侧脑室注射共轭亚油酸（CLA）的外周效应研究
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摘要
共轭亚油酸(conjugated linoleic acids, CLA)是一组天然存在的具有18个碳原子,含有共轭双键的多不饱和脂肪酸,是必需脂肪酸-亚油酸(linoleic acid, LA)的异构体。近年来研究发现:CLA有减轻肥胖、抗肿瘤、防止动脉粥样硬化、提高机体免疫力、增加骨密度、促进生长等多种生理功能,其中减轻肥胖的作用最受到研究者的重视。已有的研究显示,CLA减轻肥胖的作用是通过多途径、多因素发挥作用的,中枢神经系统(CNS)也是可能的途径之一。中枢神经肽、神经递质和激素在体重调节中起着非常重要的角色。有关营养物质的储存、饱腹感、对食物的口感等等都通过内分泌激素、营养代谢的信号或是联络大脑与外周的神经通路与脑发生关系。本实验通过给SD大鼠侧脑室注射CLA,与非共轭的亚油酸(LA)进行比较,观察大鼠体重、食欲、血脂、leptin及脑组织NPY、AgRP、POMCmRNA、肝脏组织CPT-1mRNA的表达,以证明CLA能够通过中枢神经系统调节全身的营养代谢,为人们用CLA的食物预防和治疗肥胖提供理论基础。
实验方法
雄性成年SD大鼠,单笼饲养,正常饮食。实验分组:NS对照组:脑室内注射生理盐水(N.S.),0.5μl/只;LA对照组:脑室内注射亚油酸(LA),0.5μl/只(150nmol);CLA对照组:脑室内注射共轭亚油酸(CLA),0.5μl/只(150nmol)。将大鼠麻醉后,固定于脑立体定向仪。坐标参考Bregma图谱:前囟后0.92mm,矢状缝旁开1.4mm,脑表面下3.3mm。牙科钻钻开颅骨,暴露硬脑膜。微量注射器侧脑室注射CLA0.5μl(150nmol)。分别于注射后2、4、8、12、24小时减尾采血,取动物血清,用试剂盒法测定血清中血脂水平,放射免疫法测Leptin浓度;分别于2、4、8、14天处死动物,取脏器组织,称重,用RT-PCR法测脑组织中NPY、AgRP、POMCmRNA表达和肝脏组织中CPT-1mRNA表达。
实验结果
1、侧脑室注射CLA对大鼠体重、食欲的影响:(1)大鼠体重的变化:侧脑室注射后,CLA组动物体重持续降低,与NS对照组(第4天后)和LA对照组(第14天)相比有显著性差异(p<0.05)。(2)CLA对摄食量的影响:与注射生理盐水相比,注射LA和CLA都能够引起大鼠食欲的下降,但是与LA组相比(6天),CLA作用的时间更为持久(>8天)。(3)脑组织食欲肽mRNA表达的改变:侧脑室注射后第2,4,8天,CLA注射组大鼠下丘脑NPYmRNA表达水平低于LA对照组和NS对照组(p<0.05),与NS对照组相比下降了大约60%; CLA注射组大鼠下丘脑AgRP mRNA表达水平低于LA对照组和NS对照组(p<0.05),与NS对照组相比下降了大约75%;CLA注射组和LA对照组大鼠下丘脑POMC mRNA表达水平基本正常。
2、侧脑室注射CLA对大鼠脂肪代谢的影响:(1)对脂肪分布的影响:与LA组和NS组相比,注射CLA组的皮下脂肪、睾周脂肪和脂体比均有显著的改变(p<0.05);(2)大鼠血脂的改变:注射CLA后2小时血清甘油三酯有显著的增高(p<0.05);注射CLA2小时左右血清总胆固醇有显著的降低(p<0.05);注射CLA4小时左右血清高密度脂蛋白有显著的增高(p<0.05);侧脑室注射CLA2小时后血清瘦素开始升高,一直持续到12小时(p<0.05)。(3)对肝脏脂质沉积的影响:注射CLA后肝脏内甘油三酯含量减少;肝脏CPT-1mRNA表达增高,与注射前相比有显著差异(p<0.05)。
实验结论
1.侧脑室注射CLA后大鼠体重减轻,食欲下降;
2.CLA抑制食欲的效应是通过影响NPY和AgRPmRNA表达发挥作用的;
3.侧脑室注射CLA能够影响短期(48h)内血脂水平,能够减少肝脏组织的脂质沉积;
4.CLA影响脂质沉积的机制可能与增强CPT-1的表达有关。
5.中枢神经系统对机体食物摄取和能量代谢的影响非常复杂,脂肪酸在其中扮演了重要角色。共轭亚油酸对中枢神经系统的影响有可能是通过多个环节实现的,需要进一步的深入研究。
Conjugated linoleic acid (CLA) refers to a group of polyunsaturated fatty acids that exist as positional and geometric isomers of linoleic acid (LA; 18:2). CLA possess many physiologic properties including reduce obesity and antiatherosclerosis, anticarcinogenesis, improve immune function, antidiabetogenesis and growth. Researchs have shown: CLA can reduce obesity through multi-ways and multi-factors. Research on the function of has suggested an important role in appetite regulation and energy metabolism. It is clear that the changes of food intake occur by hypothalamic neuropeptides. By Intracerebroventricular administration of CLA compared with non-conjugated LA, we observed the change of weight, appetite, blood lipid, leptin, NPY、AgRP、POMC mRNA expression in brain and CPT-1 mRNA expression in liver. Our experiment was conducted to extend these observations to hypothalamus and other regions within the central nervous system so that the mechanism of the actions of CLA might be more easily elucidated. Accordingly, and it is also beneficial for us to prevent and cure adiposity by using foods rich in CLA or CLA supplement. Methods
For the experiment, normal Sprague-Dawley rats were divided into three groups (CLA, LA, NS group) and received ICV injections of either 150 nmol CLA, or LA as non-conjugated control, or normal saline. After the rats were anesthetized, a stainless steel ICV cannula was implanted 0.95 mm anterior to the lambdoidal suture, 1.4 mm lateral to the midline, and 3.3 mm from the skull surface. We collected the blood sample at 2, 4, 8, 12, 24 hours and triglycerides, total cholesterol, HDL cholesterol concentrations in the plasma were measured using kits. The rats were dissected in 48 hours and adipose tissues (subcutaneous, mesenteric, retroperitoneal, epididymal) were removed, blotted dry, and immediately weighed. To study the effects of exogenous CLA administration for 14 days on the expression of hypothalamic neuropeptides, we quantified the expression of NPY, AgRP and POMC mRNA by reverse transcriptase–polymerase chain reaction (RT-PCR).
Results
1. The effect of intracerebroventricular administration of CLA on weight and appetite. (1) The change of animal weight. After ICV administration, body weight was markedly reduced in CLA rats after 2 weeks of treatment. (2) The change of feeding behavior. ICV conjugated linoleic acid resulted in a 6-8 days marked inhibition on food intake, respectively. As control, the inhibition effect of linoleic acid is for 2-4 days. The administration of Normal Saline did not cause any change. (3) ICV CLA suppressed NPY mRNA expression by ~60% compared with before treatment, suppressed AgRP expression by ~75% as compared with before treatment and hypothalamic POMC expression was not altered following ICV CLA treatment.
2. The effect of intracerebroventricular administration of CLA on lipid metabolism. (1) The change of fat distribution. The fat/body weight, subcutaneous and retro-peritoneal adipose tissue decreased in 48 hours. (2) The change of blood lipid. The plasma triglycerides increased and total cholesterol decreased at 2 hour and HDL concentration increased at 4 hour. (3) The lack of adipose stores was mirrored in the reduced liver triacylglycerol content of CLA-treated rats (no significant difference with control). The CPT-1 mRNA expression increased.
Conclusions
1. The body weight and food intake is decreased by ICV CLA;
2. The inhibition of appetite by CLA is conducted by decreasing gene expression of NPY and AgRP;
3. CLA can affect lipid metabolism through central nervous system (CNS), which may be related with the beneficial effect on weight-loss;
4. The effect on lipid metabolism is related with increased CPT-1 expression;
5. The effect of CNS on food intake and energy metabolism is very complicated and fatty acid makes an important role. CLA can affect CNS by multi-ways which need further investigation.
实验方法
雄性成年SD大鼠,单笼饲养,正常饮食。实验分组:NS对照组:脑室内注射生理盐水(N.S.),0.5μl/只;LA对照组:脑室内注射亚油酸(LA),0.5μl/只(150nmol);CLA对照组:脑室内注射共轭亚油酸(CLA),0.5μl/只(150nmol)。将大鼠麻醉后,固定于脑立体定向仪。坐标参考Bregma图谱:前囟后0.92mm,矢状缝旁开1.4mm,脑表面下3.3mm。牙科钻钻开颅骨,暴露硬脑膜。微量注射器侧脑室注射CLA0.5μl(150nmol)。分别于注射后2、4、8、12、24小时减尾采血,取动物血清,用试剂盒法测定血清中血脂水平,放射免疫法测Leptin浓度;分别于2、4、8、14天处死动物,取脏器组织,称重,用RT-PCR法测脑组织中NPY、AgRP、POMCmRNA表达和肝脏组织中CPT-1mRNA表达。
实验结果
1、侧脑室注射CLA对大鼠体重、食欲的影响:(1)大鼠体重的变化:侧脑室注射后,CLA组动物体重持续降低,与NS对照组(第4天后)和LA对照组(第14天)相比有显著性差异(p<0.05)。(2)CLA对摄食量的影响:与注射生理盐水相比,注射LA和CLA都能够引起大鼠食欲的下降,但是与LA组相比(6天),CLA作用的时间更为持久(>8天)。(3)脑组织食欲肽mRNA表达的改变:侧脑室注射后第2,4,8天,CLA注射组大鼠下丘脑NPYmRNA表达水平低于LA对照组和NS对照组(p<0.05),与NS对照组相比下降了大约60%; CLA注射组大鼠下丘脑AgRP mRNA表达水平低于LA对照组和NS对照组(p<0.05),与NS对照组相比下降了大约75%;CLA注射组和LA对照组大鼠下丘脑POMC mRNA表达水平基本正常。
2、侧脑室注射CLA对大鼠脂肪代谢的影响:(1)对脂肪分布的影响:与LA组和NS组相比,注射CLA组的皮下脂肪、睾周脂肪和脂体比均有显著的改变(p<0.05);(2)大鼠血脂的改变:注射CLA后2小时血清甘油三酯有显著的增高(p<0.05);注射CLA2小时左右血清总胆固醇有显著的降低(p<0.05);注射CLA4小时左右血清高密度脂蛋白有显著的增高(p<0.05);侧脑室注射CLA2小时后血清瘦素开始升高,一直持续到12小时(p<0.05)。(3)对肝脏脂质沉积的影响:注射CLA后肝脏内甘油三酯含量减少;肝脏CPT-1mRNA表达增高,与注射前相比有显著差异(p<0.05)。
实验结论
1.侧脑室注射CLA后大鼠体重减轻,食欲下降;
2.CLA抑制食欲的效应是通过影响NPY和AgRPmRNA表达发挥作用的;
3.侧脑室注射CLA能够影响短期(48h)内血脂水平,能够减少肝脏组织的脂质沉积;
4.CLA影响脂质沉积的机制可能与增强CPT-1的表达有关。
5.中枢神经系统对机体食物摄取和能量代谢的影响非常复杂,脂肪酸在其中扮演了重要角色。共轭亚油酸对中枢神经系统的影响有可能是通过多个环节实现的,需要进一步的深入研究。
Conjugated linoleic acid (CLA) refers to a group of polyunsaturated fatty acids that exist as positional and geometric isomers of linoleic acid (LA; 18:2). CLA possess many physiologic properties including reduce obesity and antiatherosclerosis, anticarcinogenesis, improve immune function, antidiabetogenesis and growth. Researchs have shown: CLA can reduce obesity through multi-ways and multi-factors. Research on the function of has suggested an important role in appetite regulation and energy metabolism. It is clear that the changes of food intake occur by hypothalamic neuropeptides. By Intracerebroventricular administration of CLA compared with non-conjugated LA, we observed the change of weight, appetite, blood lipid, leptin, NPY、AgRP、POMC mRNA expression in brain and CPT-1 mRNA expression in liver. Our experiment was conducted to extend these observations to hypothalamus and other regions within the central nervous system so that the mechanism of the actions of CLA might be more easily elucidated. Accordingly, and it is also beneficial for us to prevent and cure adiposity by using foods rich in CLA or CLA supplement. Methods
For the experiment, normal Sprague-Dawley rats were divided into three groups (CLA, LA, NS group) and received ICV injections of either 150 nmol CLA, or LA as non-conjugated control, or normal saline. After the rats were anesthetized, a stainless steel ICV cannula was implanted 0.95 mm anterior to the lambdoidal suture, 1.4 mm lateral to the midline, and 3.3 mm from the skull surface. We collected the blood sample at 2, 4, 8, 12, 24 hours and triglycerides, total cholesterol, HDL cholesterol concentrations in the plasma were measured using kits. The rats were dissected in 48 hours and adipose tissues (subcutaneous, mesenteric, retroperitoneal, epididymal) were removed, blotted dry, and immediately weighed. To study the effects of exogenous CLA administration for 14 days on the expression of hypothalamic neuropeptides, we quantified the expression of NPY, AgRP and POMC mRNA by reverse transcriptase–polymerase chain reaction (RT-PCR).
Results
1. The effect of intracerebroventricular administration of CLA on weight and appetite. (1) The change of animal weight. After ICV administration, body weight was markedly reduced in CLA rats after 2 weeks of treatment. (2) The change of feeding behavior. ICV conjugated linoleic acid resulted in a 6-8 days marked inhibition on food intake, respectively. As control, the inhibition effect of linoleic acid is for 2-4 days. The administration of Normal Saline did not cause any change. (3) ICV CLA suppressed NPY mRNA expression by ~60% compared with before treatment, suppressed AgRP expression by ~75% as compared with before treatment and hypothalamic POMC expression was not altered following ICV CLA treatment.
2. The effect of intracerebroventricular administration of CLA on lipid metabolism. (1) The change of fat distribution. The fat/body weight, subcutaneous and retro-peritoneal adipose tissue decreased in 48 hours. (2) The change of blood lipid. The plasma triglycerides increased and total cholesterol decreased at 2 hour and HDL concentration increased at 4 hour. (3) The lack of adipose stores was mirrored in the reduced liver triacylglycerol content of CLA-treated rats (no significant difference with control). The CPT-1 mRNA expression increased.
Conclusions
1. The body weight and food intake is decreased by ICV CLA;
2. The inhibition of appetite by CLA is conducted by decreasing gene expression of NPY and AgRP;
3. CLA can affect lipid metabolism through central nervous system (CNS), which may be related with the beneficial effect on weight-loss;
4. The effect on lipid metabolism is related with increased CPT-1 expression;
5. The effect of CNS on food intake and energy metabolism is very complicated and fatty acid makes an important role. CLA can affect CNS by multi-ways which need further investigation.
引文
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