and immune response. In obesity, elevated cholesterol levels trigger proinflammatory responses; however, the specific contributions of LXRs to adipose tissue (AT) macrophage (ATM) phenotype and metabolic programming are not fully understood. In this study, we determine the role of LXR isoforms in diet-induced obesity AT inflammation and insulin resistance.

METHODS

For in vivo studies, to evaluate the effects of LXR activation on AT inflammation, obese and insulin-resistant wild-type mice were treated with 10 mg/kg of the LXR modulator naringenin (NAR) for 4 weeks, and systemic insulin sensitivity and AT inflammation were assessed. To evaluate the effects of LXR deficiency on AT inflammation, we used LXRα, LXRβ, and LXRαβ knockout (KO) mice. For in vitro studies, to assess the role of LXRs specifically in macrophages, bone marrow-derived macrophages from wild-type, LXRαKO, LXRβKO, and LXRαβKO mice were treated with 0.5μM NAR 1 h prior to lipopolysaccharide (LPS) stimulation (100 ng/mL), and the effects on macrophage function and metabolism were evaluated 24 h after LPS stimulation.

RESULTS

We found that LXR deletion intensifies AT inflammation in an LXRβ-dependent manner. LXR deficiency in immune cells exacerbates obesity-induced AT inflammation, increasing the numbers of CD11c, TNF-α, and IL-1β ATMs. We also identified NAR as a novel LXR agonist in macrophages that reduces proinflammatory cytokine secretion by mitigating glycolysis and mitochondrial dysfunction in LPS - and LPS + IFNγ-activated macrophages. Furthermore, NAR-treated obese mice display reduced AT inflammation, characterized by decreased CD11c, IL-1β, and TNF-α ATM numbers and monocyte infiltration compared with vehicle-treated obese mice.

CONCLUSIONS

Our study highlights distinct roles for each LXR isoform in AT inflammation regulation, with LXRβ being crucial for maintaining the anti- and proinflammatory balance in ATMs. Thus, LXRβ holds therapeutic potential as a target to treat AT inflammation and insulin resistance.

摘要

目的

肝脏X受体（LXRs）在胆固醇稳态和免疫反应中发挥着重要作用。在肥胖状态下，胆固醇水平升高会引发促炎反应；然而，LXRs对脂肪组织（AT）巨噬细胞（ATM）表型和代谢编程的具体作用尚未完全明确。在本研究中，我们确定了LXR亚型在饮食诱导的肥胖AT炎症和胰岛素抵抗中的作用。

方法

在体内研究中，为了评估LXR激活对AT炎症的影响，给肥胖和胰岛素抵抗的野生型小鼠腹腔注射10mg/kg的LXR调节剂柚皮素（NAR），持续4周，然后评估全身胰岛素敏感性和AT炎症。为了评估LXR缺乏对AT炎症的影响，我们使用了LXRα、LXRβ和LXRαβ基因敲除（KO）小鼠。在体外研究中，为了评估LXRs在巨噬细胞中的具体作用，在脂多糖（LPS）刺激（100ng/mL）前1小时，用0.5μM NAR处理野生型、LXRαKO、LXRβKO和LXRαβKO小鼠的骨髓来源巨噬细胞，在LPS刺激24小时后评估对巨噬细胞功能和代谢的影响。

结果

我们发现LXR缺失以LXRβ依赖的方式加剧AT炎症。免疫细胞中LXR缺乏会加剧肥胖诱导的AT炎症，增加CD11c、TNF-α和IL-1β阳性的ATM数量。我们还确定NAR是巨噬细胞中的一种新型LXR激动剂，它通过减轻LPS和LPS+IFNγ激活的巨噬细胞中的糖酵解和线粒体功能障碍来减少促炎细胞因子的分泌。此外，与用载体处理的肥胖小鼠相比，用NAR处理的肥胖小鼠的AT炎症减轻，其特征是CD11c、IL-1β和TNF-α阳性的ATM数量以及单核细胞浸润减少。