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

Autor: da Silva Pereira JA; 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.; Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA., de Souza GP; Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.; Laboratory of Aging Biology, Department of Biochemistry and Tissue Biology, State University of Campinas Institute of Biology, Campinas, Brazil., Virgilio-da-Silva JV; 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., Prodonoff JS; Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, State University of Campinas Institute of Biology, Campinas, Brazil., de Castro G; 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., Pimentel LF; Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, State University of Campinas Institute of Biology, Campinas, Brazil., Mousovich-Neto F; Laboratory of Aging Biology, Department of Biochemistry and Tissue Biology, State University of Campinas Institute of Biology, Campinas, Brazil., Davanzo GG; Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, State University of Campinas Institute of Biology, Campinas, Brazil., Aguiar CF; Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, State University of Campinas Institute of Biology, Campinas, Brazil., Breda CNS; Graduate Program in Immunology, University of São Paulo Institute of Biomedical Sciences, São Paulo, Brazil.; Laboratory of Transplant Immunobiology, State University of Campinas Institute of Biology, Campinas, Brazil., Guereschi MG; Laboratory of Neuroimmunology, Department of Microbiology, Immunology and Parasitology, Paulista Medical School, Federal University of São Paulo, São Paulo, Brazil., Araújo RC; Laboratory of Exercise Genetics and Metabolism, Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil., Mori MA; Laboratory of Aging Biology, Department of Biochemistry and Tissue Biology, State University of Campinas Institute of Biology, Campinas, Brazil.; Obesity and Comorbidities Research Center (OCRC), State University of Campinas, Campinas, Brazil., Câmara NOS; Graduate Program in Immunology, University of São Paulo Institute of Biomedical Sciences, São Paulo, Brazil.; Laboratory of Transplant Immunobiology, State University of Campinas Institute of Biology, Campinas, Brazil., Souza DP; Division of Cell Biology, Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge, UK., Basso AS; Laboratory of Neuroimmunology, Department of Microbiology, Immunology and Parasitology, Paulista Medical School, Federal University of São Paulo, São Paulo, Brazil., Moraes-Vieira PM; Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, State University of Campinas Institute of Biology, Campinas, Brazil.; Obesity and Comorbidities Research Center (OCRC), State University of Campinas, Campinas, Brazil.; Experimental Medicine Research Cluster (EMRC), State University of Campinas, Campinas, Brazil.
Jazyk: angličtina
Zdroj: Obesity (Silver Spring, Md.) [Obesity (Silver Spring)] 2024 Dec 04. Date of Electronic Publication: 2024 Dec 04.
DOI: 10.1002/oby.24158
Abstrakt: 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.
(© 2024 The Obesity Society.)
Databáze: MEDLINE
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