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

被引：1

作者：

Pereira, Jessica Aparecida da Silva ^{[1
,2
,3
]}

de Souza, Gerson Profeta ^{[4
,5
]}

Virgilio-da-Silva, Joao V. ^{[1
,2
]}

Prodonoff, Juliana S. ^{[1
]}

de Castro, Gisele ^{[1
,2
]}

Pimentel, Leonardo F. ^{[1
]}

Mousovich-Neto, Felippe ^{[5
]}

Davanzo, Gustavo G. ^{[1
]}

Aguiar, Cristhiane F. ^{[1
]}

Breda, Cristiane N. S. ^{[2
,6
]}

Guereschi, Marcia G. ^{[7
]}

Araujo, Ronaldo C. ^{[8
]}

Mori, Marcelo A. ^{[5
,9
]}

Camara, Niels O. S. ^{[2
,6
]}

Souza, Diorge P. ^{[10
]}

Basso, Alexandre S. ^{[7
]}

Moraes-Vieira, Pedro M. ^{[1
,9
,11
]}

机构：

[1] Univ Estadual Campinas, Inst Biol, Lab Immunometabolism, Dept Genet Evolut Microbiol & Immunol, Rua Monteiro Lobato 255,BLH,1st floor,Cidade Univ, BR-13083970 Campinas, SP, Brazil

[2] Univ Sao Paulo, Inst Biomed Sci, Grad Program Immunol, Sao Paulo, Brazil

[3] Harvard Med Sch, Joslin Diabet Ctr, Islet Cell & Regenerat Biol, Boston, MA 02115 USA

[4] Harvard Med Sch, Joslin Diabet Ctr, Div Res, Sect Integrat Physiol & Metab, Boston, MA 02115 USA

[5] Univ Estadual Campinas, Inst Biol, Lab Aging Biol, Dept Biochem & Tissue Biol, Campinas, Brazil

[6] Univ Estadual Campinas, Inst Biol, Lab Transplant Immunobiol, Campinas, Brazil

[7] Univ Fed Sao Paulo, Paulista Med Sch, Lab Neuroimmunol, Dept Microbiol Immunol & Parasitol, Sao Paulo, Brazil

[8] Fed Univ Sao Paulo UNIFESP, Lab Exercise Genet & Metab, Dept Biophys, Sao Paulo, Brazil

[9] Univ Estadual Campinas, Obes & Comorbid Res Ctr OCRC, Campinas, Brazil

[10] Med Res Council MRC, Lab Mol Biol, Div Cell Biol, Cambridge, England

[11] Univ Estadual Campinas, Expt Med Res Cluster EMRC, Campinas, Brazil

来源：

OBESITY | 2025年 / 33卷 / 01期

关键词：

X-RECEPTOR; NUCLEAR RECEPTORS; LIPID-METABOLISM; LIVER; GLUCOSE; ACTIVATION; EXPRESSION; GENE; TRANSCRIPTION; ADIPOCYTES;

D O I：

10.1002/oby.24158

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

ObjectiveLiver 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.MethodsFor 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 LXR alpha, LXR beta, and LXR alpha beta knockout (KO) mice. For in vitro studies, to assess the role of LXRs specifically in macrophages, bone marrow-derived macrophages from wild-type, LXR alpha KO, LXR beta KO, and LXR alpha beta KO mice were treated with 0.5 mu M 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.ResultsWe found that LXR deletion intensifies AT inflammation in an LXR beta-dependent manner. LXR deficiency in immune cells exacerbates obesity-induced AT inflammation, increasing the numbers of CD11c+, TNF-alpha+, and IL-1 beta+ 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 + IFN gamma-activated macrophages. Furthermore, NAR-treated obese mice display reduced AT inflammation, characterized by decreased CD11c+, IL-1 beta+, and TNF-alpha+ ATM numbers and monocyte infiltration compared with vehicle-treated obese mice.ConclusionsOur study highlights distinct roles for each LXR isoform in AT inflammation regulation, with LXR beta being crucial for maintaining the anti- and proinflammatory balance in ATMs. Thus, LXR beta holds therapeutic potential as a target to treat AT inflammation and insulin resistance.

引用

页码：78 / 90

页数：13