Nf1 heterozygous mice recapitulate the anthropometric and metabolic features of human neurofibromatosis type 1.
Nf1 heterozygous mice recapitulate the anthropometric and metabolic features of human neurofibromatosis type 1.
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Nf1杂合子小鼠再现了人类1型神经纤维瘤病的人体测量学和代谢特征。
DOI：
10.1016/j.trsl.2020.08.001
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Stansfield BK
中科院分区：
文献类型：
--
作者：
Tritz R;Benson T;Harris V;Hudson FZ;Mintz J;Zhang H;Kennard S;Chen W;Stepp DW;Csanyi G;Belin de Chantemèle EJ;Weintraub NL;Stansfield BK
1型神经纤维瘤病(NF1)是一种可遗传的癌症易感综合征，由NF1肿瘤抑制基因突变引起。由于NF1的大量突变和修饰基因在NF1表现中的作用，NF1的基因型和表型相关性很少；然而，新出现的报告表明，NF1患者表现出独特的人体测量和代谢表型，表现为身材矮小、体重指数(BMI)低、胰岛素敏感性增加以及对糖尿病的保护。NF1杂合子(NF1+/−)小鼠准确地反映了NF1的显性遗传，经常被用作NF1的模型。在这里，我们试图确定NF1+/−小鼠是否概括了NF1患者的人体测量和代谢特征。对16-20周龄雄性野生型(WT)和NF1+/−C57B/6J小鼠进行了核磁共振、间接量热法和葡萄糖/胰岛素/丙酮酸耐量试验。在一些实验中，采集组织进行核磁共振和组织学表征。Nf1+/−小鼠更瘦，内脏和皮下脂肪质量显著减少，这与小脂肪细胞密度增加和瘦素水平降低相对应。此外，NF1+/−小鼠高度依赖碳水化合物作为能量底物，表现出葡萄糖清除和胰岛素敏感性增加，但对丙酮酸的正常反应表明葡萄糖利用增强和糖异生保存。最后，给予高糖饮食的WT和NF1+/−小鼠可免受饮食诱导的肥胖和高血糖的影响。我们的数据表明，NF1+/−小鼠与NF1患者的人体测量和代谢表型非常相似，这将影响对之前和未来对NF1的翻译研究的解释。
Neurofibromatosis type 1 (NF1) is a heritable cancer predisposition syndrome resulting from mutations in the NF1 tumor suppressor gene. Genotype-phenotype correlations for NF1 are rare due to the large number of NF1 mutations and role of modifier genes in manifestations of NF1; however, emerging reports suggest that persons with NF1 display a distinct anthropometric and metabolic phenotype featuring short stature, low body mass index (BMI), increased insulin sensitivity, and protection from diabetes. Nf1 heterozygous (Nf1+/−) mice accurately reflect the dominant inheritance of NF1 and are regularly employed as a model of NF1. Here, we sought to identify whether Nf1+/− mice recapitulate the anthropometric and metabolic features identified in persons with NF1. Littermate 16–20 week-old male wildtype (WT) and Nf1+/− C57B/6J mice underwent nuclear magnetic resonance (NMR), indirect calorimetry, and glucose/insulin/pyruvate tolerance testing. In some experiments, tissues were harvested for NMR and histologic characterization. Nf1+/− mice are leaner with significantly reduced visceral and subcutaneous fat mass, which corresponds with an increased density of small adipocytes and reduced leptin levels. Additionally, Nf1+/− mice are highly reliant on carbohydrates as an energy substrate and display increased glucose clearance and insulin sensitivity, but normal response to pyruvate suggesting enhanced glucose utilization and preserved gluconeogenesis. Finally, WT and Nf1+/− mice subjected to high glucose diet were protected from diet-induced obesity and hyperglycemia. Our data suggest that Nf1+/− mice closely recapitulate the anthropometric and metabolic phenotype identified in persons with NF1, which will impact the interpretation of previous and future translational studies of NF1.
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影响因子：
15.9
作者：
Lasater, Elisabeth A.;Li, Fang;Ingram, David A., Jr.
通讯作者：
Ingram, David A., Jr.
影响因子：
3.5
作者：
Bessler, Waylan K.;Kim, Grace;Stansfield, Brian K.
通讯作者：
Stansfield, Brian K.
NF1中的基因型 - 表型相关性：与影响NF1密码子844-848的错义突变有关的更严重表型的证据。
影响因子：
9.8
作者：
Koczkowska M;Chen Y;Callens T;Gomes A;Sharp A;Johnson S;Hsiao MC;Chen Z;Balasubramanian M;Barnett CP;Becker TA;Ben-Shachar S;Bertola DR;Blakeley JO;Burkitt-Wright EMM;Callaway A;Crenshaw M;Cunha KS;Cunningham M;D'Agostino MD;Dahan K;De Luca A;Destrée A;Dhamija R;Eoli M;Evans DGR;Galvin-Parton P;George-Abraham JK;Gripp KW;Guevara-Campos J;Hanchard NA;Hernández-Chico C;Immken L;Janssens S;Jones KJ;Keena BA;Kochhar A;Liebelt J;Martir-Negron A;Mahoney MJ;Maystadt I;McDougall C;McEntagart M;Mendelsohn N;Miller DT;Mortier G;Morton J;Pappas J;Plotkin SR;Pond D;Rosenbaum K;Rubin K;Russell L;Rutledge LS;Saletti V;Schonberg R;Schreiber A;Seidel M;Siqveland E;Stockton DW;Trevisson E;Ullrich NJ;Upadhyaya M;van Minkelen R;Verhelst H;Wallace MR;Yap YS;Zackai E;Zonana J;Zurcher V;Claes K;Martin Y;Korf BR;Legius E;Messiaen LM
通讯作者：
Messiaen LM
影响因子：
37.8
作者：
Li F;Downing BD;Smiley LC;Mund JA;Distasi MR;Bessler WK;Sarchet KN;Hinds DM;Kamendulis LM;Hingtgen CM;Case J;Clapp DW;Conway SJ;Stansfield BK;Ingram DA Jr
通讯作者：
Ingram DA Jr
影响因子：
5.8
作者：
Cozzo AJ;Fuller AM;Makowski L
通讯作者：
Makowski L