不同能量供需下棕色田鼠下丘脑NPY、PAM和消化道NOS的适应性变化
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摘要
动物个体内存在着复杂的生理调节系统,有效地平衡着能量摄入和消耗,有机体的体重和体脂才能保持在一个相对稳定的水平。
机体的能量平衡与中枢以及外周的调节都有关。而下丘脑是机体的摄食及食欲调节的重要中枢,其内存在着复杂的“食欲调节网络(appetite regulation network,ARN)”,网络内产生的众多食欲调节因子(包括多种食欲促进因子和抑制因子)对食欲起着极其重要的信息传递作用。多种神经递质和激素能影响摄食行为,这些递质和激素间又有相互作用,构成复杂的神经体液调节网络。神经肽Y(Neuropeptide Y,NPY)作为该食欲网络中的一种很强的促食欲因子,在机体的摄食活动中发挥着重要的调节作用。NPY主要分布在下丘脑弓状核(arcuatenucleus,ARC),并有神经纤维投射到室旁核(paraventricular nucleus,PVN)、腹内侧核(ventromedial,VMH)及下丘脑背正中核(dorsomedial,DMH)形成复杂的NPY网络;其中ARC-PVN神经元轴在摄食调控中发挥重要的作用;研究表明与摄食相关的NPY主要在弓状核处合成,经过轴突运输到室旁核,由室旁核分泌而参与摄食的调控。研究发现动物在饥饿、运动量增加、寒冷及妊娠、哺乳等能量负平衡及能量需求增加时,NPY以及NPYmMRA的合成均增加。中枢注射NPY可显著增加摄食量,且动物采食量的增加与NPY剂量在一定范围内呈线性关系,注射NPY反义核苷酸或拮抗剂能够抑制食欲。肽基甘氨酸α酰胺化酶(Peptidylglycineα-amidating monooxygenase,PAM)是20年前发现的产生具有生物活性的神经肽的基本限速酶,可以使NPY等神经肽羧基末端的甘氨酸残基酰胺化而具备生理活性。PAM基因半敲除的鼠癫痫敏感和焦虑行为增加,PAM可能通过酰胺化NPY起到抗焦虑和癫痫的作用。但关于PAM在食欲和摄食调节方面的研究未见报道。
动物消化道形态结构的变化是动物消化道重要的适应策略。一般认为,食性是导致种间消化道形态差异的主要原因;动物消化道形态结构的种内差异与食物质量及能量需求密切相关。而消化道活动的调节是十分复杂的生理学问题,消化道神经分布丰富,既受自主神经支配,又有内在神经丛分布;同时,消化道又是全身最大的内分泌器官,有多种内分泌细胞,分泌多种神经肽和激素。一氧化氮(Nitricoxide,NO)是胃肠道非肾上腺能非胆碱能(NANC)神经的抑制性递质之一,它在消化道肌间神经丛广泛存在。NO作用较多,除了可以引起胃肠道的平滑肌松弛外,还可调节黏膜血管基础张力,增加黏膜血流量,从而引起黏膜厚度增加,同时还直接调节胃粘液分泌。
为研究在不同能量需求与能量供应状态下,棕色田鼠消化吸收功能的中枢适应性调节机制,并探讨中枢与外周的关系,实验采用免疫组织化学法,NADPH—黄递酶(NDP)组织化学法和整装铺片技术,对哺乳、禁食、非哺乳棕色田鼠下丘脑神经肽Y及其限速酶肽基甘氦酸α酰胺化酶PAM的阳性表达以及胃肠道管壁肌间神经丛一氧化氮合酶(NOS)阳性神经元的分布进行观察,并通过侧脑室注射NPY,观察胃肠道NOS阳性神经元的分布。
结果显示:
1.NPY,PAM免疫反应阳性颗粒主要分布在下丘脑弓状核(arcuate nucleus,ARC),室旁核(paraventricular nucleus,PVN),腹正中核(ventromedial,VMH),背正中核(dorsomedial,DMH)等区域;
2.哺乳雌鼠和禁食雌鼠在下丘脑的NPY阳性颗粒较非哺乳雌鼠均显著上升,且禁食雌鼠和注射NPY雌鼠ARC,PVN的PAM阳性颗粒较非哺乳期雌鼠和哺乳期雌鼠显著增加;禁食雌鼠在VMH的PAM阳性颗粒也显著高于非哺乳期雌鼠。
3.哺乳雌鼠、禁食雌鼠和注射NPY雌鼠的胃及十二指肠肌间神经丛NOS阳性神经元的分布显著高于非哺乳雌鼠和注射生理盐水组雌鼠。
4.哺乳雌鼠和脑室注射NPY雌鼠空肠肌间神经丛NOS阳性神经节及神经元总数均显著高于非哺乳雌鼠和注射生理盐水组雌鼠。
5.哺乳期雌鼠盲肠肌间神经丛单个神经节内NOS阳性神经元数显著高于非哺乳雌鼠:而注射NPY组雌鼠盲肠NOS性神经节数以及NOS阳性神经元总数显著高于生理盐水。
6.禁食雌鼠回肠的NOS阳性神经节数显著高于非哺乳期雌鼠
7.脑室注射NPY,动物摄食量显著提高。
以上结果说明:在能量需求与供应相矛盾的不同生理状态下,中枢与外周均参与了消化的适应性调节,且面对不同程度的能量胁迫,适应性调节的机制有所差别。下丘脑NPY是一个重要的食欲调节肽,对机体的能量平衡起着重要的作用,在能量需求增加或能量供应不足时,激活了下丘脑内的NPY能神经元,从而使得NPY高表达,既能直接通过增加摄食量,提高消化能,来满足自身的营养与能量需求,又可通过调节消化道NOS神经元的分布格局来发挥消化功能的调节作用。然而,禁食加剧了动物能量摄入与支出间的矛盾,禁食期雌鼠不仅通过激活下丘脑内的NPY能神经元,使得NPY高表达,还通过PAM表达的增加,加强对NPY的修饰作用,提高NPY的活性,调节摄食活动,减少能量支出,维持能量平衡。
There is a complex physiological regulating system in organism which can balance energy intake and comsume,so that body weight and fat content maintain in a relatively stable level.
It has been demonstrated that both central never system(CNS) and peripheral nervous system (PNS) participate in energy balance.Hypothalamus which is a relatively advanced central nervous system plays an important role in the regulation of food intake and energy balance.Recent research has identified the existence of an appetite regulation network(ARN) network in the hypothalamus involved in the regulation of daily food intake,which can produce many orexigenic and anorexigenic peptides.Neuropeptide Y(NPY) is a primary orexigenic signal within this network, which appears to be an important peptide for the action of in the regulation of food intake.NPY is mainly distributed in the arcuate nucleus(ARC),paraventricular nucleus(PVN),ventromedial nucles (VMH),dorsomedial nucleus(DMH) of the hypothalamus and lateral hypothalamus(LH); therefore,it is believed that there is a complicated NPY-Network in hypothalamus,and ARC-PVN axis plays important role in energy balance.In the hypothalamus,NPY is synthesized primarily in the ARC and from there it is transported to terminals via axonal transportation from which it is released primarily in the PVN.Higher NPY and NPY mMRA density were observed in states of food deprivation or increased energy demands such as starvation,diabetes,,cold enviroment,obesity, intense exercise,pregnancy and lactation.Central administration of NPY causes remarkable increase of food consumption and there was good linearity relationship between increased food intake and NPY dosage in certain extent;while inhibition of appetite by continuous intraventricular infusion of NPY antisense oligodeoxynucleotides or antagonist of NPY suppresses food intake.
PAM was discovered more than 20 years ago in the seminal studies of Eipper and is a post-translational processing enzyme which catalyzes the hydroxylation of the C-terminal glycine in a large number of inactive neuropeptides and is responsible for the posttranslational modification of many important neuropeptides.PAM is a rate limiting step in the biosynthesis of NPY and many other neuropeptides,which is the only enzyme that catalyzes peptide amidation modification.Repeated electroconvulsive shock increased amounts of NPY and PAM in mossy fibers, and dentate granule cell dendrites contained increased amounts of NPY,PAM.However effects of PAM on feeding behavior has not been evaluated.Repeated electroconvulsive shock increased amounts of NPY and PAM in mossy fibers,and dentate granule cell dendrites contained increased amounts of NPY,PAM,However effects of PAM on feeding behavior has not been evaluated,
The morphological and structural changes of digestive tract is an important adaptive strategy. Research shows that feeding habit is the main cause of different morphological and structural of digestive tract within interspecies and the differences mainly display in length of digestive tract;while intraspecific difference closely relates with food quality and energy demands. Gastroenteric activity is dominated both by autonomic nerve and extrinsic nerve plexus,therefore regulation of gastroenteric activity is a very complex process,nitric oxide(NO) is one of nonadrenergic noncholinergic(NANC) neurotransmitters which exhibit a wide range of biologic functions including inhibiting contraction of smooth muscles,affecting basal tension of mucosal blood vessels,increasing volume of mucosal blood flow and mucosal thickness,and regulating secretion of gastric mucus.
To investigate CNS's adaptation mechanism in digestion and absorption under different energy demands and supplies,and discuss regulating relationship between central never system(CNS) and peripheral nervous system(PNS),We used the mandarin vole Microtus mandarinus as the animal model.In our study,immunohistochemisty and NADPH-NDP histochemistry were employed to test the expression of hypothalamic neuropeptide Y(NPY),its rate-limiting enzyme -Peptidylglycineα-amidating monooxygenase(PAM) in hypothalamus and the distribution of nitric oxide synthase (NOS) in gastrointestinal myenteric plexus among non-Lactating female,lactating female and fasting female.Furthermore,the effects of intra- cerebroventricular(icv 8ug/ul) microinjection of NPY on the distribution of NOS in gastrointestinal myenteric plexus were also observed.Results were as follows
1.positive immunohistochemical spots of NPY and PAM were mainly distributed in regions of arcuate nucleus(ARC),paraventricular nucleus(PVN),ventromedial nucles(VMH),dorsomedial nucleus(DMH) of hypothalamus;
2.hypothalamic positive NPY spots in lactating females and fasting females ascended significantly compared with non-lactating females,and positive PAM spots in ARC and PVN of fasting females significantly elevated compared with non-lactating females and lactating females,so did NPY microinjected females compared with saline microinjected females;
3.higher levels of NOS positive ganglions and neurons were observed in gastric and duodenum in myenteric plexus of lactating females and fasting females in comparison with non-lactating females,and NPY microinjected females presented the same changes compared with saline microinjected females;
4.Both NOS positive ganglions,neurons in jejunum of lactating females compared with non-lactating females and microinjected NPY females compared with microinjected saline females were higher;
5.Number of NOS positive neurons in every NOS positive ganglions in Cecum of lactating females were more that of non-lactating females;while NOS positive ganglions and positive neurons of NPY-injected females were more compared with saline-injected females.
6.Higher level of NOS positive ganglions were observed in myenteric plexus of Ileum of lactating females in comparison with non-lactating females.
7.Food consumption were prominently increased by icy injection of NPY.
We conclude that:both CNS and PNS take part in gastrointestinal adaptive regulation to settle higher energy demands and supply-demand contradiction in energy,and the adaptation mechanism are varied under different energy threatening.Our results also suggest that NPY in hypothalamus is an important regulating peptide,functioning not only directly via enhancing food intake and digestive efficiency to meet the requirements of nutrition and energy,but also via regulating distribution of NOS neurons in digestive tract to modulate digestion.However,the contradiction of energy intake and expenditure is escalated by fasting,both expression of NPY and PAM were increased suggest that biological activity is also a important strategy under severe energy threatening.
机体的能量平衡与中枢以及外周的调节都有关。而下丘脑是机体的摄食及食欲调节的重要中枢,其内存在着复杂的“食欲调节网络(appetite regulation network,ARN)”,网络内产生的众多食欲调节因子(包括多种食欲促进因子和抑制因子)对食欲起着极其重要的信息传递作用。多种神经递质和激素能影响摄食行为,这些递质和激素间又有相互作用,构成复杂的神经体液调节网络。神经肽Y(Neuropeptide Y,NPY)作为该食欲网络中的一种很强的促食欲因子,在机体的摄食活动中发挥着重要的调节作用。NPY主要分布在下丘脑弓状核(arcuatenucleus,ARC),并有神经纤维投射到室旁核(paraventricular nucleus,PVN)、腹内侧核(ventromedial,VMH)及下丘脑背正中核(dorsomedial,DMH)形成复杂的NPY网络;其中ARC-PVN神经元轴在摄食调控中发挥重要的作用;研究表明与摄食相关的NPY主要在弓状核处合成,经过轴突运输到室旁核,由室旁核分泌而参与摄食的调控。研究发现动物在饥饿、运动量增加、寒冷及妊娠、哺乳等能量负平衡及能量需求增加时,NPY以及NPYmMRA的合成均增加。中枢注射NPY可显著增加摄食量,且动物采食量的增加与NPY剂量在一定范围内呈线性关系,注射NPY反义核苷酸或拮抗剂能够抑制食欲。肽基甘氨酸α酰胺化酶(Peptidylglycineα-amidating monooxygenase,PAM)是20年前发现的产生具有生物活性的神经肽的基本限速酶,可以使NPY等神经肽羧基末端的甘氨酸残基酰胺化而具备生理活性。PAM基因半敲除的鼠癫痫敏感和焦虑行为增加,PAM可能通过酰胺化NPY起到抗焦虑和癫痫的作用。但关于PAM在食欲和摄食调节方面的研究未见报道。
动物消化道形态结构的变化是动物消化道重要的适应策略。一般认为,食性是导致种间消化道形态差异的主要原因;动物消化道形态结构的种内差异与食物质量及能量需求密切相关。而消化道活动的调节是十分复杂的生理学问题,消化道神经分布丰富,既受自主神经支配,又有内在神经丛分布;同时,消化道又是全身最大的内分泌器官,有多种内分泌细胞,分泌多种神经肽和激素。一氧化氮(Nitricoxide,NO)是胃肠道非肾上腺能非胆碱能(NANC)神经的抑制性递质之一,它在消化道肌间神经丛广泛存在。NO作用较多,除了可以引起胃肠道的平滑肌松弛外,还可调节黏膜血管基础张力,增加黏膜血流量,从而引起黏膜厚度增加,同时还直接调节胃粘液分泌。
为研究在不同能量需求与能量供应状态下,棕色田鼠消化吸收功能的中枢适应性调节机制,并探讨中枢与外周的关系,实验采用免疫组织化学法,NADPH—黄递酶(NDP)组织化学法和整装铺片技术,对哺乳、禁食、非哺乳棕色田鼠下丘脑神经肽Y及其限速酶肽基甘氦酸α酰胺化酶PAM的阳性表达以及胃肠道管壁肌间神经丛一氧化氮合酶(NOS)阳性神经元的分布进行观察,并通过侧脑室注射NPY,观察胃肠道NOS阳性神经元的分布。
结果显示:
1.NPY,PAM免疫反应阳性颗粒主要分布在下丘脑弓状核(arcuate nucleus,ARC),室旁核(paraventricular nucleus,PVN),腹正中核(ventromedial,VMH),背正中核(dorsomedial,DMH)等区域;
2.哺乳雌鼠和禁食雌鼠在下丘脑的NPY阳性颗粒较非哺乳雌鼠均显著上升,且禁食雌鼠和注射NPY雌鼠ARC,PVN的PAM阳性颗粒较非哺乳期雌鼠和哺乳期雌鼠显著增加;禁食雌鼠在VMH的PAM阳性颗粒也显著高于非哺乳期雌鼠。
3.哺乳雌鼠、禁食雌鼠和注射NPY雌鼠的胃及十二指肠肌间神经丛NOS阳性神经元的分布显著高于非哺乳雌鼠和注射生理盐水组雌鼠。
4.哺乳雌鼠和脑室注射NPY雌鼠空肠肌间神经丛NOS阳性神经节及神经元总数均显著高于非哺乳雌鼠和注射生理盐水组雌鼠。
5.哺乳期雌鼠盲肠肌间神经丛单个神经节内NOS阳性神经元数显著高于非哺乳雌鼠:而注射NPY组雌鼠盲肠NOS性神经节数以及NOS阳性神经元总数显著高于生理盐水。
6.禁食雌鼠回肠的NOS阳性神经节数显著高于非哺乳期雌鼠
7.脑室注射NPY,动物摄食量显著提高。
以上结果说明:在能量需求与供应相矛盾的不同生理状态下,中枢与外周均参与了消化的适应性调节,且面对不同程度的能量胁迫,适应性调节的机制有所差别。下丘脑NPY是一个重要的食欲调节肽,对机体的能量平衡起着重要的作用,在能量需求增加或能量供应不足时,激活了下丘脑内的NPY能神经元,从而使得NPY高表达,既能直接通过增加摄食量,提高消化能,来满足自身的营养与能量需求,又可通过调节消化道NOS神经元的分布格局来发挥消化功能的调节作用。然而,禁食加剧了动物能量摄入与支出间的矛盾,禁食期雌鼠不仅通过激活下丘脑内的NPY能神经元,使得NPY高表达,还通过PAM表达的增加,加强对NPY的修饰作用,提高NPY的活性,调节摄食活动,减少能量支出,维持能量平衡。
There is a complex physiological regulating system in organism which can balance energy intake and comsume,so that body weight and fat content maintain in a relatively stable level.
It has been demonstrated that both central never system(CNS) and peripheral nervous system (PNS) participate in energy balance.Hypothalamus which is a relatively advanced central nervous system plays an important role in the regulation of food intake and energy balance.Recent research has identified the existence of an appetite regulation network(ARN) network in the hypothalamus involved in the regulation of daily food intake,which can produce many orexigenic and anorexigenic peptides.Neuropeptide Y(NPY) is a primary orexigenic signal within this network, which appears to be an important peptide for the action of in the regulation of food intake.NPY is mainly distributed in the arcuate nucleus(ARC),paraventricular nucleus(PVN),ventromedial nucles (VMH),dorsomedial nucleus(DMH) of the hypothalamus and lateral hypothalamus(LH); therefore,it is believed that there is a complicated NPY-Network in hypothalamus,and ARC-PVN axis plays important role in energy balance.In the hypothalamus,NPY is synthesized primarily in the ARC and from there it is transported to terminals via axonal transportation from which it is released primarily in the PVN.Higher NPY and NPY mMRA density were observed in states of food deprivation or increased energy demands such as starvation,diabetes,,cold enviroment,obesity, intense exercise,pregnancy and lactation.Central administration of NPY causes remarkable increase of food consumption and there was good linearity relationship between increased food intake and NPY dosage in certain extent;while inhibition of appetite by continuous intraventricular infusion of NPY antisense oligodeoxynucleotides or antagonist of NPY suppresses food intake.
PAM was discovered more than 20 years ago in the seminal studies of Eipper and is a post-translational processing enzyme which catalyzes the hydroxylation of the C-terminal glycine in a large number of inactive neuropeptides and is responsible for the posttranslational modification of many important neuropeptides.PAM is a rate limiting step in the biosynthesis of NPY and many other neuropeptides,which is the only enzyme that catalyzes peptide amidation modification.Repeated electroconvulsive shock increased amounts of NPY and PAM in mossy fibers, and dentate granule cell dendrites contained increased amounts of NPY,PAM.However effects of PAM on feeding behavior has not been evaluated.Repeated electroconvulsive shock increased amounts of NPY and PAM in mossy fibers,and dentate granule cell dendrites contained increased amounts of NPY,PAM,However effects of PAM on feeding behavior has not been evaluated,
The morphological and structural changes of digestive tract is an important adaptive strategy. Research shows that feeding habit is the main cause of different morphological and structural of digestive tract within interspecies and the differences mainly display in length of digestive tract;while intraspecific difference closely relates with food quality and energy demands. Gastroenteric activity is dominated both by autonomic nerve and extrinsic nerve plexus,therefore regulation of gastroenteric activity is a very complex process,nitric oxide(NO) is one of nonadrenergic noncholinergic(NANC) neurotransmitters which exhibit a wide range of biologic functions including inhibiting contraction of smooth muscles,affecting basal tension of mucosal blood vessels,increasing volume of mucosal blood flow and mucosal thickness,and regulating secretion of gastric mucus.
To investigate CNS's adaptation mechanism in digestion and absorption under different energy demands and supplies,and discuss regulating relationship between central never system(CNS) and peripheral nervous system(PNS),We used the mandarin vole Microtus mandarinus as the animal model.In our study,immunohistochemisty and NADPH-NDP histochemistry were employed to test the expression of hypothalamic neuropeptide Y(NPY),its rate-limiting enzyme -Peptidylglycineα-amidating monooxygenase(PAM) in hypothalamus and the distribution of nitric oxide synthase (NOS) in gastrointestinal myenteric plexus among non-Lactating female,lactating female and fasting female.Furthermore,the effects of intra- cerebroventricular(icv 8ug/ul) microinjection of NPY on the distribution of NOS in gastrointestinal myenteric plexus were also observed.Results were as follows
1.positive immunohistochemical spots of NPY and PAM were mainly distributed in regions of arcuate nucleus(ARC),paraventricular nucleus(PVN),ventromedial nucles(VMH),dorsomedial nucleus(DMH) of hypothalamus;
2.hypothalamic positive NPY spots in lactating females and fasting females ascended significantly compared with non-lactating females,and positive PAM spots in ARC and PVN of fasting females significantly elevated compared with non-lactating females and lactating females,so did NPY microinjected females compared with saline microinjected females;
3.higher levels of NOS positive ganglions and neurons were observed in gastric and duodenum in myenteric plexus of lactating females and fasting females in comparison with non-lactating females,and NPY microinjected females presented the same changes compared with saline microinjected females;
4.Both NOS positive ganglions,neurons in jejunum of lactating females compared with non-lactating females and microinjected NPY females compared with microinjected saline females were higher;
5.Number of NOS positive neurons in every NOS positive ganglions in Cecum of lactating females were more that of non-lactating females;while NOS positive ganglions and positive neurons of NPY-injected females were more compared with saline-injected females.
6.Higher level of NOS positive ganglions were observed in myenteric plexus of Ileum of lactating females in comparison with non-lactating females.
7.Food consumption were prominently increased by icy injection of NPY.
We conclude that:both CNS and PNS take part in gastrointestinal adaptive regulation to settle higher energy demands and supply-demand contradiction in energy,and the adaptation mechanism are varied under different energy threatening.Our results also suggest that NPY in hypothalamus is an important regulating peptide,functioning not only directly via enhancing food intake and digestive efficiency to meet the requirements of nutrition and energy,but also via regulating distribution of NOS neurons in digestive tract to modulate digestion.However,the contradiction of energy intake and expenditure is escalated by fasting,both expression of NPY and PAM were increased suggest that biological activity is also a important strategy under severe energy threatening.
引文
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