The nuclear retinoid‐related orphan receptor RORα controls adipose tissue inflammation in patients with morbid obesity and diabetes

Ortega, Rebeca; Hueso, Luisa; Benito, Esther; Civera, Miguel; Sanz, María-Jesús; Real, José T.; Piqueras, Laura

doi:10.1038/s41366-021-00787-5

Cited by 5 publications

(5 citation statements)

References 51 publications

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“…During obesity, there is a chronic low-grade inflammation associated to adipose tissue dysfunction which accelerates the onset of insulin resistance and diabetes. Infiltrating immune cells produce several factors, such as cytokines/chemokines, which participate in adipose tissue remodeling and cell signaling ( 28 , 29 ). It is well known that human visceral and subcutaneous fat depots have significantly different properties, this makes visceral adipose tissue a more pathogenic depot linked to higher metabolic risk ( 30 – 32 ); however, the underlying mechanisms have not yet been completely elucidated.…”

Section: Discussionmentioning

confidence: 99%

CCL17 and CCL22 chemokines are upregulated in human obesity and play a role in vascular dysfunction

et al. 2023

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Background/AimsChemokines are known to play critical roles mediating inflammation in many pathophysiological processes. The aim of this study was to investigate the role of chemokine receptor CCR4 and its ligands CCL17 and CCL22 in human morbid obesity.MethodsCirculating levels of CCL17 and CCL22 were measured in 60 morbidly obese patients (mean age, 45 ± 1 years; body mass index/BMI, 44 ± 1 kg/m2) who had undergone bariatric bypass surgery, and 20 control subjects. Paired subcutaneous (SCAT) and visceral adipose tissue (VCAT) from patients were analysed to measure expression of CCR4 and its ligands by RT-PCR, western blot and immunohistochemical analysis. The effects of CCR4 neutralization ex vivo on leukocyte-endothelial cells were also evaluated.ResultsCompared with controls, morbidly obese patients presented higher circulating levels of CCL17 (p=0.029) and CCL22 (p<0.001) and this increase was positively correlated with BMI (p=0.013 and p=0.0016), and HOMA-IR Index (p=0.042 and p< 0.001). Upregulation of CCR4, CCL17 and CCL22 expression was detected in VCAT in comparison with SCAT (p<0.05). Using the parallel-plate flow chamber model, blockade of endothelial CCR4 function with the neutralizing antibody anti-CCR4 in morbidly obese patients significantly reduced leucocyte adhesiveness to dysfunctional endothelium, a key event in atherogenesis. Additionally, CCL17 and CCL22 increased activation of the ERK1/2 mitogen-activated protein kinase signalling pathway in human aortic endothelial cells, which was significantly reduced by CCR4 inhibition (p=0.016 and p<0.05).ConclusionBased on these findings, pharmacological modulation of the CCR4 axis could represent a new therapeutic approach to prevent adipose tissue dysfunction in obesity.

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Section: Discussionmentioning

confidence: 99%

CCL17 and CCL22 chemokines are upregulated in human obesity and play a role in vascular dysfunction

et al. 2023

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“…Lau et al reported that RORα was a key factor in fat accumulation, staggerer mice had reduced level of serum triglycerides and exhibited resistance to diet‐induced obesity 33 . Clinical studies also showed that RORα modulated adipose tissue inflammation in obese patients 34 . In the content of the liver, RORα is an essential regulator in bile acid and cholesterol homeostasis and mediates reprogramming of glucose metabolism in glutamine‐deficient hepatoma cells 35,36 .…”

Section: Discussionmentioning

confidence: 99%

“… 33 Clinical studies also showed that RORα modulated adipose tissue inflammation in obese patients. 34 In the content of the liver, RORα is an essential regulator in bile acid and cholesterol homeostasis and mediates reprogramming of glucose metabolism in glutamine‐deficient hepatoma cells. 35 , 36 In accordance with individual performance, researchers observed abnormal thymus and spleen sizes and impaired cellularity of lymphoid tissue in staggerer mice, 37 so it is reasonable to assume that RORα is critical in lymphocyte development.…”

Section: Discussionmentioning

confidence: 99%

“…Retinoic acid‐related orphan receptor α (RORα) is a multi‐faceted nuclear receptor in tissue regeneration beyond an ability to regulate immune signalling 17 . A significant body of work has focused on the roles of the RORs, and elegant genetic studies have established that RORα expression is closely related to DM and is indispensable to orchestrate immune microenvironment and osteogenesis 18–21 . Therefore, we speculated that RORα may be a vital factor in regulating inflammatory microenvironment in the early stage of bone defect and inflammatory imbalance in DM, providing a novel target for treating diabetic bone regeneration deficiency.…”

Section: Introductionmentioning

confidence: 99%

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Targeting RORα in macrophages to boost diabetic bone regeneration

et al. 2023

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Diabetes mellitus (DM) has become a serious threat to human health. Bone regeneration deficiency and nonunion caused by DM is perceived as a worldwide epidemic, with a very high socioeconomic impact on public health. Here, we find that targeted activation of retinoic acid‐related orphan receptor α (RORα) by SR1078 in the early stage of bone defect repair can significantly promote in situ bone regeneration of DM rats. Bone regeneration relies on the activation of macrophage RORα in the early bone repair, but RORα of DM rats fails to upregulation as hyperglycemic inflammatory microenvironment induced IGF1‐AMPK signalling deficiency. Mechanistic investigations suggest that RORα is vital for macrophage‐induced migration and proliferation of bone mesenchymal stem cells (BMSCs) via a CCL3/IL‐6 depending manner. In summary, our study identifies RORα expressed in macrophages during the early stage of bone defect repair is crucial for in situ bone regeneration, and offers a novel strategy for bone regeneration therapy and fracture repair in DM patients.

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“…Retinoic acid receptor-related orphan receptor alpha (RORα) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors that link inflammatory and metabolic signaling pathways ( Jetten, 2009 ). A study by Rebeca Ortega found that activation of RORα might promote inflammation during adipose tissue expansion, resulting in metabolic dysfunction ( Ortega et al, 2021 ). Thus, upregulation of RORα might play a critical role in the cytopathological process of hypoxia and hypoglycemia in ADSCs.…”

Section: Discussionmentioning

confidence: 99%

Identification of hub genes regulating the cell activity and function of adipose-derived stem cells under oxygen-glucose deprivation

Yang

et al. 2022

Front. Mol. Biosci.

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While oxygen-glucose deprivation (OGD) has been widely utilized in many cell lines to mimic certain biological changes, it has yet to be validated in mesenchymal stem cells. We performed RNA sequencing on adipose-derived stem cells (ADSCs) under hypoxic and glucose-free conditions after 4 h and 8 h. A total of 335 common differentially expressed genes (DEGs) were identified in the two OGD groups compared with the normal control group, consisting of 292 upregulated and 43 downregulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that DEGs are mainly involved in metabolic processes, programmed cell death, and DNA-binding transcription activator activity. Protein‒protein interaction and hub gene analysis revealed various potential hub genes, in which response to oxygen levels, the IL-17-related biological function and the hypoxia-inducible factor 1 signaling pathway have been of vital importance. In summary, changes in transcription factor activity may play pivotal roles in oxygen-glucose deprivation. Through RNA sequencing, we have a deeper understanding of the changes in ADSCs after OGD treatment, providing more precise insight into predicting and regulating the stemness of ADSCs.

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The nuclear retinoid‐related orphan receptor RORα controls adipose tissue inflammation in patients with morbid obesity and diabetes

Cited by 5 publications

References 51 publications

CCL17 and CCL22 chemokines are upregulated in human obesity and play a role in vascular dysfunction

CCL17 and CCL22 chemokines are upregulated in human obesity and play a role in vascular dysfunction

Targeting RORα in macrophages to boost diabetic bone regeneration

Identification of hub genes regulating the cell activity and function of adipose-derived stem cells under oxygen-glucose deprivation

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