Protracted rosiglitazone treatment exacerbates inflammation in white adipose tissues of adipocyte-specific Nfe2l1 knockout mice

Ren, Suping; Hou, Yongyong; Zuo, Zhuo; Liu, Zhiyuan; Xu, Yuanyuan; Yamamoto, Masayuki; Zhang, Qiang; Fu, Jingqi; Pi, Jingbo

doi:10.1016/j.fct.2020.111836

Cited by 11 publications

(12 citation statements)

References 52 publications

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“…The target gene primer pairs were synthesized by Tsingke Biotechnology Co., Ltd. (Beijing, China). The primer sequence was shown in Supplementary Table 1 (27)(28)(29). The 2 −DDCt method was used to determine the relative gene expression (30).…”

Section: Real-time Reverse Transcription Quantitative Polymerase Chai...mentioning

confidence: 99%

Benzene Exposure Leads to Lipodystrophy and Alters Endocrine Activity In Vivo and In Vitro

Cui

et al. 2022

Front. Endocrinol.

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Benzene is a ubiquitous pollutant and mainly accumulates in adipose tissue which has important roles in metabolic diseases. The latest studies reported that benzene exposure was associated with many metabolic disorders, while the effect of benzene exposure on adipose tissue remains unclear. We sought to investigate the effect using in vivo and in vitro experiments. Male adult C57BL/6J mice were exposed to benzene at 0, 1, 10 and 100 mg/kg body weight by intragastric gavage for 4 weeks. Mature adipocytes from 3T3-L1 cells were exposed to hydroquinone (HQ) at 0, 1, 5 and 25 μM for 24 hours. Besides the routine hematotoxicity, animal experiments also displayed significant body fat content decrease from 1 mg/kg. Interestingly, the circulating non-esterified fatty acid (NEFA) level increased from the lowest dose (ptrend < 0.05). Subsequent analysis indicated that body fat content decrease may be due to atrophy of white adipose tissue (WAT) upon benzene exposure. The average adipocyte area of WAT decreased significantly even from 1 mg/kg with no significant changes in total number of adipocytes. The percentages of small and large adipocytes in WAT began to significantly increase or decrease from 1 mg/kg (all p < 0.05), respectively. Critical genes involved in lipogenesis and lipolysis were dysregulated, which may account for the disruption of lipid homeostasis. The endocrine function of WAT was also disordered, manifested as significant decrease in adipokine levels, especially the leptin. In vitro cell experiments displayed similar findings in decreased fat content, dysregulated critical lipid metabolism genes, and disturbed endocrine function of adipocytes after HQ treatment. Pearson correlation analysis showed positive correlations between white blood cell (WBC) count with WAT fat content and plasma leptin level (r = 0.330, 0.344, both p < 0.05). This study shed light on the novel aspect that benzene exposure could induce lipodystrophy and disturb endocrine function of WAT, and the altered physiology of WAT might in turn affect benzene-induced hematotoxicity and metabolic disorders. The study provided new insight into understanding benzene-induced toxicity and the relationship between benzene and adipose tissue.

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Section: Real-time Reverse Transcription Quantitative Polymerase Chai...mentioning

confidence: 99%

Benzene Exposure Leads to Lipodystrophy and Alters Endocrine Activity In Vivo and In Vitro

Cui

et al. 2022

Front. Endocrinol.

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“…To further clarify the regulatory role of NFE2L1 in lipid metabolism of adipocytes and verify the mechanisms underlying the phenotype of Nfe2l1 (f)-KO mice, we used protracted rosiglitazone (RGZ) treatment to create an extremely positive lipid content balance in Nfe2l1 (f)-KO mice. While three weeks of RGZ treatment significantly down-regulated mRNA levels of a group of inflammation-related genes in WAT of adult Nfe2l1 -Floxed control mice, the adipose phenotype of Nfe2l1 (f)-KO mice was aggravated showing further increased inflammation and macrophage infiltration, enhanced transcript expression related to inflammation and pyroptosis in WAT [ 14 ]. In addition, the effect of CL316243, a β3 adrenergic agonist that promotes lipolysis via a post-translational mechanism, on adipose inflammation in juvenile Nfe2l1 (f)-KO mice was also studied [ 98 ].…”

Section: Unraveling the Emerging Roles Of Nfe2l1 In Atmentioning

confidence: 99%

“…While 7 days of CL316243 treatment showed no significant effect on adipose inflammation in Nfe2l1 -Floxed control mice, the same treatment dramatically alleviated macrophage infiltration and mRNA expression of inflammation and pyroptosis-related genes in WAT of Nfe2l1 (f)-KO mice. The adipose tissue phenotypes of Nfe2l1 (f)-KO mice and Nfe2l1 -Floxed control mice under different treatment conditions were summarized in Table 3 [ 13 , 14 , 98 ].…”

Section: Unraveling the Emerging Roles Of Nfe2l1 In Atmentioning

confidence: 99%

“…Following translation of Nfe2l1 , multiple topovectorial processes facilitate selective post-synthetic processing of NFE2L1 in different tempo-spatial subcellular locations from the endoplasmic reticulum (ER) to the nucleus. Various genetic loss and gain of function studies of NFE2L1 over the past decades have shown that NFE2L1 has profound roles in adipose biology involving adipogenesis, lipid and glucose metabolism, thermogenesis, oxidation-reduction and proteasome homeostasis [ [11] , [12] , [13] , [14] ]. Besides, a single nucleotide polymorphism (SNP), rs3764400, occurring in the 5′-flanking region of the human NFE2L1 gene appears to be associated with obesity in humans [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

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The roles of NFE2L1 in adipocytes: Structural and mechanistic insight from cell and mouse models

et al. 2021

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Adipocytes play pivotal roles in maintaining energy homeostasis by storing lipids in adipose tissue (AT), regulating the flux of lipids between AT and the circulation in response to the body's energy requirements and secreting a variety of hormones, cytokines and other factors. Proper AT development and function ensure overall metabolic health. Nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as NRF1) belongs to the CNC-bZIP family and plays critical roles in regulating a wide range of essential cellular functions and varies stress responses in many cells and tissues. Human and rodent Nfe2l1 genes can be transcribed into multiple splice variants resulting in various protein isoforms, which may be further modified by a variety of post-translational mechanisms. While the long isoforms of NFE2L1 have been established as master regulators of cellular adaptive antioxidant response and proteasome homeostasis, the exact tissue distribution and physiological function of NFE2L1 isoforms, the short isoforms in particular, are still under intense investigation. With regard to key roles of NFE2L1 in adipocytes, emerging data indicates that deficiency of Nfe2l1 results in aberrant adipogenesis and impaired AT functioning. Intriguingly, a single nucleotide polymorphism (SNP) of the human NFE2L1 gene is associated with obesity. In this review, we summarize the most significant findings regarding the specific roles of the multiple isoforms of NFE2L1 in AT formation and function. We highlight that NFE2L1 plays a fundamental regulatory role in the expression of multiple genes that are crucial to AT metabolism and function and thus could be an important target to improve disease states involving aberrant adipose plasticity and lipid homeostasis.

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“…In line with the findings that NFE2L1 is potentially involved in the pathogenesis of obesity, BAC-specific deletion of Nfe2l1 in mice resulted in endoplasmic reticulum (ER) stress, tissue inflammation, markedly diminished mitochondrial function and whitening of the BAT, highlighting NFE2L1 as a critical driver in proteasomal adaption under thermogenic conditions [ 9 , 17 ]. Our recent studies demonstrated that adipocyte-specific Nfe2l1 knockout [ Nfe2l1 (f)-KO] mice, in which the Nfe2l1 gene was disrupted specifically in the adiponectin-expressing adipocytes, exhibit a dramatically reduced subcutaneous adipose tissue mass, adipocyte hypertrophy, and severe adipose inflammation mediated via disturbed expression of lipolytic genes in adipocytes [ [18] , [19] , [20] ]. In addition, NFE2L1 regulates adipogenesis in an isoform-specific manner.…”

Section: Introductionmentioning

confidence: 99%

Single-nucleus RNA-sequencing reveals NRF1/NFE2L1 as a key factor determining the thermogenesis and cellular heterogeneity and dynamics of brown adipose tissues in mice

Shen,

Ren,

Hou

et al. 2023

Redox Biology

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Protracted rosiglitazone treatment exacerbates inflammation in white adipose tissues of adipocyte-specific Nfe2l1 knockout mice

Cited by 11 publications

References 52 publications

Benzene Exposure Leads to Lipodystrophy and Alters Endocrine Activity In Vivo and In Vitro

Benzene Exposure Leads to Lipodystrophy and Alters Endocrine Activity In Vivo and In Vitro

The roles of NFE2L1 in adipocytes: Structural and mechanistic insight from cell and mouse models

Single-nucleus RNA-sequencing reveals NRF1/NFE2L1 as a key factor determining the thermogenesis and cellular heterogeneity and dynamics of brown adipose tissues in mice

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