Adipocyte-specific deficiency of Nfe2l1 disrupts plasticity of white adipose tissues and metabolic homeostasis in mice

Hou, Yongyong; Liu, Zhiyuan; Zuo, Zhuo; Gao, Tianchang; Fu, Jingqi; Wang, Huihui; Xu, Yuanyuan; Liu, Dianxin; Yamamoto, Masayuki; Zhu, Beibei; Zhang, Yiguo; Andersen, Melvin E.; Zhang, Qiang; Pi, Jingbo

doi:10.1016/j.bbrc.2018.06.013

Cited by 37 publications

(32 citation statements)

References 34 publications

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“…Other proteins as Nrf1 has been described with an important role in adaptative thermogenesis. Nrf1 is considered to play a key role in cellular responses to stress and ablation of this protein in white adipocytes leading to reduced adipose tissue mass which is in keeping with the phenotype here reported in p107‐ablated mice although they also exhibited a marked insulin resistance in contrast to our ablated p107‐mice. Indeed the overexpression of Nrf1 in BAT resulted in improved insulin sensitivity …”

Section: Discussionsupporting

confidence: 90%

p107 Deficiency Increases Energy Expenditure by Inducing Brown‐Fat Thermogenesis and Browning of White Adipose Tissue

Cuñarro

Buqué

Casado

et al. 2018

Molecular Nutrition Food Res

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Scope The tumor suppressor p107, a pocket protein member of the retinoblastoma susceptibility protein family, plays an important role in the cell cycle and cellular adipocyte differentiation. Nonetheless, the mechanism by which it influences whole body Energy homeostasis is unknown. Methods and Results The phenotype of p107 knockout (KO) mixed‐background C57BL6/129 mice phenotype is studied by focusing on the involvement of white and brown adipose tissue (WAT and BAT) in energy metabolism. It is shown that p107 KO mice are leaner and have high‐fat diet resistence. This phenomenon is explained by an increase of energy expenditure. The higher energy expenditure is caused by the activation of thermogenesis and may be mediated by both BAT and the browning of WAT. Consequently, it leads to the resistance of p107 KO mice to high‐fat diet effects, prevention of liver steatosis, and improvement of the lipid profile and glucose homeostasis. Conclusion These data allowed the unmasking of a mechanism by which a KO of p107 prevents diet‐induced obesity by increasing energy expenditure via increased thermogenesis in BAT and browning of WAT, indicating the relevance of p107 as a modulator of metabolic activity of both brown and white adipocytes. Therefore, it can be targeted for the development of new therapies to ameliorate the metabolic syndrome.

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Section: Discussionsupporting

confidence: 90%

p107 Deficiency Increases Energy Expenditure by Inducing Brown‐Fat Thermogenesis and Browning of White Adipose Tissue

Cuñarro

Buqué

Casado

et al. 2018

Molecular Nutrition Food Res

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“…Among Nrf1-regulated genes, those encoding A2M, EPHA8, FBXO2, KCND1, SLC2A3, SORL1, OLIG2, and RAPGEF4 may be responsible for the nervous system, albeit it is unclear whether they are relevant to those phenotypes of Nrf1α / -leading neurodegenerative diseases as reported by (Kobayashi et al, 2011;Lee et al, 2011). Only ACSS2, FA2H, and KLF15 genes are associated with lipid metabolism, but it is required to determine their roles in relevant phenotypes, as described by (Bartelt et al, 2018;Hirotsu et al, 2014;Hou et al, 2018;Xu et al, 2005). By contrast, a portion of Nrf2-specific genes are critical for the development of various tissues and organs, neurons and cardiomyocytes, but none of the specific physio-pathological phenotypes in the Nrf2 /DBD mice are observed, implying their functions can be compensated.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic activation of Nrf2 by specific knockout of Nrf1α that acts as a dominant tumor repressor

Qiu

Wang

et al. 2018

Preprint

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HIGHLIGHTS  Opposing and unifying inter-regulatory cross-talks between Nrf1 and Nrf2  Malignant growth of Nrf1 / -derived tumor is prevented by silencing Nrf2  Hyper-activation of Nrf2 by Nrf1 / results from decreased Keap1 and PTEN  Nrf1 / -tumor is repressed by Nrf2 /TA , but unaltered by its active caNrf2 ΔN SUMMARY Liver-specific knockout of Nrf1 in mice leads to non-alcoholic steatohepatitis with dyslipidemia, and its deterioration results in spontaneous hepatoma, but the underlying mechanism remains elusive. A similar pathological model is herein reconstructed by using human Nrf1-specific knockout cell lines. We demonstrated that a marked increase of the inflammation marker COX2 in Nrf1 / cells. Loss of Nrf1 leads to hyperactivation of Nrf2, which results from substantial decreases in both Keap1 and PTEN in Nrf1 / cells. Further investigation of xenograft mice showed that malignant growth of Nrf1 / -derived tumor is almost abolished by silencing Nrf2, while Nrf1 / -tumor is markedly repressed by inactive Nrf2 /TA , but unaffected by a priori constitutive activator of caNrf2 ΔN . Mechanistic studies unraveled there exist opposing and unifying inter-regulatory cross-talks between Nrf1 and Nrf2. Collectively, Nrf1 manifests a dominant tumor-suppressive effect by confining Nrf2 oncogenicity, while Nrf2 can directly activate the transcriptional expression of Nrf1 to form a negative feedback loop.

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“…This occurs via induction of the induction of the ER-localized transcription factor nuclear factor erythroid-2, like-1 (Nfe2l1, also known as Nrf1) (130). Deletion of Nfe2l1, specifically in brown adipocytes, results in ER stress, inflammation, mitochondrial dysfunction, insulin resistance, and whitening of the BAT (130,131).…”

Section: Impact Of Inflammation and Inflammatory Mediators On Brown Amentioning

confidence: 99%

Inflammatory Signaling and Brown Fat Activity

Omran

Christian

2020

Front. Endocrinol.

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Obesity is characterized by a state of chronic inflammation in adipose tissue mediated by the secretion of a range of inflammatory cytokines. In comparison to WAT, relatively little is known about the inflammatory status of brown adipose tissue (BAT) in physiology and pathophysiology. Because BAT and brown/beige adipocytes are specialized in energy expenditure they have protective roles against obesity and associated metabolic diseases. BAT appears to be is less susceptible to developing inflammation than WAT. However, there is increasing evidence that inflammation directly alters the thermogenic activity of brown fat by impairing its capacity for energy expenditure and glucose uptake. The inflammatory microenvironment can be affected by cytokines secreted by immune cells as well as by the brown adipocytes themselves. Therefore, pro-inflammatory signals represent an important component of the thermogenic potential of brown and beige adipocytes and may contribute their dysfunction in obesity.

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Adipocyte-specific deficiency of Nfe2l1 disrupts plasticity of white adipose tissues and metabolic homeostasis in mice

Cited by 37 publications

References 34 publications

p107 Deficiency Increases Energy Expenditure by Inducing Brown‐Fat Thermogenesis and Browning of White Adipose Tissue

p107 Deficiency Increases Energy Expenditure by Inducing Brown‐Fat Thermogenesis and Browning of White Adipose Tissue

Oncogenic activation of Nrf2 by specific knockout of Nrf1α that acts as a dominant tumor repressor

Inflammatory Signaling and Brown Fat Activity

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