CN117858716A - 具有肥胖症和肌肉损失抑制活性的肽及其用途 - Google Patents
具有肥胖症和肌肉损失抑制活性的肽及其用途 Download PDFInfo
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Abstract
本发明涉及一种具有肥胖症和肌肉损失抑制活性的肽及其用途。所述肽具有抑制食欲、促进能量代谢、抑制脂肪积累和促进脂肪分解的优异效果,在促进肌肉合成的同时抑制肌肉萎缩,使得所述肽可以有效地用于预防或治疗肥胖症和肌肉减少症。
Description
技术领域
本发明涉及一种新的具有肥胖症和肌肉损失抑制活性的肽及其用于抑制肥胖症和肌肉减少症的用途。
背景技术
肥胖症是一种由于内分泌因素、遗传因素、饮食习惯以及社会和环境因素引起的代谢过程不平衡而导致体内多余能量以脂肪积累的现象。肥胖症导致明显的症状,如呼吸急促和关节痛,并且在引起各种并发症方面更严重。由肥胖症引起的并发症包括心血管疾病、高血压、睡眠呼吸暂停和血脂异常。因此,世界卫生组织将肥胖症视为一种必须治疗的疾病,而不仅仅是危害健康的风险因素。
同时,最近,肌肉减少性肥胖症(sarcopenic obesity)的患病率很高,其为肥胖症和肌肉减少症的结合。肌肉减少性肥胖症抑制肌肉中的蛋白质代谢以导致肌肉质量下降,还增加胰岛素抵抗,导致体力活动减少,基础代谢率降低,进而增加体脂,造成恶性循环。肌肉减少性肥胖症不仅导致诸如由于肌肉质量和肌肉功能下降而导致的跌倒、功能性残疾、生活质量下降以及死亡率增加等问题,还会增加心血管疾病和代谢紊乱的风险。然而,仍然没有用于肌肉减少性肥胖症的治疗剂。
根据其作用机理,目前用于肥胖症的治疗剂可以分为作用于中枢神经系统并影响食欲的那些和作用于胃肠道并抑制吸收的那些。作用于中枢神经系统的药物包括:抑制血清素(5-HT)再摄取的芬氟拉明(fenfluramine)和右芬氟拉明(dexfenfluramine),抑制去甲肾上腺素再摄取的麻黄碱和咖啡因,以及最近同时作用于血清素和去甲肾上腺素能神经系统的西布曲明(sibutramine)。通过作用于胃肠道来抑制肥胖症的药物是奥利司他(orlistat),其被批准通过抑制胰腺中产生的脂肪酶并减少脂肪吸收来治疗肥胖症。然而,在以前使用的药物中,作为食欲抑制剂的芬氟拉明被归类为麻醉成分且由于诸如原发性肺动脉高压和心脏瓣膜病变等副作用而被禁止使用,其他食欲抑制药物也可降低血压或引起乳酸性酸中毒,因此其使用仅限于患有心力衰竭和肾病的患者。脂肪分解抑制剂奥利司他也引起胃肠道副作用,导致不适并抑制脂溶性维生素的吸收,而美国FDA批准用于长期治疗肥胖症的西布曲明因引起诸如心悸或眩晕等心血管疾病而被禁止在市场上出售。
因此,需要一种能够更根本地预防和抑制肥胖症并改善肌肉损失而没有上述药物副作用的治疗剂。
发明内容
技术问题
提供本发明是为了解决上述问题。本发明人发现了几种类型的新的肽,并证实了诸如抑制食欲、促进能量代谢、抑制脂肪积累和促进脂肪分解等抗肥胖症的作用,从而完成了本发明。
此外,证实了肽可用于治疗肌肉减少性肥胖症或肌肉减少症本身,因为它们促进肌肉生物合成并抑制肌肉萎缩。
因此,本发明旨在提供一种具有抗肥胖症活性和肌肉损失抑制活性的肽;一种用于预防或治疗/改善肥胖症的组合物,其包括该肽;以及一种用于治疗/改善肌肉减少症的组合物。
技术方案
本发明的一个方面提供了一种用于预防或治疗肥胖症的药物组合物,其包括作为活性成分的肽,所述肽包括选自由SEQ ID NO:1、2、3和5组成的组中的氨基酸序列。
本文所使用的术语“预防”是指通过施用根据本发明的药物组合物来抑制疾病进展或延迟其发作的所有行为。
本文所使用的术语“治疗”是指通过施用根据本发明的药物组合物来减轻或有益地改变疾病的症状所涉及的所有行为。
根据本发明的一个实施方案,SEQ ID NO:1、4、6、7和8的氨基酸序列具有共同的SEQ ID NO:1的序列,并且SEQ ID NO:2、4、7和8的氨基酸序列包括共同的SEQ ID NO:2的序列。此外,SEQ ID NO:3、7和8的序列包括共同的SEQ ID NO:3的序列,并且SEQ ID NO:5和6的序列包括共同的SEQ ID NO:5的序列。
根据本发明的一个实施方案,包括由SEQ ID NO:1表示的氨基酸序列的所述肽可以是由SEQ ID NO:1、4、6、7或8表示的氨基酸序列组成的肽。
另外,包括选自由SEQ ID NO:2、3和5组成的组中的氨基酸序列的肽可以分别是选自由SEQ ID NO:2、3和5组成的组中的氨基酸序列的肽。
根据本发明的一个实施方案,所述药物组合物可以包括由选自由SEQ ID NO:1至8组成的组中的氨基酸序列组成的肽,与所述氨基酸序列具有80%或更高序列同源性的肽,或作为其片段的肽。
更具体地,本文公开的肽可以包括具有80%或更高、85%或更高、90%或更高、95%或更高、96%或更高、97%或更高、98%或更高或者99%或更高序列同源性的肽。此外,本文公开的肽可包括这样的肽或其片段,其中该肽的一个或多个、2个或更多个、3个或更多个、4个或更多个、5个或更多个、6个或更多个、或者7个或更多个氨基酸相对于选自由SEQID NO:1至8组成的组中的氨基酸序列组成的肽改变。
在一个实施方案中,氨基酸改变是允许肽的物理化学性质被改变的性质。例如,可以实施改善热稳定性、改变底物特异性和改变最佳pH的氨基酸改变。
说明书中使用的“氨基酸”不仅包括天然掺入肽中的22种标准氨基酸,还包括D-异构体和修饰的氨基酸。因此,在本发明的一个方面,肽可以是包含D-氨基酸的肽。同时,在本发明的另一方面,肽可以包括经历了翻译后修饰的非标准氨基酸。翻译后修饰的示例包括磷酸化、糖基化、酰化(例如,包括乙酰化、肉豆蔻酰化和棕榈酰化)、烷基化、羧化、羟基化、糖化、生物素化、泛素化、化学性质的改变(例如,β-消除、脱亚胺化、脱氨基化)和结构改变(例如,二硫键的形成)。此外,翻译后修饰包括在与交联剂结合形成肽缀合物的过程中发生的化学反应引起的氨基酸改变,如氨基、羧基或侧链的改变。
说明书中公开的肽可以是从天然来源鉴定和分离的野生型肽。同时,说明书中公开的肽可以是人工变体:与由选自由SEQ ID NO:1至8组成的组的氨基酸序列组成的肽相比,其包括其中一个或多个氨基酸被替换、缺失和/或插入的氨基酸序列。野生型多肽以及人工变体中的氨基酸改变包括保守的氨基酸替换,其不会显著影响蛋白质的折叠和/或活性。在碱性氨基酸(精氨酸(Ala)、赖氨酸(Lys)和组氨酸(His))、酸性氨基酸(谷氨酸(Glu)和天冬氨酸(Asp))、极性氨基酸(谷氨酰胺(Gln)和天冬酰胺(Asp))、疏水性氨基酸(亮氨酸(Leu)、异亮氨酸(Ile)和甲硫氨酸(Met))、芳香族氨基酸(苯丙氨酸(Phe)、色氨酸(Trp)和酪氨酸(Tyr))和小氨基酸(甘氨酸(Gly)、丙氨酸(Ala)和苏氨酸(Thr))的组中进行保守替换。通常不改变比活性(specific activity)的氨基酸替换是本领域已知的。最常见的交换是Ala/Ser,Val/Ile,Asp/Glu,Thr/Ser,Ala/Gly,Ala/Thr,Ser/Asn,Ala/Val,Ser/Gly,Tyr/Phe,Ala/Pro,Lys/Arg,Asp/Asn,Leu/Ile,Leu/Val,Ala/Glu,Asp/Gly,反之亦然。
通过选择在以下方面显著不同的替换来实施肽的生物学特性的实质性修饰:(a)其在替换区域中维持多肽骨架的结构(例如片状或螺旋状构象)中的效果,(b)其在靶位点中维持分子的电荷或疏水性中的效果,或(c)其在维持侧链的体积方面的效果。基于共同的侧链特性将天然残基分类为以下组:
(1)疏水性残基:正亮氨酸(Nle)、Met、Ala、缬氨酸(Val)、Leu、Ile;
(2)中性亲水性残基:半胱氨酸(Cys)、丝氨酸(Ser)、Thr;
(3)酸性残基:Asp、Glu;
(4)碱性残基:天冬酰胺(Asn)、Gln、His、Lys、精氨酸(Arg);
(5)影响链取向的残基:Gly、脯氨酸(Pro);以及
(6)芳香族残基:Trp、Tyr、Phe。
可以通过将这些类别之一的成员与另一类别的成员交换来进行非保守替换。任何不参与维持肽的正确构象的半胱氨酸残基通常可以被丝氨酸替换,以提高分子的氧化稳定性并防止异常交联。相反地,半胱氨酸键可以添加到肽中以提高其稳定性。
肽中的另一类型氨基酸变体具有改变的糖基化模式。这种改变是指在肽中发现的一个或多个碳水化合物部分的缺失和/或肽中不存在的一个或多个糖基化位点的添加。
肽的糖基化通常是N-连接的或O-连接的。“N-连接的”是指附接至天冬酰胺残基的侧链的碳水化合物部分。三肽序列,天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸(本文中,X是除脯氨酸以外的任何氨基酸),是将烃部分酶促连接到天冬酰胺侧链的识别序列。因此,由于这些三肽序列中的一个存在于多肽中,因此产生了潜在的糖基化位点。O-连接的糖基化是指糖、N-乙酰半乳糖胺、半乳糖或木糖中的一种与羟基氨基酸(最常见的是丝氨酸或苏氨酸)的连接。可替代地,也可以使用5-羟脯氨酸或5-羟赖氨酸。
通过改变氨基酸序列以包含一个或多个上面提到的三肽序列,可以方便地将糖基化位点添加到肽中(在N-连接的糖基化位点的情况下)。可以通过在初始抗体的序列中添加一个或多个丝氨酸或苏氨酸残基或用一个或多个丝氨酸或苏氨酸残基替换来实现这种改变(在O-连接的糖基化位点的情况下)。
根据本发明一个实施方案的药物组合物可应用于所有动物,包括人、狗、鸡、猪、奶牛、绵羊、豚鼠和猴子。
如果需要,根据本发明一个实施方案的药物组合物可以包括添加剂,如稀释剂、赋形剂、润滑剂、粘合剂、崩解剂、缓冲剂、分散剂、表面活性剂、着色剂、调味剂或甜味剂。根据本发明一个实施方案的药物组合物可以通过本领域的常规方法制备。
在本发明中,包含在药物组合物中的载体、赋形剂和稀释剂可以包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿泉水。
根据本发明一个实施方案的药物组合物可以口服、直肠、经皮、静脉内、肌肉内、腹膜内、髓内、鞘内或皮下施用。
用于口服施用的剂型可以包括片剂、丸剂、软胶囊或硬胶囊、颗粒剂、粉剂、溶液剂和乳剂,但本发明不限于此。用于肠胃外施用的剂型可以包括注射剂、滴剂、凝胶剂、混悬剂、乳剂、栓剂、贴剂和喷雾剂,但本发明不限于此。
药物组合物可以无菌注射剂的形式制备为用于无菌注射的水性或油基混悬剂。混悬剂可以根据本领域已知的技术,使用合适的分散剂或润湿剂(例如吐温80)和合适的悬浮剂来配制。无菌注射剂可以是在无毒的胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液(例如,1,3-丁二醇溶液)。可接受的载体和溶剂可以是甘露醇、水、林格氏溶液和等渗氯化钠溶液。此外,无菌不挥发油通常用作溶剂或悬浮介质。为此,可以使用任何无刺激性的不挥发油,包括合成的甘油单酯或甘油二酯。脂肪酸,如油酸及其甘油酯衍生物,可用于注射剂,药学上可接受的天然油(如橄榄油或蓖麻油),特别是它们的聚氧乙基化对应物也是如此。
当期望的治疗涉及通过局部施用容易到达的区域或器官时,根据本发明的药物组合物的肠胃外施用是特别有用的。用于局部施用本发明的组合物的载体包括但不限于:矿物油、液体石蜡、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。
根据本发明的药物组合物的活性成分的量可以根据待施用的受试者的年龄、性别和体重、病理状况及其严重程度、施用途径和处方者的判断而改变。基于这些因素的施用量可以在本领域普通技术人员的水平上确定,并且,根据本发明的药物组合物的每日剂量可以是,例如,10ng/kg/天至10mg/kg/天,具体地,0.1μg/kg/天至1mg/kg/天,更具体地,1μg/kg/天至100μg/kg/天,甚至更具体地,2μg/kg/天至50μg/kg/天,并且当根据剂量存在效果差异时可以适当地调节。根据本发明一个实施方案的药物组合物可以每天施用一至三次,但本发明不限于此。
本发明的另一方面提供了由选自由SEQ ID NO:1至14组成的组中的氨基酸序列组成的肽。
根据本发明的一个实施方案,SEQ ID NO:1、4、6、7和8的氨基酸序列包括共同的SEQ ID NO:1的序列,并且SEQ ID NO:2、4、7和8的氨基酸序列包括共同的SEQ ID NO:2的序列。此外,SEQ ID NO:3、7和8的序列包括共同的SEQ ID NO:3的序列。SEQ ID NO:5和6的序列包括共同的SEQ ID NO:5的序列。
SEQ ID NO:1至8的序列是人源序列,并且相应的小鼠序列如下表1所示。
[表1]
如表1所示,SEQ ID NO:1的序列对于人类和小鼠是相同的,并且包括在SEQ IDNO:10和12至14的序列中。此外,SEQ ID NO:9的序列包括在SEQ ID NO:10、13和14的序列中。SEQ ID NO:10的序列包括在SEQ ID NO:13和14的序列中,并且SEQ ID NO:11的序列包括在SEQ ID NO:12的序列中。同时,SEQ ID NO:3的序列对于人类和小鼠是相同的。
本文所使用的术语并非旨在限制本发明,而是为了描述具体的实施方案。没有数字的术语(在名词之前)不旨在表示它们的数量,而是表示存在所提及的一个或多个名词项。术语“包括”、“具有”和“含有”以开放术语解释(即,意指“包括但不限于”)。
这是因为陈述值的范围仅仅是单独陈述包括在该范围中的每个单独值的简单替代,并且除非另有明确说明,否则每个单独值被并入,如同其在本文中单独陈述一样。范围的端值包含在该范围中,并且可以独立组合。
除非另有说明或与上下文明显矛盾,否则本文提及的所有方法可以以任何适当的顺序实施。除非包括在权利要求中,否则任何一个和所有示例或示例性语言(例如,“如”)的使用仅旨在更好地描述本发明,而不是限制本发明的范围。说明书中的任何语言都不应被解释为要求任何未要求保护的要素对于实施本发明是必需的。除非另有定义,否则本文所使用的技术和科学术语具有本发明所属领域的普通技术人员通常理解的相同含义。
本发明人发现,用抗肥胖症肽处理脂肪细胞促进了能量代谢,这是通过抑制脂肪酸结合蛋白4(FABP4)和脂蛋白脂肪酶(LPL)以及激素敏感性脂肪酶(HSL)基因的表达来实现的。
此外,抗肥胖症肽可以通过抑制下丘脑的细胞中刺鼠相关蛋白(AgRP)和神经肽Y(NPY)(它们是促进食欲的肽)的表达来抑制食欲。此外,在具有糖尿病诱导的体重增加的小鼠模型中,体重增加被抑制。
因此,本发明的另一方面提供了一种治疗肥胖症的方法,该方法包括向有需要的受试者施用用于预防或治疗肥胖症的所述药物组合物。所述药物组合物及施用其的方法与上述相同。
同时,抗肥胖症肽可以增加Akt(图8)、S6(图9)和FoxO1(图10)蛋白的磷酸化,从而促进肌肉生物合成并抑制肌肉萎缩,因此它可以用于治疗肌肉减少性肥胖症和肌肉减少症。
本发明的另一个方面提供了一种用于预防或治疗肌肉减少症的药物组合物,其包括作为活性成分的肽,所述肽包括选自由SEQ ID NO:1、2、3和5组成的组中的氨基酸序列。
由于与用于预防或治疗肌肉减少症的药物组合物中的肽相关的内容和所述药物组合物与上述相同,因此将省略重复内容的描述。
本发明的又一方面提供了一种治疗肌肉减少症的方法,该方法包括向有需要的受试者施用用于预防或治疗肌肉减少症的药物组合物。所述药物组合物及施用其的方法与上述相同。
有益效果
根据本发明一个实施方案的肽具有抑制食欲、促进能量代谢、抑制脂肪积累和促进脂肪分解的优异效果,因此其可有效用于预防或治疗肥胖症和肌肉减少症。
附图说明
图1示出了根据用肽(No.1、2、3、5和8)处理脂肪细胞(3T3-L1脂肪细胞)证实UCP-1蛋白变化的结果。
图2示出了根据用肽(No.1、3、4、5和6)处理脂肪细胞(3T3-L1脂肪细胞)证实ACC蛋白的磷酸化变化的结果。
图3示出了根据用肽(No.3、5和8)处理脂肪细胞(3T3-L1脂肪细胞),证实与脂质代谢相关的基因的表达变化的结果(与对照相比,*p<0.05和***p<0.001)。
图4示出了根据用肽(No.3、5和8)处理脂肪细胞(3T3-L1脂肪细胞),定量并比较脂滴尺寸、每个细胞的总脂滴面积以及每个细胞的最大脂滴直径的变化的结果(与对照相比,*p<0.05,**p<0.01,***p<0.001和****
p<0.001)。
图5示出了根据用肽(No.1、2、4、5、6、7和8)处理N41神经细胞,证实作为食欲促进因子的AgRP和NPY的表达变化的结果(与对照相比,*p<0.05)。
图6示出了根据用肽(No.7和No.8)处理高脂肪诱导的体重增加的小鼠模型,比较体重(A)、体重增加(B)和食物摄取量(C)的变化的结果(与对照相比,*p<0.05)。
图7示出了根据用肽(No.7和No.8)处理具有糖尿病诱导的体重的小鼠模型,定量脂肪细胞中UCP-1表达水平的变化的结果(与对照相比,*p<0.05)。
图8示出了根据用肽(No.1至8)处理肌肉细胞(L6骨骼肌细胞系)的Akt磷酸化的变化。
图9示出了根据用肽(No.3、6和7)处理肌肉细胞(L6骨骼肌细胞系)的S6磷酸化的变化。
图10示出了根据用肽(No.1至8)处理肌肉细胞(L6骨骼肌细胞系)的FoxO1磷酸化的变化。
图11示出了根据用肽(No.7和No.8)处理具有糖尿病诱导的体重增加的小鼠模型的肌肉量的变化(与对照相比,*p<0.05)。
具体实施方式
在下文中,将参照实施例更详细地描述一个或多个具体实施例。然而,提供这些实施例是为了说明一个或多个具体实施例,并且本发明的范围不限于这些实施例。
肽
下表2列出了本发明中使用的抗肥胖症肽。
[表2]
肽序列 | SEQ ID NO: | |
No.1 | YFR | 1 |
No.2 | EQAEEER | 2 |
No.3 | REAGGAFGKR | 3 |
No.4 | EQAEEERYFR | 4 |
No.5 | AQSREQLAALKK | 5 |
No.6 | YFRAQSREQLAALKKHH | 6 |
No.7 | AGSIREAGGAFGKREQAEEERYFR | 7 |
No.8 | VDRGAGSIREAGGAFGKREQAEEERYFR | 8 |
实施例1:促进脂肪细胞中能量代谢和改善脂质代谢的效果的验证
本发明的抗肥胖症肽对解偶联蛋白-1(UCP-1)表达和乙酰辅酶A羧化酶α(ACCα)蛋白磷酸化的效果证实如下。UCP-1在促进能量代谢(如生热作用和褐化效应)中起关键作用,而Accα响应于UCP-1参与能量储存和消耗。
在将作为前脂肪细胞的3T3-L1细胞接种到6孔板中以分化成脂肪细胞后,将细胞在含有10%FBS、10μg/ml胰岛素、1μM地塞米松和0.5mM异丁基甲基黄嘌呤(IBMX)的培养基中培养2天以诱导第一次分化。随后,每两天用含有10%FBS和10μg/mL胰岛素的培养基更换一次该培养基,并维持4天以诱导第二次分化。第二次分化后,用100nM的每种肽处理细胞并培养36小时。从细胞中提取蛋白质,并且通过蛋白质印迹证实UCP-1表达和Accα磷酸化的变化。
结果是,证实了通过肽处理增加了UCP-1的表达(图1),并且Accα磷酸化也增加(图2),表明本发明的肽促进了能量代谢。
同时,由于脂肪细胞中能量代谢的促进导致脂肪酸氧化和脂肪分解,在肽处理(100nM,24小时)后,通过RT-PCR确认脂肪酸结合蛋白4(FABP4)、脂蛋白脂肪酶(LPL)和激素敏感性脂肪酶(HSL)相关基因的表达水平。
结果是,诱导脂质储存和抑制降解的FABP4的表达水平降低,并且诱导脂质转运到组织和细胞中的LPL的表达水平也降低。另一方面,促进中性脂肪降解的HSL的表达水平增加(图3)。通过上述结果,证实了本发明的肽改善了脂肪的脂质代谢。
为了观察实际脂肪细胞中能量代谢和脂质代谢的变化,用100nM的肽处理分化的3T3-L1脂肪细胞24小时,然后实施BODIPY染色。使用共聚焦显微镜获得荧光图像,并分析信号以确认脂滴(LD)的变化。
结果是,进一步验证了LD的尺寸、最大直径和每细胞面积都降低,表明本发明的肽改善了脂质代谢(图4)。
实施例2:神经细胞中食欲抑制效果的验证
证实了本发明的抗肥胖症肽对食欲相关因子的效果,该食欲相关因子是与体重增加直接相关的因子。
培养神经细胞(N41 mHyopE下丘脑细胞系),用100nM肽处理,并进一步培养24小时。然后,回收细胞,并且通过RT-PCR证实了刺鼠相关蛋白(AgRP)和神经肽Y(NPY)因子的表达的变化,这些因子在下丘脑中表达并且已知促进食欲。
结果是,可见通过肽处理显著降低了Agrp和NPY的表达(图5)。
实施例3:体重增加的小鼠模型的分析
3-1.肥胖小鼠模型的构建
C57BL/6N 5周龄雄性小鼠购自Orient Bio,提供正常饮食1周,并在适应期后使用。饲养环境保持在18℃至24℃和50%至60%的湿度,并且在适应期和实验期期间实施自由喂养,自由获得食物和水。在1周的适应期后,用高脂肪饮食对小鼠进行肥胖症诱导,以诱导葡萄糖耐量受损。如下表3所示,制备并提供正常饮食和高脂肪饮食。
[表3]
正常饮食(ND)和40%高脂肪饮食(HFD)的组成表
成分 | ND(g) | HFD(g) |
玉米淀粉 | 15 | 15 |
酪素 | 20 | 20 |
蔗糖 | 50 | 34 |
玉米油 | 5 | 3 |
矿物混合物 | 3.5 | 3.5 |
维生素混合物 | 1 | 1 |
纤维素 | 5 | 5 |
DL-甲硫氨酸 | 0.3 | 0.3 |
酒石酸氢胆碱 | 0.2 | 0.2 |
猪油 | 17 | |
胆固醇 | 1 | |
BHT | 0.001 | 0.001 |
合计 | 100(g) | 100(g) |
将经历适应期的小鼠分为对照组和肽处理组。对照组施用PBS,而肽处理组每天腹膜内施用No.7或No.8肽(2.5mg/kg),共持续24天。
作为实验期间食物摄入量和体重的改变的结果,与对照组相比,在肽处理组中,证实了显著的体重减轻效果(图6A)。在肽处理组中,从初始体重增加的体重也显著减少(图6B),并且作为最终比较结果,证实了食物摄入量的显著减少(图6C),验证了每种肽的抗肥胖症效果。
3-2.糖尿病小鼠模型的构建
通过在由于瘦素受体缺陷而诱发糖尿病的动物模型中诱导体重增加,证实了肽的肥胖症改善效果。具体而言,从中央实验动物公司(Central Laboratory Animal Inc.)购买C57BLKS/J-db/db 5周龄雄性小鼠,提供正常饮食1周,并在适应期后使用。饲养环境保持在18℃至24℃和50%至60%的湿度,并且在适应期和实验期期间实施自由喂养,自由获取正常饲料和水。
将经历适应期的小鼠分为对照组和肽处理组。对照组施用PBS,而肽处理组每天腹膜内施用No.7或No.8肽(2.5mg/kg),共持续8周。
为了更详细地观察肽在相应小鼠模型中的抗肥胖症效果,通过组织染色证实了分离的脂肪组织中UCP-1表达的改变。结果是,在细胞水平(图1),由于肽处理,观察到脂肪组织中UCP-1的表达显著增加,证实了在生物系统中促进能量代谢的作用(图7)。
实施例4:促进肌肉生物合成和抑制肌肉萎缩的效果的验证
证实了本发明的肽对肌肉的效果。在6孔板中培养L6骨骼肌细胞后,用0.5%FBS使细胞饥饿。然后,将100nM的每种肽处理1小时,收集蛋白质并进行蛋白质印迹。
结果是,通过观察Akt(图8)和S6(No.3、No.6和No.7,图9)蛋白(已知其作为肌肉生物合成的主要指标激活细胞信号传导途径)的磷酸化被所述肽增加,能够证实促进肌肉生物合成的效果;并且通过观察FoxO1(已知其抑制肌肉萎缩)的磷酸化进一步证实了本发明对肌肉减少症的效果(图10)。本文中,S6蛋白的磷酸化被No.1肽增加了188%,被No.2肽增加了365%,被No.4肽增加了224%,被No.5肽增加了494%,被No.8肽增加了414%。此外,No.1肽增加了FoxO1的磷酸化,并降低了总FoxO1的表达水平。
此外,作为检查实施例3-2中获得的小鼠模型的肌肉组织的结果,发现肌肉量增加(图11)。RT-PCR结果证实了,通过No.7或No.8肽的处理,参与脂质积聚的脂肪细胞蛋白2(AP2)和CCAAT增强子结合蛋白α(C/EBPα)基因的表达减少,并且参与脂肪酸氧化的过氧化物酶体增殖物激活的受体α(PPARα)基因的表达增加。此外,通过确认导致肌肉损失和肌肉萎缩的肌肉环状指-1(Muscle RING Finger-1,Murf-1)基因的减少,进一步验证了改善肌肉损失的效果(表4)。
[表4]
项目/材料 | No.7 | No.8 |
AP2 | -52.5% | -54.7% |
PPARα | +94.1% | +12.9% |
C/EBPα | -18.6% | -45.5% |
Murf-1 | -90.1% | -36.0% |
通过迄今为止的结果,证实了本发明的肽具有抗肥胖症效果和改善肌肉损失的效果。
<110> 高丽大学校产学协力团
<120> 具有肥胖症和肌肉损失抑制活性的肽及其用途
<130> X22U13C0133
<150> KR 10-2021-0084288
<151> 2021-06-28
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Claims (11)
1.一种用于预防或治疗肥胖症的药物组合物,包含作为活性成分的肽,所述肽包括选自由SEQ ID NO:1、2、3和5组成的组中的氨基酸序列。
2.根据权利要求1所述的药物组合物,其中,包括由SEQ ID NO:1表示的氨基酸序列的所述肽是由SEQ ID NO:1、4、6、7或8表示的氨基酸序列组成的肽。
3.根据权利要求1所述的药物组合物,其中,所述肽抑制食欲。
4.根据权利要求3所述的药物组合物,其中,食欲抑制是通过抑制刺鼠相关蛋白(AgRP)或神经肽Y(NPY)的表达而引起的。
5.根据权利要求1所述的药物组合物,其中,所述肽增加解偶联蛋白-1(UCP-1)的表达,所述解偶联蛋白-1(UCP-1)激活脂肪组织中的生热作用和能量稳态。
6.根据权利要求1所述的药物组合物,其中,所述肽抑制脂肪细胞中的脂肪积累或促进脂肪降解。
7.根据权利要求1所述的药物组合物,其中,所述肽促进肌肉生物合成或抑制肌肉萎缩。
8.一种治疗肥胖症的方法,包括:
向有需要的受试者施用根据权利要求1所述的用于预防或治疗肥胖症的药物组合物。
9.一种用于预防或治疗肌肉减少症的药物组合物,包含:
作为活性成分的肽,其包括选自由SEQ ID NO:1、2、3和5组成的组中的氨基酸序列。
10.根据权利要求9所述的药物组合物,其中,包括由SEQ ID NO:1表示的氨基酸序列的所述肽是由SEQ ID NO:1、4、6、7或8表示的氨基酸序列组成的肽。
11.一种治疗肌肉减少症的方法,包括:
向有需要的受试者施用根据权利要求9所述的用于预防或治疗肌肉减少症的药物组合物。
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