Ghrelin在糖尿病小鼠摄食调节与能量平衡中的作用
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摘要
Ghrelin由胃底部粘膜泌酸腺X/A细胞合成并分泌,其参与机体的能量代谢平衡,是启动进食并促进食欲的重要调节因子。有研究发现糖尿病大鼠血浆Ghrelin水平明显升高,但对于Ghrelin在摄食调控中的作用机制和在糖尿病多食、消瘦中的病理生理作用尚未完全明了。离体实验结果表明,在没有受体激动剂存在的情况下,Ghrelin受体仍保持其50%的基本活性(constitutive activity)。Ghrelin受体既可被受体激动剂,也可被至今尚未阐明的内源性受体反激动剂所调节。[D-Arg~1,D-phe~5,D-Trp~(7.9),Leu~(11)]-P-物质(Substance P,PS)是Ghrelin受体的高效、重要的反激动剂。体外实验证明,PS可降低Ghrelin受体基本活性,抑制Ghrelin细胞信号转导,产生较弱的拮抗剂效应。
目的:1.探讨内源性Ghrelin对糖尿病大鼠摄食和能量平衡的调节及其机制。2.研究Ghrelin和GHRP-6对糖尿病小鼠胃肠动力学改变的影响及机制。3.探讨Ghrelin对下丘脑参与摄食及能量代谢调节的中枢机制。
方法:
1.采用腹腔注射链脲霉素(STZ)诱导产生STZ-糖尿病小鼠模型。经腹腔注射生理盐水或Ghrelin受体拮抗剂(D-Lys~3-GHRP-6),连续观察正常小鼠(NMRI小鼠)和STZ-糖尿病小鼠5天的摄食、体重和血糖的变化。
2.采用腹腔注射STZ方法,诱导Ghrelin基因敲除小鼠(Ghrelin~(-/-))形成Ghrelin~(-/-)STZ-糖尿病小鼠模型,比较Ghrelin~(+/+)STZ-糖尿病小鼠和Ghrelin~(-/-)STZ-糖尿病小鼠在摄食和能量代谢方面的改变。
3.采用放射免疫分析法(RIA),观察Ghrelin受体阻断剂D-Lys~3-GHRP-6对正常和STZ-糖尿病小鼠血浆Ghrelin及胰高血糖素水平的影响。
4.采用免疫荧光组化染色方法,观察D-Lys~3-GHRP-6对STZ-糖尿病小鼠下丘脑NPY和α-MSH表达的影响。
5.采用~(14)C辛酸呼吸实验法,观察STZ-糖尿病小鼠胃肠动力学的改变及受体活性机制。
6.采用免疫组化染色方法,观察GHRP-6对下丘脑c-Fos表达的影响及机制。
Ghrelin synthesized and secreted by X/A cells whin the oxyntic glands of gastric fundus mucosa is an important orexigenic peptide involved in the regulation of meal initiation and the energy balance of the body. Investigations have reported that hyperghrelinemia with hyperphagia and weight lose are commonly complicated in diabetes. However, the roles and its mechanism of ghrelin in regulations of food intake and hyperphgia in diabetes are still unclear. In vitro study, surprisingly, even in the absence of agonist, the ghrelin receptor signals with around 50% activity. It indicated that ghrelin receptor in fact is highly constitutive active in both of ligands regulated not only by the ghrelin agonist but also by a yet unknown endogenous inverse agonist. As shown in vitro study, ([D-Arg~1, D-phe~5, D-Trp~(7,9), Leu~(11)) - substance P is a high efficacy and important inverse agonist for the receptor which act by decreasing the constitutive activity of the ghrelin receptor, as a result of antagonist effects.Aimed of the study: 1. The mechanism of endogenous ghrelin in uncontrolled insulin deficient diabetic hyperphagia induced by streptozotocin;2. To study the role of ghrelin and GHRP6 (mimic of ghrelin) on gastric motility, and to investigate whether gastric emptying is altered in diabetic mice and whether this is related to changes of constitutive ghrelin receptor activity;3. To investigate ghrelin mimic in regulation of food intake and energy homeostasis and hypothalamic signalling.Methods:1. Diabetes was induced by i.p. injection of 140 mg/kg STZ. The hyperphagic responses were compared in NMRI mice treated for 5 days with either saline or the ghrelin receptor antagonist (D-Lys3-GHRP-6). Food intake, body weight and blood glucose levels were monitored;2. The role of endogenous ghrelin in ghrelin wild type (ghrelin+/+) and ghrelin gene knockout (ghrelin-/-) mice, to observe the changes of relative elements with energy metabolism (blood glucose, food intake fat pad mass);
3. Glucagon and ghrelin were measured in the plasma samples with a RIA (radioimmunoassay);4. Immunocytochemical technique and Confocol microscopy to analyze the expression of orexigenic (NPY-,Orexin-) and anorexigenic(a-MSH -) peptide containing neurons in hypothalamus;5. The effect of the inverse ghrelin agonist [D-Arg\ D-Phe5, D-Trp7'9, Leu"]-substance P on gastric emptying was evaluated before and at several time points after STZ using the 14C octanoic breath test;6. Brain sections were stained for c-Fos by means of the streptavidin-biotin-peroxidase method to study the effect of peripheral of GHRP-6, a ghrelin mimetic, on the activity of central neuronal network of food intake regulation.Results:1. Blood glucose level was increased after STZ treated 24 hours compared with citrate buffer (PO.001). 24h food intake and 2h food intake (10-12 am) was increased after STZ treated 4 days (PO.001). Treatment with the antagonist of ghrelin (D-Lys3-GHRP-6)( for 5 days) reversed the increased 24h food intake and 2h food intake (10-12 am) and blood glucose level. D-Lys3-GHRP-6 decreased the blood glucose (PO.05) and 24h food intake(PO.05) and 2h food intake (PO.01) in STZ-induced diabetic mice.2. Compared with normal control mice, the NPY immunoreactive (IR) neurons significant increased (249±7/mm2 vs 587±9/mm2, PO.001) and a-MSH (IR) neurons decreased(386±35.6/mm2 vs 232±30/mm2, PO.05) respectively in hypothalamus accurate nucleus diabetic mice. D-Lys3-GHRP-6 treatment decreased the number of NPY (587 ± 9/mm2 vs 324±36/mm2, PO.0005) and increased the number of a-MSH (587±9/mm2 vs 324±36/mm2, PO.0005) immunoreactive (IR) neurons.3. In ghrelin7" mice the induction of hyperphagic response was attenuated and the maximal increase in food intake was much smaller in the mutant (70%) than in the wild-type mice (141%). Ghrelin'7" mice lost 12.4% more body weight than ghrelin+/+ mice. In contrast to the ghrelin+/+ mice, the number of NPY IR-neurons were not significantly increased by the induction of diabetes in ghrelin''" mice (P>0.05) .4. Plasma ghrelin levels were increased in diabetic NMRI mice (1266±200 pg/ml vs 576±108 pg/ml, PO.05). Treatment with the ghrelin receptor antagonist further increased
plasma ghrelin levels in control mice to 1240±246 pg/ml and to 1570±373 pg/ml in diabetic mice (PO.05). At the end of the experiment, plasma glucagon levels were lower (PO.05) in the diabetic treated saline group (199±30 pg/ml) than in the vehicle treated control group (401 ±24 pg/ml). Treatment of diabetic mice with D-Lys3-GHRP-6 normalized plasma glucagon levels. In control mice treatment with the antagonist did not affect plasma glucagon levels (P>0.05) .5. Ghrelin and GHRP-6 increased gastric empty times (Ghrelin: 77.8±5min vs 60.52±3.05min, PO.05;GHRP-6: 77.8±5min vs 58.78±35.2min, PO.01) respectively compared with saline treatment. Administration of the inverse agonist delayed gastric emptying to 99.8±6 min (PO.05). Combined injection of ghrelin and substance P together could partially inhibited ghrelin activity in gastric motility (99.8±6 min vs 83.4±5.1 min, PO.05);6. Six days after the STZ gastric emptying (ti/2) was significantly accelerated from 77.8±5 min to 45±3 min (day 6), 42±8min (day 10) and 30±4 min (day 34) ( PO.01). In contrast to the control conditions, the inverse agonist was unable to delay gastric emptying at day 13 (34±3 min) and day 39 (32±2 min) (P>0.05) .7. Combining with the results of that food intake significantly increased from 0.60±0.10g to 1.48±0.48g after i.p. injection of GHRP-6 (compared to saline treated mice). The number of c-Fos immunoreactive positive neurons were increased in the arcuate nucleus(2504±40/mm2 ,PO.001 )and in the paraventricular nucleus(2056±32/mm2, PO.001) and in supraoptic nucleus (1051 ±52/mm2, PO.01) 3h after the peripheral injection of GHRP-6 in NMRI mice.Conclusions.1. Blood glucose level and food intake were increased in STZ-induced diabetic mice. Treatment with the antagonist of ghrelin (D-Lys3-GHRP-6) (for 5 days) reversed the increased food intake and blood glucose level.2. Compared with normal control mice, the NPY immunoreactive (IR) neurons significant increased and a-MSH (IR) neurons decreased respectively in hypothalamus accurate nucleus diabetic mice. D-Lys3-GHRP-6 treatment decreased the number of NPY and increased the number of a-MSH IR neurons.
3. In ghrelin"'" mice the induction of hyperphagic response was attenuated and the body weight lost more than ghrelin+/+ mice.4. Plasma ghrelin levels were increased and plasma glucagon levels were lower in diabetic NMRI mice. Treatment with the ghrelin receptor antagonist further increased plasma ghrelin levels both in control mice and in diabetic mice. D-Lys3-GHRP-6 normalized plasma glucagon levels in diabetic mice.5. Ghrelin and GHRP-6 increased gastric empty times. Substance P (the inverse agonist) delayed gastric emptying. Gastric emptying (ti/2) was significantly accelerated in STZ-induced diabetic mice.6. GHRP-6 increased food intake. The number of c-Fos immunoreactive positive neurons were increased in the arcuate nucleus and in the paraventricular nucleus and in supraoptic nucleus after the peripheral injection of GHRP-6 in NMRI mice.
目的:1.探讨内源性Ghrelin对糖尿病大鼠摄食和能量平衡的调节及其机制。2.研究Ghrelin和GHRP-6对糖尿病小鼠胃肠动力学改变的影响及机制。3.探讨Ghrelin对下丘脑参与摄食及能量代谢调节的中枢机制。
方法:
1.采用腹腔注射链脲霉素(STZ)诱导产生STZ-糖尿病小鼠模型。经腹腔注射生理盐水或Ghrelin受体拮抗剂(D-Lys~3-GHRP-6),连续观察正常小鼠(NMRI小鼠)和STZ-糖尿病小鼠5天的摄食、体重和血糖的变化。
2.采用腹腔注射STZ方法,诱导Ghrelin基因敲除小鼠(Ghrelin~(-/-))形成Ghrelin~(-/-)STZ-糖尿病小鼠模型,比较Ghrelin~(+/+)STZ-糖尿病小鼠和Ghrelin~(-/-)STZ-糖尿病小鼠在摄食和能量代谢方面的改变。
3.采用放射免疫分析法(RIA),观察Ghrelin受体阻断剂D-Lys~3-GHRP-6对正常和STZ-糖尿病小鼠血浆Ghrelin及胰高血糖素水平的影响。
4.采用免疫荧光组化染色方法,观察D-Lys~3-GHRP-6对STZ-糖尿病小鼠下丘脑NPY和α-MSH表达的影响。
5.采用~(14)C辛酸呼吸实验法,观察STZ-糖尿病小鼠胃肠动力学的改变及受体活性机制。
6.采用免疫组化染色方法,观察GHRP-6对下丘脑c-Fos表达的影响及机制。
Ghrelin synthesized and secreted by X/A cells whin the oxyntic glands of gastric fundus mucosa is an important orexigenic peptide involved in the regulation of meal initiation and the energy balance of the body. Investigations have reported that hyperghrelinemia with hyperphagia and weight lose are commonly complicated in diabetes. However, the roles and its mechanism of ghrelin in regulations of food intake and hyperphgia in diabetes are still unclear. In vitro study, surprisingly, even in the absence of agonist, the ghrelin receptor signals with around 50% activity. It indicated that ghrelin receptor in fact is highly constitutive active in both of ligands regulated not only by the ghrelin agonist but also by a yet unknown endogenous inverse agonist. As shown in vitro study, ([D-Arg~1, D-phe~5, D-Trp~(7,9), Leu~(11)) - substance P is a high efficacy and important inverse agonist for the receptor which act by decreasing the constitutive activity of the ghrelin receptor, as a result of antagonist effects.Aimed of the study: 1. The mechanism of endogenous ghrelin in uncontrolled insulin deficient diabetic hyperphagia induced by streptozotocin;2. To study the role of ghrelin and GHRP6 (mimic of ghrelin) on gastric motility, and to investigate whether gastric emptying is altered in diabetic mice and whether this is related to changes of constitutive ghrelin receptor activity;3. To investigate ghrelin mimic in regulation of food intake and energy homeostasis and hypothalamic signalling.Methods:1. Diabetes was induced by i.p. injection of 140 mg/kg STZ. The hyperphagic responses were compared in NMRI mice treated for 5 days with either saline or the ghrelin receptor antagonist (D-Lys3-GHRP-6). Food intake, body weight and blood glucose levels were monitored;2. The role of endogenous ghrelin in ghrelin wild type (ghrelin+/+) and ghrelin gene knockout (ghrelin-/-) mice, to observe the changes of relative elements with energy metabolism (blood glucose, food intake fat pad mass);
3. Glucagon and ghrelin were measured in the plasma samples with a RIA (radioimmunoassay);4. Immunocytochemical technique and Confocol microscopy to analyze the expression of orexigenic (NPY-,Orexin-) and anorexigenic(a-MSH -) peptide containing neurons in hypothalamus;5. The effect of the inverse ghrelin agonist [D-Arg\ D-Phe5, D-Trp7'9, Leu"]-substance P on gastric emptying was evaluated before and at several time points after STZ using the 14C octanoic breath test;6. Brain sections were stained for c-Fos by means of the streptavidin-biotin-peroxidase method to study the effect of peripheral of GHRP-6, a ghrelin mimetic, on the activity of central neuronal network of food intake regulation.Results:1. Blood glucose level was increased after STZ treated 24 hours compared with citrate buffer (PO.001). 24h food intake and 2h food intake (10-12 am) was increased after STZ treated 4 days (PO.001). Treatment with the antagonist of ghrelin (D-Lys3-GHRP-6)( for 5 days) reversed the increased 24h food intake and 2h food intake (10-12 am) and blood glucose level. D-Lys3-GHRP-6 decreased the blood glucose (PO.05) and 24h food intake(PO.05) and 2h food intake (PO.01) in STZ-induced diabetic mice.2. Compared with normal control mice, the NPY immunoreactive (IR) neurons significant increased (249±7/mm2 vs 587±9/mm2, PO.001) and a-MSH (IR) neurons decreased(386±35.6/mm2 vs 232±30/mm2, PO.05) respectively in hypothalamus accurate nucleus diabetic mice. D-Lys3-GHRP-6 treatment decreased the number of NPY (587 ± 9/mm2 vs 324±36/mm2, PO.0005) and increased the number of a-MSH (587±9/mm2 vs 324±36/mm2, PO.0005) immunoreactive (IR) neurons.3. In ghrelin7" mice the induction of hyperphagic response was attenuated and the maximal increase in food intake was much smaller in the mutant (70%) than in the wild-type mice (141%). Ghrelin'7" mice lost 12.4% more body weight than ghrelin+/+ mice. In contrast to the ghrelin+/+ mice, the number of NPY IR-neurons were not significantly increased by the induction of diabetes in ghrelin''" mice (P>0.05) .4. Plasma ghrelin levels were increased in diabetic NMRI mice (1266±200 pg/ml vs 576±108 pg/ml, PO.05). Treatment with the ghrelin receptor antagonist further increased
plasma ghrelin levels in control mice to 1240±246 pg/ml and to 1570±373 pg/ml in diabetic mice (PO.05). At the end of the experiment, plasma glucagon levels were lower (PO.05) in the diabetic treated saline group (199±30 pg/ml) than in the vehicle treated control group (401 ±24 pg/ml). Treatment of diabetic mice with D-Lys3-GHRP-6 normalized plasma glucagon levels. In control mice treatment with the antagonist did not affect plasma glucagon levels (P>0.05) .5. Ghrelin and GHRP-6 increased gastric empty times (Ghrelin: 77.8±5min vs 60.52±3.05min, PO.05;GHRP-6: 77.8±5min vs 58.78±35.2min, PO.01) respectively compared with saline treatment. Administration of the inverse agonist delayed gastric emptying to 99.8±6 min (PO.05). Combined injection of ghrelin and substance P together could partially inhibited ghrelin activity in gastric motility (99.8±6 min vs 83.4±5.1 min, PO.05);6. Six days after the STZ gastric emptying (ti/2) was significantly accelerated from 77.8±5 min to 45±3 min (day 6), 42±8min (day 10) and 30±4 min (day 34) ( PO.01). In contrast to the control conditions, the inverse agonist was unable to delay gastric emptying at day 13 (34±3 min) and day 39 (32±2 min) (P>0.05) .7. Combining with the results of that food intake significantly increased from 0.60±0.10g to 1.48±0.48g after i.p. injection of GHRP-6 (compared to saline treated mice). The number of c-Fos immunoreactive positive neurons were increased in the arcuate nucleus(2504±40/mm2 ,PO.001 )and in the paraventricular nucleus(2056±32/mm2, PO.001) and in supraoptic nucleus (1051 ±52/mm2, PO.01) 3h after the peripheral injection of GHRP-6 in NMRI mice.Conclusions.1. Blood glucose level and food intake were increased in STZ-induced diabetic mice. Treatment with the antagonist of ghrelin (D-Lys3-GHRP-6) (for 5 days) reversed the increased food intake and blood glucose level.2. Compared with normal control mice, the NPY immunoreactive (IR) neurons significant increased and a-MSH (IR) neurons decreased respectively in hypothalamus accurate nucleus diabetic mice. D-Lys3-GHRP-6 treatment decreased the number of NPY and increased the number of a-MSH IR neurons.
3. In ghrelin"'" mice the induction of hyperphagic response was attenuated and the body weight lost more than ghrelin+/+ mice.4. Plasma ghrelin levels were increased and plasma glucagon levels were lower in diabetic NMRI mice. Treatment with the ghrelin receptor antagonist further increased plasma ghrelin levels both in control mice and in diabetic mice. D-Lys3-GHRP-6 normalized plasma glucagon levels in diabetic mice.5. Ghrelin and GHRP-6 increased gastric empty times. Substance P (the inverse agonist) delayed gastric emptying. Gastric emptying (ti/2) was significantly accelerated in STZ-induced diabetic mice.6. GHRP-6 increased food intake. The number of c-Fos immunoreactive positive neurons were increased in the arcuate nucleus and in the paraventricular nucleus and in supraoptic nucleus after the peripheral injection of GHRP-6 in NMRI mice.
引文
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