The 14th Ile residue is essential for Leptin function in regulating energy homeostasis in rat

Shou, Xu; Zhu, Xianmin; Li, Hong; Hu, Yijun; Zhou, Jinping; He, Dongyang; Feng, Yun; Lu, Liping; Du, Guizhen; Hu, Youjin; Liu, Tiancheng; Wang, Zhen; Ding, Guohui; Chen, Jiayu; Gao, Shaorong; Wu, Fang; Xue, Zhigang; Li, Yixue; Fan, Guoping

doi:10.1038/srep28508

Cited by 9 publications

(14 citation statements)

References 61 publications

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“…We previously generated Leptin deficient (Lep ∆I14/∆I14 ) rats by CRISPR technology. (14) Interestingly, we found that Lep ∆I14/∆I14 rats display distinctive NASH phenotypes, which needs to be further characterized.…”

Section: Introductionmentioning

confidence: 80%

“…Lep ∆I14/∆I14 rats share many similar phenotypes with ob/ob mice, such as obesity, hyperglycaemia, hyperinsulinemia, NAFLD, and infertility. (14) Our previous histopathological examination showed that NAFLD starts at postnatal week 8. (14) Consistently, body weight and relative liver weight of Lep ∆I14/∆I14 rats were significantly higher than those of their wild-type (WT) littermates after 8 postnatal weeks (fig.…”

Section: Leptin Deficiency Leads To Nash Phenotypes In Ratsmentioning

confidence: 99%

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Leptindeficient rats develop nonalcoholic steatohepatitis with unique disease progression

Lü

Yang

et al. 2019

Preprint

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Nonalcoholic steatohepatitis (NASH) is an aggressive liver disease threatening public health, however its natural history is poorly understood. Unlike ob/ob mice, Lep ∆I14/∆I14 rats develop unique NASH phenotype with steatosis, lymphocyte infiltration and ballooning after postnatal week 16. Using Lep ∆I14/∆I14 rats as NASH model, we studied the natural history of NASH progression by performing an integrated analysis of hepatic transcriptome from postnatal week 4 to 48. Leptin deficiency results in a robust increase in expression of genes encoding 9 rate-limiting enzymes in lipid metabolism such as ACC and FASN. However, genes in positive regulation of inflammatory response are highly expressed at week 16 and then remain the steady elevated expression till week 48. The high expression of cytokines and chemokines including CCL2, TNFɑ, IL6 and IL1β is correlated with the phosphorylation of several key molecules in pathways such as JNK and NF-κB.Meanwhile, we observed cell infiltration of MPO + neutrophils, CD8 + T cells, CD68 + hepatic macrophages and CCR2 + inflammatory monocyte-derived macrophages, together with macrophage polarization from M2 to M1. Importantly, Lep ∆I14/∆I14 rats share more homologous genes with NASH patients than previously established mouse models and crab eating monkeys with spontaneous hepatic steatosis. Transcriptomic analysis showed that many drug targets in clinical trials can be evaluated in Lep ∆I14/∆I14 rats. Conclusion: We characterize Lep ∆I14/∆I14 rats as a unique NASH model by performing a long-term (i.e., 4 to 48 postnatal weeks) integrated transcriptomic analysis. This work reveal the temporal dynamics of hepatic gene 6 expression in lipid metabolism and inflammation, and shed light on understanding the natural history of NASH in human beings.

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Section: Introductionmentioning

confidence: 80%

Section: Leptin Deficiency Leads To Nash Phenotypes In Ratsmentioning

confidence: 99%

Leptindeficient rats develop nonalcoholic steatohepatitis with unique disease progression

Lü

Yang

et al. 2019

Preprint

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“…1 ). We created Tshr mutant rats by CRISPR/Cas9 gene editing tool following the protocol as previously reported 15 . Briefly, we designed two specific targeting sequences in the 10th exon (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Rat is bigger in size than mouse so that to provide larger amount of blood/tissue samples for accurate assessment. Moreover, rat is more physiologically similar to human 14 and thus shows similar phenotypes to those in human which sometimes are not seen in the mouse counterpart 15 . Taking advantage of the CRISPR gene-editing technology, we sought to develop a novel rat model to functionally characterize the truncated Tshr protein in vivo .…”

Section: Introductionmentioning

confidence: 90%

Generation and characterization of a hypothyroidism rat model with truncated thyroid stimulating hormone receptor

Yang

Ning

Zhang

et al. 2018

Sci Rep

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Thyroid stimulating hormone receptor (TSHR), a G-protein-coupled receptor, is important for thyroid development and growth. In several cases, frameshift and/or nonsense mutations in TSHR were found in the patients with congenital hypothyroidism (CH), however they have not been functionally studied in an animal model. In the present work, we generated a unique TshrDf/Df rat model that recapitulates the phenotypes in TSHR Y444X patient by CRISPR/Cas genome editing technology. In this rat model, TSHR is truncated at the second transmembrane domain, leading to CH phenotypes as what was observed in the patients, including dwarf, thyroid aplasia, infertility, TSH resistant as well as low serum thyroid hormone levels. The phenotypes can be reversed, at least partially, by levothyroxine (L-T4) treatment after weaning. The thyroid development is severely impaired in the TshrDf/Df rats due to the suppression of the thyroid specific genes, i.e., thyroperoxidase (Tpo), thyroglobulin (Tg) and sodium iodide symporter (Nis), at both mRNA and protein levels. In conclusion, the TshrDf/Df rat serves as a brand new genetic model to study CH in human, and will greatly help to shed light into the development of terminal organs that are sensitive to thyroid hormones.

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“…csiro.au/; Supplemental Table S1). The plasmid construction, in vitro transcription, and subsequent 1-cell embryo injection were performed following previous protocols by Xu et al (36). The mixture of single-guide RNA (sgRNA; 50 ng/ml) and Cas9 mRNA (100 ng/ml) were injected into the cytoplasm of 1-cell embryos at the pronucleus stage.…”

Section: Human Lung Cancer Tissue Specimensmentioning

confidence: 99%

A novel immunodeficient rat model supports human lung cancer xenografts

Zhang

et al. 2018

The FASEB Journal

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Patient-derived xenograft (PDX) animal models allow the exogenous growth of human tumors, offering an irreplaceable preclinical tool for oncology research. Mice are the most commonly used host for human PDX models, however their small body size limits the xenograft growth, sample collection, and drug evaluation. Therefore, we sought to develop a novel rat model that could overcome many of these limitations. We knocked out Rag1, Rag2, and Il2rg in Sprague Dawley (SD) rats by clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 technology. The development of lymphoid organs is significantly impaired in Rag1Rag2Il2rg (designated as SD-RG) rats. Consequently, SD-RG rats are severely immunodeficient with an absence of mature T, B, and NK cells in the immune system. After subcutaneous injection of tumor cell lines of different origin, such as NCI-H460, U-87MG, and MDA-MB-231, the tumors grow significantly faster and larger in SD-RG rats than in nonobese diabetic- Cg-Prkdc Il2rg/SzJ mice. Most important of all, we successfully established a PDX model of lung squamous cell carcinoma in which the grafts recapitulate the histopathologic features of the primary tumor for several passages. In conclusion, the severely immunodeficient SD-RG rats support fast growth of PDX compared with mice, thus holding great potential to serve as a new model for oncology research.-He, D., Zhang, J., Wu, W., Yi, N., He, W., Lu, P., Li, B., Yang, N., Wang, D., Xue, Z., Zhang, P., Fan, G., Zhu, X. A novel immunodeficient rat model supports human lung cancer xenografts.

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The 14th Ile residue is essential for Leptin function in regulating energy homeostasis in rat

Cited by 9 publications

References 61 publications

Leptindeficient rats develop nonalcoholic steatohepatitis with unique disease progression

Leptindeficient rats develop nonalcoholic steatohepatitis with unique disease progression

Generation and characterization of a hypothyroidism rat model with truncated thyroid stimulating hormone receptor

A novel immunodeficient rat model supports human lung cancer xenografts

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