WO2023216749A1 - 一种irx3基因在制备药物中的应用 - Google Patents

一种irx3基因在制备药物中的应用 Download PDF

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WO2023216749A1
WO2023216749A1 PCT/CN2023/084658 CN2023084658W WO2023216749A1 WO 2023216749 A1 WO2023216749 A1 WO 2023216749A1 CN 2023084658 W CN2023084658 W CN 2023084658W WO 2023216749 A1 WO2023216749 A1 WO 2023216749A1
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irx3ov
mice
preparation
hirx3
gene
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宁光
王计秋
刘瑞欣
洪洁
张织茵
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上海交通大学医学院附属瑞金医院
上海市内分泌代谢病研究所
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    • A01K2267/0362—Animal model for lipid/glucose metabolism, e.g. obesity, type-2 diabetes

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  • the invention belongs to the field of medicine, and particularly relates to the application of an IRX3 gene in the preparation of medicines.
  • the transcription factor encoded by the IRX3 gene belongs to the Iroquois homeodomain structural protein family.
  • the IRX3 gene is initially expressed during embryogenesis and is involved in the development and formation of multiple tissues, including the nervous system, heart, and bones.
  • Fat in the human body can be divided into white adipose tissue and brown adipose tissue based on function.
  • White adipose tissue is an important energy storage place. In the case of excessive caloric intake, excess energy is stored in the form of triglycerides; brown adipose tissue It is an important body temperature maintenance organ that maintains body temperature stability through its thermogenic activity through uncoupling protein 1 (UCP1) located on its internal mitochondrial membrane.
  • UCP1 uncoupling protein 1
  • the technical problem to be solved by the present invention is to provide an application of IRX3 gene in the preparation of medicines.
  • the drug contains a preparation that enhances IRX3 gene expression and promotes brown/beige fat differentiation.
  • the medicine also contains auxiliary preparations.
  • mice overexpressing hIRX3 in brown/beige adipose tissue exhibit increased energy expenditure, decreased body fat, and weight loss.
  • Overexpression of hIRX3 during in vitro differentiation can enhance the thermogenic ability of brown and beige adipocytes, which provides a basis for the application of IRX3 gene agonists in the preparation of drugs.
  • Figure 1 shows the technical roadmap for hIRX3 knock-in (Rosa26hIRX3, hIRX3 knock-in) mouse model construction (a) and the gene identification structure diagram (b);
  • FIG. 2 is a diagram of the breeding strategy of U-IRX3ov mice
  • Figure 3 shows that under normal diet and feeding conditions, the weight of U-IRX3ov mice was significantly lighter than that of the control group.
  • B Average body weight of 10-week-old male U-IRX3ov and control mice.
  • C Comparison of the average body fat content of 10-week-old male U-IRX3ov and control mice.
  • E Average body weight of 10-week-old female U-IRX3ov and control mice.
  • F Comparison of the average body fat content of 10-week-old female U-IRX3ov and control mice. Data are presented as mean ⁇ SEM. *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001, ****P ⁇ 0.0001.
  • Figure 4 shows the body fat content and lean tissue content percentage of U-IRX3ov and control mice;
  • A Body fat content percentage of male U-IRX3ov and control mice.
  • B Percentage of lean tissue content in male U-IRX3ov and control mice.
  • C Percent body fat content of female U-IRX3ov and control mice.
  • D Percentage of lean tissue content in female U-IRX3ov and control mice.
  • Data are presented as mean ⁇ SEM. *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001, ****P ⁇ 0.0001.
  • FIG. 5 shows that there is no significant difference in food intake and exercise between U-IRX3ov and control mice, but the overall metabolic level is significantly increased.
  • 24-hour X-axis movement frequency curve of male U-IRX3ov and control mice (left) and sum of circadian movements (right), n 6-8.
  • G. 24-hour Y-axis movement frequency curve of male U-IRX3ov and control mice (left) and sum of circadian movements (right), n 6-8.
  • H. 24-hour Z-axis movement frequency curve of male U-IRX3ov and control mice (left) and sum of circadian movements (right), n 6-8.
  • Data are presented as mean ⁇ SEM. *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001, ****P ⁇ 0.0001.
  • Figure 6 shows the verification of the efficiency of overexpression of hIRX3 during in vitro induction of differentiation
  • A RNA expression levels of exogenous hIRX3 in brown adipocytes and beige adipocytes derived from subcutaneous white adipose tissue
  • Data are presented as mean ⁇ SEM. *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001, ****P ⁇ 0.0001.
  • FIG. 7 shows that overexpression of hIRX3 in mature brown/beige adipocytes induced in vitro can increase thermogenesis;
  • U-IRX3ov and controls were raised by Shanghai Nanmo Biology.
  • the circadian rhythm of mice is 12-12 hours, and the lights are on 7:00am-19:00pm, lights off time 19:00pm-7:00am, the relative humidity of the environment is maintained at 55 ⁇ 10%, and the temperature is maintained at 21 ⁇ 1°C.
  • Drinking water is sterilized by high temperature and high pressure, feed is sterilized by UV irradiation for 12 hours, water and food are fully supplied, the energy of ordinary feed is 1.404kcal/g, and the nutritional content is 21% protein, 4% cellulose, and 4.5% fat.
  • Mice can eat freely; mice After weaning (about 4 weeks old), they are divided into cages, with 4-5 animals in one cage.
  • the human IRX3 (hIRX3) cDNA-polyA cassette (GenBank accession number: NM_024336.2; Ensembl: ENSG00000177508) was cloned into intron 1 of the Rosa26 gene locus, and CAG-loxP-stop was inserted upstream of the cDNA-polyA cassette. -loxP fragment, the construction process is shown in Figure 1.
  • the hIRX3 genotype identification primer sequence is as follows:
  • Ucp1-Cre driven hIRX3 overexpression mouse model (Ucp1-Cre; Rosa26hIRX3, denoted as U-IRX3ov) was constructed (as shown in Figure 2).

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Abstract

提供一种IRX3基因在制备药物中的应用，体外诱导分化过程中过表达hIRX3可以增强棕色和米色脂肪细胞的产热能力，这为IRX3基因激动剂在制备药物中的应用提供了依据。

Description

一种IRX3基因在制备药物中的应用 技术领域
本发明属于药物领域，特别涉及一种IRX3基因在制备药物中的应用。
背景技术
IRX3基因(Iroquois家族3号同源框基因)编码的转录因子属于Iroquois同源域结构蛋白家族。IRX3基因最初在胚胎发生过程中表达，参与多种组织(包括神经系统，心脏和骨骼)的发育和形成。
人体的脂肪以功能可以分为白色脂肪组织和棕色脂肪组织，其中白色脂肪组织是重要的能量储存场所，在热量摄入过多的情况下将多余能量以甘油三酯的形式存储；棕色脂肪组织是重要的体温维持器官，通过定位于其内部线粒体膜上的解偶联蛋白1(UCP1)发挥产热活性而维持体温稳定。
发明内容
本发明所要解决的技术问题是提供一种IRX3基因在制备药物中的应用。
本发明的一种IRX3基因在制备抵抗肥胖药物中的应用。
本发明的一种IRX3基因在制备减少体脂药物中的应用。
本发明的一种IRX3基因在制备促进棕/米色脂肪分化药物中的应用。
所述药物为含增强IRX3基因表达的制剂，促进棕/米色脂肪分化。
所述药物中还含有辅助制剂。
有益效果
棕色/米色脂肪组织过表达hIRX3小鼠(Rosa26hIRX3；Ucp1-Cre)表现为能量消耗增加、体脂减少和体重减轻。体外诱导分化过程中过表达hIRX3可以增强棕色和米色脂肪细胞的产热能力，这为IRX3基因激动剂在制备药物中的应用提供了依据。
附图说明
图1为hIRX3敲入(Rosa26hIRX3,hIRX3 knock-in)小鼠模型构建技术路线图(a)和基因鉴定结构图(b)；
图2为U-IRX3ov小鼠繁殖策略图；
图3为正常饮食饲养条件下，U-IRX3ov小鼠体重较对照组明显偏轻。A.雄性U-IRX3ov与对照组小鼠体重变化曲线图。n＝6-8。B.10周龄雄性U-IRX3ov与对照组小鼠平均体重图。C.10周龄雄性U-IRX3ov与对照组小鼠平均体脂含量比较图。D.雌性U-IRX3ov与对照组小鼠体重变化曲线图。n＝9-11。E.10周龄雌性U-IRX3ov与对照组小鼠平均体重图。F.10周龄雌性U-IRX3ov与对照组小鼠平均体脂含量比较图。数据以平均值±SEM形式展示。*P <0.05，**P<0.01，***P<0.001，****P<0.0001。
图4为U-IRX3ov与对照小鼠体脂含量、瘦组织含量百分比；A.雄性U-IRX3ov与对照小鼠体脂含量百分比。B.雄性U-IRX3ov与对照小鼠瘦组织含量百分比。C.雌性U-IRX3ov与对照小鼠体脂含量百分比。D.雌性U-IRX3ov与对照小鼠瘦组织含量百分比。数据以平均值±SEM形式展示。*P<0.05，**P<0.01，***P<0.001，****P<0.0001。
图5为U-IRX3ov与对照小鼠相比摄食及运动无显著差异，但总体代谢水平显著升高。
图注：A.雄性U-IRX3ov与对照小鼠每日平均摄食量(n＝6-8,取三次测量均值)。B.雌性U-IRX3ov与对照小鼠每日平均摄食量(n＝9-11,取三次测量均值)。C.雄性U-IRX3ov与对照小鼠每日平均能量消耗(n＝6-8)。D.雄性U-IRX3ov与对照小鼠24小时氧吸入氧气量曲线图(左)及昼夜耗氧量总和(右),n＝6-8。E.雄性U-IRX3ov与对照小鼠24小时二氧化碳呼出量曲线图(左)及昼夜耗氧量总和(右)，n＝6-8。F.雄性U-IRX3ov与对照小鼠24小时X轴运动次数曲线图(左)及昼夜运动总和(右),n＝6-8。G.雄性U-IRX3ov与对照小鼠24小时Y轴运动次数曲线图(左)及昼夜运动总和(右),n＝6-8。H.雄性U-IRX3ov与对照小鼠24小时Z轴运动次数曲线图(左)及昼夜运动总和(右),n＝6-8。数据以平均值±SEM形式展示。*P<0.05，**P<0.01，***P<0.001，****P<0.0001。
图6为体外诱导分化过程中过表达hIRX3效率验证；：A.棕色脂肪细胞及皮下白色脂肪组织来源的米色脂肪细胞外源性hIRX3的RNA表达水平；n＝4。B.棕色脂肪细胞及皮下白色脂肪组织来源的米色脂肪细胞内源性mIRX3的RNA表达水平；n＝4。数据以平均值±SEM形式展示。*P<0.05，**P<0.01，***P<0.001，****P<0.0001。
图7为体外诱导成熟的棕色/米色脂肪细胞内过表达hIRX3可致产热增加；(A-F)U-IRX3ov和对照小鼠的棕色脂肪来源的SVF体外诱导分化5天结果：油红O染色(A)，细胞耗氧率检测(OCR)(B-C)，产热相关基因RNA表达(D)，蛋白表达(E)及蛋白定量(F)结果；n＝3-4。(G-L)U-IRX3ov和对照小鼠的皮下白色脂肪来源的SVF体外米色化诱导分化8天结果：油红O染色(G)，细胞耗氧率检测(OCR)(H-I)；产热相关基因RNA表达(J)，蛋白表达(K)及蛋白定量(L)结果；n＝3-4。数据以平均值±SEM形式展示。*P<0.05，**P<0.01，***P<0.001，****P<0.0001。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
U-IRX3ov及对照由上海南模生物饲养。小鼠饲养昼夜节律为12—12小时，开灯时间 7:00am-19:00pm,关灯时间19:00pm-7:00am,环境相对湿度保持在55±10％，温度维持在21±1℃。饮水高温高压消毒，饲料紫外辐照12小时消毒，水和食物充分供给，普通饲料能量1.404kcal/g，营养成份比例为蛋白质21％、纤维素4％、脂肪4.5％，自由取食；小鼠断奶后(约4周龄)分笼，4-5只一笼。
实施例1
一、动物模型构建
1.hIRX3敲入(Rosa26 hIRX3,hIRX3 knock-in)小鼠模型构建
将人源IRX3(hIRX3)cDNA-polyA盒(GenBank登录号：NM_024336.2；Ensembl：ENSG00000177508)克隆到Rosa26基因座位的1号内含子中，并在cDNA-polyA盒上游插入CAG-loxP-stop-loxP片段，构建流程见图1所示。
hIRX3基因型鉴定引物序列如下所示：
产物大小：纯合子＝～243bp，杂合子＝243bp和617bp，野生型＝～617bp。
PCR反应体系如下表所示：
PCR循环数及反应温度如下表所示：
琼脂糖凝胶电泳：浓度1.5％，165V,30分钟。Maker：100bp DNA Ladder Marker(Takara，3422A)。结果如图1(b)所示。
2.hIRX3棕色/米色脂肪组织特异性过表达小鼠模型构建(Ucp1-Cre；Rosa26hIRX3(U-IRX3ov)
使用Cre/loxP系统实现基因重组，将Ucp1-Cre小鼠(获自Jackson实验室，Jax号024670)与Rosa26hIRX3小鼠杂交得到Ucp1-Cre；Rosa26hIRX3(U-IRX3ov)子代。其对照小鼠基因型为Rosa26hIRX3单基因纯合小鼠。
具体地，构建了Ucp1-Cre驱动的hIRX3过表达小鼠模型(Ucp1-Cre；Rosa26hIRX3，记为U-IRX3ov)(如图2所示)。
当给予正常饮食方案进行饲养时，10周龄的雄性和雌性U-IRX3ov小鼠体重均显著低于对照组(Rosa26hIRX3)(如图3所示)。对实验组及对照组小鼠进行了体脂含量测定后发现,U-IRX3ov小鼠的脂肪含量百分比与对照组相比显著降低，且存在统计学差异(p<0.05)；但是U-IRX3ov小鼠的瘦组织含量百分比与对照组小鼠相比没有显著差异(图4所示)。影响小鼠体重及体脂的因素主要包含摄食量和代谢率(基础代谢及活动代谢)两个方面。为了明确体重及体脂百分比差异的产生原因，利用代谢笼检测，对U-IRX3ov和对照组小鼠的24小时食物摄入、活动情况和能量消耗水平进行了全面评估。发现，与对照组小鼠相比，U-IRX3ov小鼠的每日食物摄入量无显著升高；在水平面的活动度及抬头摄食次数在24小时内有若干时间点有升高，但12小时总活动量无显著差异。与此同时，U-IRX3ov的昼夜O2消耗量及CO2产生量较对照组显著升高，以夜间代谢水平升高尤为明显，并存在统计学差异(p<0.05)，这提示U-IRX3ov小鼠与对照组相比显示出更高的每小时平均能量消耗水平(图5)。上述结果说明，U-IRX3ov小鼠出现体重较轻，脂肪量较少的表型很可能是由于其代谢水平升高导致的能量消耗增加所致。
二、过表达人源IRX3增强棕色及白色脂肪原代细胞体外诱导分化能力
为了印证体内过表达hIRX3的表型，同时进一步探究hIRX3增强脂肪组织产热的具体分子生物学机制，分离了U-IRX3ov小鼠棕色脂肪组织/白色脂肪组织来源的原代脂肪前体细胞(SVF)，并对其分别进行了诱导分化/米色化诱导。体外诱导成熟的U-IRX3ov棕色/米色脂肪细胞成功过表达hIRX3(图6)。与对照组相比，U-IRX3ov小鼠棕色脂肪组织来源的SVF成脂分化能力显著增强，油红O染色拍照结果可见培养皿中脂滴面积显著缩小，数目明显增加(图7A)。为了明确U-IRX3ov和对照来源的两组脂肪细胞的产热能力差异，进一步对诱导分化的成熟脂肪细胞进行线粒体呼吸耗氧量测定(seahorse)。结果显示，hIRX3过表达组棕色成熟脂肪细胞的基础状态氧耗量、线粒体呼吸链质子漏显著增加，同时最大氧耗量、ATP 生成也有升高趋势(图7B-C)。与之对应，hIRX3过表达组棕色成熟脂肪细胞Ucp1，Pgc-1α，Cidea，Cox7a1和Cox8b的转录水平均显著增加(图7D)，同时Ucp1和Pgc-1α的蛋白水平也显著高于对照(图7E-F)。上述结果说明，体外诱导成熟的棕色脂肪细胞内过表达hIRX3可致产热增加。而在体外诱导成熟的米色脂肪细胞上同样观察到了类似的氧耗量、质子漏、ATP合成增加；Ucp1，Pgc-1α，Cidea，Cox7a1和Cox8b的转录水平均增加；Ucp1和Pgc-1α的蛋白表达水平升高等现象(图7G-L)。
综合上述体外表型，结论：体外诱导分化过程中过表达hIRX3可以增强棕色和米色脂肪细胞的产热能力。

Claims (5)

  1. 一种IRX3基因在制备抵抗肥胖药物中的应用。
  2. 一种IRX3基因在制备减少体脂药物中的应用。
  3. 一种IRX3基因在制备促进棕/米色脂肪分化药物中的应用。
  4. 根据权利要求1-3任一所述应用，其特征在于，所述药物为含增强IRX3基因表达的制剂。
  5. 根据权利要求1-3任一所述应用，其特征在于，所述药物中还含有辅助制剂。
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