Macrophage IRX3 promotes diet-induced obesity and metabolic inflammation

Yao, Jingfei; Wu, Dongmei; Zhang, Chunyan; Yan, Ting; Zhao, Yiheng; Shen, Huan; Xue, Kaili; Huang, Xun; Wang, Zihao; Qiu, Yifu

doi:10.1038/s41590-021-01023-y

Cited by 49 publications

(26 citation statements)

References 51 publications

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“…LRRK1 has been implicated with short stature in humans ( van Duyvenvoorde et al 2014 ) and with the regulation of bone mass ( Iida et al 2016 ). Likewise, the paralogs IRX3 and IRX6 are transcription factors active during brain development ( Anselme et al 2007 ), and have been related to obesity ( Zou et al 2017 ; de Araújo and Velloso 2020 ) and inflammation ( Yao et al 2021 ). These genes regulate the size of the pallium, which is an important brain structure that covers the upper surface of the brain ( Medina and Abellán 2009 ).…”

Section: Resultsmentioning

confidence: 99%

Positive Selection and Enhancer Evolution Shaped Lifespan and Body Mass in Great Apes

Tejada‐Martinez

Avelar

Lopes

et al. 2021

Molecular Biology and Evolution

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Within primates, the great apes are outliers both in terms of body size and lifespan, since they include the largest and longest-lived species in the order. Yet, the molecular bases underlying such features are poorly understood. Here, we leveraged an integrated approach to investigate multiple sources of molecular variation across primates, focusing on over ten thousand genes, including ∼1,500 previously associated with lifespan, and additional ∼9,000 for which an association with longevity has never been suggested. We analyzed dN/dS rates, positive selection, gene expression (RNA-seq) and gene regulation (ChIP-seq). By analyzing the correlation between dN/dS, maximum lifespan and body mass we identified 276 genes whose rate of evolution positively correlates with maximum lifespan in primates. Further, we identified 5 genes, important for tumor suppression, adaptive immunity, metastasis and inflammation, under positive selection exclusively in the great ape lineage. RNA-seq data, generated from the liver of six species representing all the primate lineages, revealed that 8% of ∼1,500 genes previously associated with longevity are differentially expressed in apes relative to other primates. Importantly, by integrating RNA-seq with ChIP-seq for H3K27ac (which marks active enhancers), we show that the differentially expressed longevity genes are significantly more likely than expected to be located near a novel “ape-specific” enhancer. Moreover, these particular ape-specific enhancers are enriched for young transposable elements, and specifically SINE-Vntr-Alus (SVAs). In summary, we demonstrate that multiple evolutionary forces have contributed to the evolution of lifespan and body size in primates.

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Section: Resultsmentioning

confidence: 99%

Positive Selection and Enhancer Evolution Shaped Lifespan and Body Mass in Great Apes

Tejada‐Martinez

Avelar

Lopes

et al. 2021

Molecular Biology and Evolution

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“…The upregulation of hsa-circRNA9102-5 expression was accompanied by the downregulation of hsa-miR-150-5p expression ( Zheng et al, 2020 ), which was proven to promote angiogenesis and EC migration in vitro and in vivo in vascular ECs ( Li et al, 2013 ). In addition, hsa-circ-0105015 expression was upregulated and hsa-miR-637 expression was downregulated in HAECs and human vein ECs (HUVECs) treated with TNF-α, suggesting that these circRNAs may be associated with vascular inflammation and endothelial dysfunction in hypertension ( Yao et al, 2021 ).…”

Section: Ev-circrnas Are Involved In As Risk Factorsmentioning

confidence: 99%

Emerging Roles of Extracellular Vesicle-Delivered Circular RNAs in Atherosclerosis

Wen

Nie

et al. 2022

Front. Cell Dev. Biol.

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Atherosclerosis (AS) is universally defined as chronic vascular inflammation induced by dyslipidaemia, obesity, hypertension, diabetes and other risk factors. Extracellular vesicles as information transmitters regulate intracellular interactions and their important cargo circular RNAs are involved in the pathological process of AS. In this review, we summarize the current data to elucidate the emerging roles of extracellular vesicle-derived circular RNAs (EV-circRNAs) in AS and the mechanism by which EV-circRNAs affect the development of AS. Additionally, we discuss their vital role in the progression from risk factors to AS and highlight their great potential for use as diagnostic biomarkers of and novel therapeutic strategies for AS.

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“… Deletion of Irx3 in macrophage, or expression of a “dominant-negative form of mouse IRX3 ” in adipose tissue ( aP2-Cre ; Rosa26 EnR–Irx3 /+ ) or “human IRX3 ” in brown adipose tissue ( Ucp1 - Cre ; Rosa26 hIRX3 /+ ) leads to a lean phenotype with adipose beiging and elevated energy expenditure ( Smemo et al, 2014 ; Yao et al, 2021 ; Zhang et al, 2021 ). *Though difference in daily food intake is not significantly different, these mutants show reduced amounts of food intake from long-term feeding analysis over life time.…”

Section: The Importance Of Irx3 and Irx5 In Metabolic Regulationmentioning

confidence: 99%

“…Using genetic mouse models, work by us and others depicts their critical roles in metabolic regulation in the brain, as well as in peripheral organs such as adipose tissue ( Smemo et al, 2014 ; Claussnitzer et al, 2015 ; Bjune et al, 2018 ; Sobreira et al, 2021 ; Son et al, 2021a , b ). More recently, macrophage Irx3 has also been associated with metabolic inflammation and body weight control ( Yao et al, 2021 ). In this review, we summarize the metabolic functions and regulatory mechanisms of Irx3 and Irx5 with a focus on the postnatal hypothalamus, where they are highly expressed, particularly in the newly identified RGL-NSCs giving rise to postnatal hypothalamic neurons, and regulate energy homeostasis.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Irx3 and Irx5 - Novel Regulatory Factors of Postnatal Hypothalamic Neurogenesis

2021

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The hypothalamus is a brain region that exhibits highly conserved anatomy across vertebrate species and functions as a central regulatory hub for many physiological processes such as energy homeostasis and circadian rhythm. Neurons in the arcuate nucleus of the hypothalamus are largely responsible for sensing of peripheral signals such as leptin and insulin, and are critical for the regulation of food intake and energy expenditure. While these neurons are mainly born during embryogenesis, accumulating evidence have demonstrated that neurogenesis also occurs in postnatal-adult mouse hypothalamus, particularly in the first two postnatal weeks. This second wave of active neurogenesis contributes to the remodeling of hypothalamic neuronal populations and regulation of energy homeostasis including hypothalamic leptin sensing. Radial glia cell types, such as tanycytes, are known to act as neuronal progenitors in the postnatal mouse hypothalamus. Our recent study unveiled a previously unreported radial glia-like neural stem cell (RGL-NSC) population that actively contributes to neurogenesis in the postnatal mouse hypothalamus. We also identified Irx3 and Irx5, which encode Iroquois homeodomain-containing transcription factors, as genetic determinants regulating the neurogenic property of these RGL-NSCs. These findings are significant as IRX3 and IRX5 have been implicated in FTO-associated obesity in humans, illustrating the importance of postnatal hypothalamic neurogenesis in energy homeostasis and obesity. In this review, we summarize current knowledge regarding postnatal-adult hypothalamic neurogenesis and highlight recent findings on the radial glia-like cells that contribute to the remodeling of postnatal mouse hypothalamus. We will discuss characteristics of the RGL-NSCs and potential actions of Irx3 and Irx5 in the regulation of neural stem cells in the postnatal-adult mouse brain. Understanding the behavior and regulation of neural stem cells in the postnatal-adult hypothalamus will provide novel mechanistic insights in the control of hypothalamic remodeling and energy homeostasis.

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Macrophage IRX3 promotes diet-induced obesity and metabolic inflammation

Cited by 49 publications

References 51 publications

Positive Selection and Enhancer Evolution Shaped Lifespan and Body Mass in Great Apes

Positive Selection and Enhancer Evolution Shaped Lifespan and Body Mass in Great Apes

Emerging Roles of Extracellular Vesicle-Delivered Circular RNAs in Atherosclerosis

Irx3 and Irx5 - Novel Regulatory Factors of Postnatal Hypothalamic Neurogenesis

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