Nesfatin-1与肥胖的关系

Nesfatin-1是一种新发现的摄食抑制性脑肠肽,在中枢神经系统和多个外周组织中均有表达.Nesfatin-1基因多态性或蛋白表达异常均可能引发摄食增多和肥胖.Nesfatin-1可直接作用于摄食相关神经元,减轻肥胖程度;也可通过影响催产素、神经肽Y等神经肽的表达和功能,间接发挥降低体重的作用.     

Nesfatin-1的研究进展

Nesfatin-1是一种厌食调节肽,在中枢和外周广泛表达.近年研究显示nesfatin-1在消化、内分泌、精神等多系统中发挥重要作用,但其作用机制尚未完全明确.本文就nesfatin-1的研究进展作一综述.     

Nesfatin-1对大鼠胃酸分泌的影响

目的:探讨Nesfatin-1对大鼠胃酸分泌的影响.方法:♂SD大鼠36只,随机分为6组,分别在侧脑室注射Nesfatin-1(0.05g/只)、Nesfatin-1(0.5g/只)及等量的注射灭菌水(5L/只),外周静脉注射Nesfatin-1(10g/kg)、Nesfatin-1(50g/kg)及等量的灭菌水(150L/只),每组6只.采用幽门结扎法收集胃液,3h后处死大鼠分别测定胃液胃酸分泌量,H+-K+-ATPase表达量.结果:侧脑室注射Nesfatin-1(0.05g/只及0.5g/只)后大鼠3h胃液的分泌量分别为2.4mL/3h±0.3mL/3h、2.5mL/3h±0.3mL/3h,与对照组(3.3mL/3h±0.3mL/3h)相比,其分泌量明显减少,差异具有统计学意义(P<0.05,n=6).侧脑室注射Nesfatin-1(0.05g/只及0.5g/只)后大鼠3h胃酸的分泌量分别为373.6mol/3h±61.5mol/3h、380.0mol/3h±55.8mol/3h,与对照组(582.7mol/3h±59.3mol/3h)相比,其分泌量明显减少,差异具有统计学意义(P<0.05,n=6).外周静脉注射Nesfatin-1(10g/kg及50g/kg)后大鼠胃液分泌量分别为3.3mL/3h±0.4mL/3h、3.8mL/3h±0.5mL/3h与对照组(3.7mL/3h±0.7mL/3h)相比差异无统计学意义(P>0.05,n=6).外周静脉注射Nesfatin-1(2g/只及10g/只)后大鼠胃酸分泌量分别为573.8mol/3h±97.4mol/3h、594.4mol/3h±121.0mol/3h与对照组(647.6mol/3h±102.8mol/3h)相比差异无统计学意义(P>0.05,n=6).侧脑室注射Nesfatin-1(0.05g/只及0.5g/只)后3h大鼠胃H+-K+-ATPasemRNA表达明显下调(P<0.05).外周静脉注射Nesfatin-1(10g/kg及50g/kg)后3h大鼠胃H+-K+-ATPasemRNA表达与对照组相比差异无统计学意义(P>0.05).结论:Nesfatin-1通过中枢注射可以明显抑制大鼠胃酸的分泌.     

MC4R在肥胖及糖代谢中的作用

黑皮质素受体4(MC4R)可通过作用于中枢阿片-促黑素细胞皮质素原(POMC)神经元、交感节前神经元、以及与其激动剂的相互作用,调控食物摄入和能量消耗,进而改善肥胖.此外,MC4R还可参与胰岛素敏感性及葡萄糖稳态的调控,为肥胖及糖尿病的治疗提供新靶点.     

Nesfatin-1的研究进展

Nesfatin-1是新发现的一种摄食调节肽,参与能量代谢。笔者对近年国内外Nesfatin-1的相关研究作一综述。     

Nesfatin-1对肥胖大鼠胃排空及胃平滑肌条收缩性的影响

目的:观察Nesfatin-1对正常及单纯性肥胖大鼠胃排空及离体胃平滑肌条收缩活性的影响.方法:高脂饲料喂养♂大鼠6wk,制作单纯性肥胖大鼠模型;正常及肥胖大鼠实验组中枢注入不同浓度Nesfatin-1(0.5μmol/L、5μmol/L、50μmol/L)后测胃排空率;生理记录仪记录大鼠胃底、胃体平滑肌条自发收缩及不同浓度Nesfatin-1(0.026μmol/L、0.26μmol/L、2.6μmol/L)作用下对乙酰胆碱(Ach)诱导的肌条收缩的影响.结果:Nesfatin-1可抑制正常及肥胖大鼠胃平滑肌条收缩,低、中、高浓度组与生理盐水对照组相比差异均有统计学意义(q=3.93-15.72,P<0.05-0.01).随Nesfatin-1浓度的增高,其抑制作用呈明显剂量依赖关系(q=3.45-5.69,P<0.05-0.01).低浓度Nesfatin-1抑制正常大鼠、肥胖大鼠胃底平滑肌条收缩作用无显著性差异(P>0.05),中、高浓度对正常大鼠胃底平滑肌条抑制作用强于肥胖大鼠(t=2.14,P<0.05;t=2.63,P<0.05).低、中浓度Nesfatin-1抑制正常大鼠、肥胖大鼠离体胃体平滑肌条收缩作用无显著性差异(P>0.05),但高浓度抑制正常大鼠离体胃体平滑肌条收缩作用显著强于肥胖大鼠(t=2.53,P<0.05).结论:Nesfatin-1可抑制正常及肥胖大鼠胃排空,胃排空率随Nesfatin-1浓度增加而降低.Nesfatin-1可抑制乙酰胆碱诱导的单纯性肥胖大鼠离体胃平滑肌条的收缩活动,其抑制作用随Nesfatin-1浓度增高而增强;相同Nesfatin-1浓度抑制正常大鼠离体平滑肌条收缩作用强于肥胖大鼠.     

Nesfatin-1对离体胃黏膜细胞胃酸分泌的影响

目的:研究nesfatin-1对离体培养的大鼠胃黏膜酸分泌的影响,探讨nesfatin-1对H+/K+-ATP酶mRNA及蛋白表达的影响.方法:酶解法分离大鼠胃黏膜细胞,细胞免疫荧光检测法鉴定细胞.用不同浓度的nesfatin-1(10-4-10-1μmol/L)对胃黏膜细胞进行处理0、1、2、3、4h,设立空白对照组,以14C-氨基比林摄取为酸分泌指标,检测nesfatin-1对大鼠离体的胃黏膜细胞酸分泌的影响.用RT-PCR法及Western印迹法检测nesfatin-1对胃黏膜细胞H+/K+-ATP酶alpha(α)亚基和beta(β)亚基mRNA及蛋白表达的影响.结果:Nesfatin-1在10-1μmol/L浓度下,在1、2h能够抑制离体培养的大鼠胃黏膜细胞的酸分泌.Nesfatin-1(10-1μmol/L)在1、2、3h均能够抑制H+/K+-ATP酶α亚基mRNA表达水平;在1、2h能够抑制H+/K+-ATP酶β亚基mRNA表达水平,分别与对照组相比,差异有统计学意义(均P<0.01).Nesfatin-1(10-4-10-1μmol/L)作用胃黏膜细胞2h时,呈剂量依赖性抑制α亚基和β亚基mRNA表达水平,分别与对照组相比,差异有统计学意义(均P<0.01).Nesfatin-1(10-1μmol/L)在1、2、3h能够抑制α亚基蛋白表达水平;在2、3h能够抑制β亚基蛋白表达水平,分别与对照组相比,差异有统计学意义(均P<0.01).Nesfatin-1(10-3-10-1μmol/L)作用胃黏膜细胞2h时,呈剂量依赖性抑制α亚基和β亚基蛋白表达水平,与对照组相比,差异有统计学意义(均P<0.01).结论:Nesfatin-1能抑制离体培养的大鼠胃黏膜细胞的酸分泌,有可能是通过下调H+/K+-ATP酶α亚基和β亚基的mRNA及蛋白表达的水平影响酸分泌.     

从瘦素到增食欲素——肥胖研究的新热点

肥胖是机体脂肪细胞数量增加或体积肥大致体重超过标准体重２０％以上的病理状态。在美国，１／３的成人已进入肥胖行列，每年用于治疗与肥胖相关疾病的费用达１０００亿美元以上。在发展中国家，随着经济的腾飞，肥胖的发病率迅速增加。然而对肥胖机制的研究长期徘徊，药...     

2型糖尿病患者血清Nesfatin-1、HSP60与下肢血管病变的相关性研究

目的 探讨2型糖尿病(T2DM)患者血清Nesfatin-1、热休克蛋白60(HSP60)与下肢血管病变(LEVD)的相关性。方法 选取120例T2DM患者,根据下肢血管超声检查是否合并LEVD分为两组,LEVD组62例,非LEVD组58例,另选取50名体检健康者为对照组,测定所有研究对象血清Nesfatin-1、HSP60水平,分析血清Nesfatin-1、HSP60水平与T2DM患者合并LEVD的关系。结果 LEVD组血清Nesfatin-1水平明显低于非LEVD组,HSP60水平明显高于非LEVD组(P＜0.05);不同LEVD分级患者血清Nesfatin-1水平随着病变分级的增加而降低,HSP60水平随着病变分级的增加而升高(P＜0.05);Pearson相关性分析显示,体质指数(BMI)、腰臀比(WHR)、糖化血红蛋白(HbA1c)、空腹血糖(FPG)、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)、低密度脂蛋白胆固醇(LDLC)、谷丙转氨酶(ALT)、血清肌酐(SCr)、血尿素氮(BUN)水平与Nesfatin-1水平呈负相关,与HSP60水平呈正相关;高密度脂蛋白胆固醇(HDLC)水平与Nesfatin-1水平呈正相关,与HSP60水平呈负相关(P＜0.05);多因素逐步Logistic回归分析显示,Nesfatin-1、HSP60为T2DM患者合并LEVD独立影响因素(P＜0.05)。结论 T2DM合并LEVD患者血清Nesfatin-1水平明显降低,HSP60水平明显升高,且随着病变严重程度而变化,为LEVD独立影响因素,及早检测血清Nesfatin-1、HSP60水平有助于及时防治LEVD。     

摄食抑制因子-1的生物学作用研究进展

摄食抑制因子-1(Nesfatin-1)是由82个氨基酸组成的分泌性多肽。最初于2006年从SQ-5细胞株中提取得到,被描述为下丘脑区的一种厌食肽。Nesfatin-1具有抑制摄食、抗炎、促细胞凋亡、调节糖脂代谢等生物学作用。Nesfatin-1包含3个结构域,其中发挥抑制摄食的关键区域为M30。目前,对介导Nesfatin-1的受体尚无定论,放射自显影技术发现,Nesfatin-1在大脑区域与125i-Nesfatin-1广泛结合,但不能据此推测其为Nesfatin-1的受体。     

不同糖耐量人群血清nesfatin-1水平及相关因素分析

目的 研究不同糖耐量人群血清nesfatin-1水平变化,及其与体重指数(BMI)、血糖、胰岛素敏感性等的关系.方法 115例研究对象分为正常糖耐量组(NGT组,33例)、糖耐量减低组(IGT组,30例)和新诊2型糖尿病组(T2DM组,52例)3组.根据BMI将T2DM组分为糖尿病肥胖组(T2DM-OB组,22例)和糖尿病正常体重组(T2DM-NW组,30例).采用ELISA法检测血清nesfatin-1水平.同时测定空腹血糖(FPG)、餐后2h血糖(2 h PG)、白细胞介素-6(IL-6)、胰岛素、糖化血红蛋白A1c(HbA1c)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白-胆固醇(LDL-C)、高密度脂蛋白-胆固醇(HDL-C).T2DM-OB组给予吡格列酮治疗,使仅BMI高于T2DM-NW组(P＜0.05)后再次检测血清nesfatin-1水平.计算稳态模型评估-胰岛素抵抗指数(HOMA-IR)、BMI、腰臀比(WHR)等.结果(1)T2DM组和IGT组血清nesfatin-1水平显著高于NGT组[(1 780±660) ng/L,(1 620±590) ng/Lvs.(1 390±610) ng/L,P＜0.05].(2)T2DM-OB组血清nesfatin-1水平显著高于T2DM-NW组[(1 897±670) ng/L vs.(1 690±650)ng/L,P＜0.05],经吡格列酮治疗后T2DM-OB组nesfatin-1水平仍高于T2DM-NW组[(1 791±634) ng/L vs.(1 690 ±650)ng/L,P＜0.05].(3)Nesfatin-1水平与TG、FPG、2hPG、HbA1c、IL-6、HOMA-IR、BMI呈正相关(r=0.582,0.568,0.587,0.552,0.546,0.523,0.562).多元逐步回归分析显示,HOMA-IR、FPG、BMI与血清nesfatin-1水平独立相关.结论 随着糖耐量受损程度的加重及肥胖的发生,nesfatin-1水平逐渐升高,nesfatin-1可能在肥胖及糖耐量受损中发挥重要作用.     

Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin

Aims/hypothesis Peptide YY (PYY) is a gut-derived hormone that has been shown to reduce short-term food intake in animals and humans. It has been proposed that deficiency of PYY contributes to obesity in humans. However, the physiology of PYY regulation by factors such as caloric restriction, or by other molecules important in energy homeostasis, e.g. leptin, remains to be fully elucidated. Materials and methods We evaluated the effect on PYY levels of: (1) caloric ingestion (a mixed meal) in five healthy normal-weight subjects; (2) fasting for 2 or 3 days in eight lean men and seven lean women respectively; and (3) recombinant human leptin administration at physiological replacement and pharmacological doses. Results PYY levels increased 50% after a mixed meal (p=0.01), and short-term complete fasting for 2 or 3 days decreased leptin and PYY levels to 20–30% and 40–60% of baseline, respectively (both p<0.05). However, recombinant human leptin administration at physiological doses to restore the fasting-induced decrease of leptin levels and at pharmacological doses over the short term had no effect on PYY levels. Conclusions/interpretation PYY increases after meal ingestion and decreases after fasting in a manner consistent with a meal-related signal of energy homeostasis. Importantly, circulating levels of this gut-secreted molecule are independent of regulation by leptin over the short term. These findings contribute towards our understanding of the homeostatic systems that regulate appetite in humans, including the possible redundancy of gastrointestinally secreted and adipocyte-secreted signals. This may be of importance for the future development of medications to treat obesity.     

A liquid mixed meal or exogenous glucagon-like peptide 1 (GLP-1) do not alter plasma leptin concentrations in healthy volunteers

Glucagon-like peptide 1 [7–36 amide] (GLP-1) and the obese gene product (leptin) are thought to be involved in the central regulation of feeding. Both may act from the peripheral circulation to influence brain function. To study potential interactions, GLP-1 ([7–36 amide]: 0.4, 0.8 pmol kg^–1 min^–1 or placebo on separate occasions) was infused intravenously (from –30 to 240 min) into nine healthy volunteers [age 26±3 years, body mass index: 22.9±1.6 kg/m², glycated haemoglobin HbA_1c: 5.0%± 0.2% (normal: 4.0%–6.2%), creatinine: 1.1±0.1 mg/dl], and (at 0 min) a liquid test meal (50 g sucrose in 400 ml 8% amino acid, total amino acids 80 g/l) was administered via a nasogastric tube. Plasma leptin (radioimmunoassay, RIA), glucose, insulin (microparticle enzyme immunoassay), C-peptide (enzyme-linked immunosorbent assay) and GLP-1 (RIA) were measured, and statistical analysis was done with repeated-measures ANOVA and Student's t-test. Plasma leptin concentrations were 31±6 pmol/l in the basal state. They did not change within 240 min after meal ingestion nor in response to the infusion of exogenous GLP-1 [7–36 amide] (P=0.99 for the interaction of experiment and time) leading to GLP-1 mean plasma levels of 25±2 and 36±3 (basal 6±1) pmol/l. On the other hand, glucose (from basal 4.7±0.1 to 6.0±0.2 mmol/l at 15 min, P<0.05) and insulin (from basal 28±2 to 325±78 pmol/l at 45 min, P<0.05) increased clearly after the meal with placebo. In conclusion, (1) plasma leptin levels in normal human subjects show no short-term changes after feeding a liquid mixed meal and (2) do not appear to be directly influenced by physiological and pharmacological elevations in plasma GLP-1 [7–36 amide] concentrations. This does not exclude interactions at the cerebral (hypothalamic) level or on more long-term temporal scales. Received: 5 February 1997 / Accepted in revised form: 18 June 1997     

Gut Hormones and Appetite Control: A Focus on PYY and GLP-1 as Therapeutic Targets in Obesity

The global obesity epidemic has resulted in significant morbidity and mortality. However, the medical treatment of obesity is limited. Gastric bypass is an effective surgical treatment but carries significant perioperative risks. The gut hormones, peptide tyrosine tyrosine (PYY) and glucagon-like peptide 1 (GLP-1), are elevated following gastric bypass and have been shown to reduce food intake. They may provide new therapeutic targets. This review article provides an overview of the central control of food intake and the role of PYY and GLP-1 in appetite control. Key translational animal and human studies are reviewed.