瘦素与胰岛细胞

瘦素抑制或促进胰岛素（NIS）分泌，又可刺激瘦素产生。体内与体外试验均证实瘦素可通过增加脂肪酸氧化和减少其酯化来减少胰岛细胞内甘油三酯的含量，通过使一氧化氮水平降低，诱导型一氧化氮合酶mRNA的表达下降，B细胞淋巴瘤白血病－2（BCL－2）等抗凋亡因素的表达增加以实现其阻止脂性凋亡及脂毒性的作用。并且瘦素可通过上调节胰岛细胞内节俭基因－解偶联蛋白－2mRNA表达以达到其下丘脑途径外的产热作用，从而调节体内的能量代谢。     

瘦素对游离脂肪酸致大鼠胰岛β细胞脂毒性的保护作用

目的 探讨瘦素对于游离脂肪酸(FFA)导致的大鼠胰岛β细胞脂毒性的保护作用。方法体外分离Wistar大鼠胰岛进行培养,根据培养液中加入不同物质而分为4组:(1)对照组,(2)瘦素组,(3)FFA组,(4)FFA+瘦素组。培养72h后测定胰岛内甘油三酯(TG)含量,基础状态及葡萄糖刺激下胰岛素分泌情况,并用RT-PCR方法检测胰岛β细胞内脂肪酸氧化酶-肉毒碱软脂酰转移酶Ⅰ(CPT-Ⅰ)、脂肪酸合成酶-乙酰辅酶A羧化酶(ACC)以及过氧化质体增殖物激活受体α(PPARα)和PPARγ的mRNA表达情况 结果 (1)FFA使胰岛内TG含量增加(P<0.01),瘦素使胰岛内TG含量减少(P<0.01)。(2)瘦素抑制基础状态及高糖负荷后胰岛素分泌(均P<0.01);FFA使基础胰岛素分泌增加而高糖负荷后胰岛素分泌的增高幅度明显低于对照组(均P<0.01)。(3)瘦素使CPT-Ⅰ和PPARα表达增加(分别P<0.01和P<0.05),ACC和PPARγ表达减少(均P<0.01);FFA使CPT-Ⅰ和ACC表达增加,PPARα和PPARγ表达减少(均P<0.01)。结论 FFA使胰岛内TC聚集增加,基础状态胰岛素分泌增加而高糖负荷后胰岛素分泌减少,形成高胰岛素血症。而瘦素可以通过PPARα和PPARγ途径使胰岛内脂肪酸氧化酶表达增加,脂肪酸合成酶表达减少,胰岛内TG聚集减少,同时抑制胰岛素分泌,减轻高胰岛素血症,从而起到对于FFA导致的大鼠胰     

瘦素与胰岛细胞

瘦素抑制或促进胰岛素 (INS)分泌 ,又可刺激瘦素产生。体内与体外试验均证实瘦素可通过增加脂肪酸氧化和减少其酯化来减少胰岛细胞内甘油三酯的含量 ,通过使一氧化氮水平降低 ,诱导型一氧化氮合酶mRNA的表达下降 ,B细胞淋巴瘤白血病 2 (BCL 2 )等抗凋亡因素的表达增加以实现其阻止脂性凋亡及脂毒性的作用。并且瘦素可通过上调节胰岛细胞内节俭基因———解偶联蛋白 2mRNA表达以达到其下丘脑途径外的产热作用 ,从而调节体内的能量代谢     

瘦素对离体大鼠胰岛分泌胰岛素的双向影响

目的 了解不同浓度的瘦素，在不同条件下对离体大鼠胰岛分泌胰岛素的影响。方法 利用细胞培养技术，在不同的葡萄糖浓度（5.6mmol/L或16.7mmol/L）和不同作用时间（10min或2h)下，以0,1,5,10,15,50ak 100μg/L瘦素作用大鼠胰岛，观察其对胰岛素分泌的影响；用放免法检测培养物上清液胰岛素浓度。结果 培养液葡萄糖浓度为5.6mmol/L，培养10min，1μg/L、5μg/L瘦素促进被孵育的胰岛的胰岛素分泌；培养2h,5μg/L瘦素促进基础胰岛素分泌，≥50μg/L瘦素抑制胰岛素分泌。葡萄糖浓度为16.7mmol/L，培养10min，≥50μg/L瘦素抑制胰岛素分泌；培养2h，≥5μg/L瘦素抑制胰岛素分泌。结论 重组瘦素对离体大鼠胰岛分泌胰岛素具有双向作用，并受瘦素浓度、作用时间和环境葡萄糖浓度等因素变化的影响。     

瘦素在免疫介导糖尿病自身免疫损伤中的作用

研究表明瘦素水平可能在免疫介导糖尿病发病之前升高。瘦素可以促进致敏T淋巴细胞、单核细胞及自然杀伤细胞等免疫细胞的增殖、活化及向胰腺的迁移；促进细胞因子的分泌而加速β细胞凋亡，另外活化的T淋巴细胞也可以分泌瘦素，并可通过瘦素对胰岛β细胞造成损伤等。瘦素可能在胰岛细胞的自身免疫损伤中起了放大作用。     

瘦素的外周效应

瘦素是一种由ob基因编码, 主要由白色脂肪组织分泌的多肽类激素。瘦素主要通过作用于下丘脑发挥降低食欲、促进能耗、减轻体重的作用。除中枢外, 瘦素还能通过外周组织和器官, 如脂肪组织、胰腺、肝脏、骨骼肌、免疫细胞和心血管等, 发挥促进葡萄糖摄取利用、促进脂解和脂肪酸氧化、减少脂质沉积、抑制胰岛分泌胰岛素和胰高糖素、促进免疫系统T、B细胞发育及炎症因子产生等作用。经外周给予瘦素, 能改善脂肪营养不良、先天性瘦素缺乏症及包括神经性厌食症在内的获得性瘦素缺乏症患者的代谢异常。对瘦素外周效应的研究, 不仅有助于进一步了解瘦素的功能, 加深对瘦素的认识, 而且可为研发基于瘦素的减肥药物提供依据。     

瘦素在免疫介导糖尿病自身免疫损伤中的作用

研究表明瘦素水平可能在免疫介导糖尿病发病之前升高。瘦素可以促进致敏T淋巴细胞、单核细胞及自然杀伤细胞等免疫细胞的增殖、活化及向胰腺的迁移;促进细胞因子的分泌而加速β细胞凋亡,另外活化的T淋巴细胞也可以分泌瘦素,并可通过瘦素对胰岛β细胞造成损伤等。瘦素可能在胰岛细胞的自身免疫损伤中起了放大作用。     

脂肪肝

瘦素与脂肪肝(综述)——张丽等(浙江杭州浙江大学医学院附属邵逸夫医院内分泌科310016)；《国外医学&;#183;内分泌学分册》，2004，24(1)：65-67[大量研究显示瘦素在脂肪肝的形成中起重要作用。瘦素缺乏或作用障碍不仅使下丘脑分泌的神经肽Y水平升高，导致高胰岛     

高血压胰岛素抵抗与瘦素受体基因变异的研究

近几年来，国外相关文献多次报道，瘦素受体（LepR）基因变异与瘦素水平、胰岛素抵抗及高血压之间存在着较密切的关系，本课题将探讨合肥地区汉族人群高血压胰岛索抵抗与LepR基因第4号外显子赖氨酸（Lys）109精氨酸（Arg）变异的关系。     

瘦素与代谢综合征及临床联系

瘦素（leptin）是肥胖基因编码的一种蛋白质产物，主要由白色脂肪组织分泌，通过与其受体结合发挥抑制食欲、减少能量摄入、增加能量消耗的生物学作用。代谢综合征是一组由多种代谢相关疾病如糖耐量减低、糖尿病、冠心病、高血压、脂代谢紊乱等中的两种或两种以上的组合，胰岛紊抵抗（胰岛紊抵抗Insulin resistance，IR是指胰岛素的靶器官对胰岛索刺激的葡萄糖摄取、利用或处置的抵抗或减弱）其病因及发病机制中起关键作用。已经证实，体内存在脂肪一胰岛内分泌轴，瘦素与胰岛素抵抗、糖代谢异常、脂质代谢紊乱、高血压等密切相关，在代谢综合征和其他肥胖相关疾病的发生发展中占有重要地位。     

OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype

In obese Zucker diabetic fatty (ZDF) rats with mutant leptin receptors, pancreatic islets have an ≈50-fold increase in fat (TG), overproduce nitric oxide (NO), and lack a normal proinsulin mRNA response to fatty acids. We overexpressed the wild-type full-length “b” isoform of the leptin receptor (OB-Rb) in ZDF islets by perfusing ZDF pancreata with recombinant adenovirus containing the cDNA encoding OB-Rb. In cultured islets isolated from these animals, leptin lowered islet TG by 87% and completely blocked TG formation from free fatty acids. Overproduction of NO was reduced, and the preproinsulin mRNA response to free fatty acids was restored. This establishes defective leptin action as the proximate cause of lipotoxic diabetes in ZDF rats.     

Protection against lipoapoptosis of β cells through leptin-dependent maintenance of Bcl-2 expression

Obesity causes its complications through functional and morphologic damage to remotely situated tissues via undetermined mechanisms. In one rodent model of obesity, the Zucker diabetic fatty fa/fa rat, overaccumulation of triglycerides in the pancreatic islets may be responsible for a gradual depletion of β cells, leading to the most common complication of obesity, non-insulin-dependent diabetes mellitus. At the onset of non-insulin-dependent diabetes mellitus, the islets from fa/fa rats contain up to 100 times the fat content of islets from normal lean rats. Ultimately, about 75% of the β cells disappear from these fat-laden islets as a consequence of apoptosis induced by long-chain fatty acids (FA). Here we quantify Bcl-2, the anti-apoptosis factor in these islets, and find that Bcl-2 mRNA and protein are, respectively, 85% and 70% below controls. In normal islets cultured in 1 mM FA, Bcl-2 mRNA declined by 68% and completely disappeared in fa/fa islets cultured in FA. In both groups, suppression was completely blocked by the fatty acyl-CoA synthetase inhibitor, triacsin C, evidence of its mediation by fatty acyl-CoA. To determine whether leptin action blocked FA-induced apoptosis, we cultured normal and fa/fa islets in 1 mM FA with or without leptin. Leptin completely blocked FA-induced Bcl-2 suppression in normal islets but had no effect on islets from fa/fa rats, which are unresponsive to leptin because of a mutation in their leptin receptors (OB-R). However, when wild-type OB-R is overexpressed in fa/fa islets, leptin completely prevented FA-induced Bcl-2 suppression and DNA fragmentation.     

How obesity causes diabetes in Zucker diabetic fatty rats.

The mechanisms of adipogenic diabetes in Zucker diabetic fatty (ZDF) rats, a model of obesity complicated by diabetes, are reviewed. In ZDF rats, a mutation in the leptin receptor, OB-R, is associated with leptin resistance, obesity, and increased fat content of islets. Exaggerated nitric oxide (NO) generation, attributed to high intracellular levels of long-chain fatty acids, impairs beta-cell function and prevents their compensation for obesity-induced diabetes. The resulting diabetic hyperglycemia can be completely prevented by agents that inhibit NO production.     

Direct antidiabetic effect of leptin through triglyceride depletion of tissues

Leptin is currently believed to control body composition largely, if not entirely, via hypothalamic receptors that regulate food intake and thermogenesis. Here we demonstrate direct extraneural effects of leptin to deplete fat content of both adipocytes and nonadipocytes to levels far below those of pairfed controls. In cultured pancreatic islets, leptin lowered triglyceride (TG) content by preventing TG formation from free fatty acids (FFA) and by increasing FFA oxidation. In vivo hyperleptinemia, induced in normal rats by adenovirus gene transfer, depleted TG content in liver, skeletal muscle, and pancreas without increasing plasma FFA or ketones, suggesting intracellular oxidation. In islets of obese Zucker Diabetic Fatty rats with leptin receptor mutations, leptin had no effect in vivo or in vitro. The TG content was ≈20 times normal, and esterification capacity was increased 3- to 4-fold. Thus, in rats with normal leptin receptors but not in Zucker Diabetic Fatty rats, nonadipocytes and adipocytes esterify FFA, store them as TG, and later oxidize them intracellularly via an “indirect pathway” of intracellular fatty acid metabolism controlled by leptin. By maintaining insulin sensitivity and preventing islet lipotoxicity, this activity of leptin may prevent adipogenic diabetes.     

Acute effects of fatty acids on insulin secretion from rat and human islets of Langerhans

Fatty acids have both stimulatory and inhibitory effects on insulin secretion. Long-term exposure to fatty acids results in impaired insulin secretion whilst acute exposure has generally been found to enhance insulin release. However, there are conflicting data in the literature as to the relative efficacy of various fatty acids and on the glucose dependency of the stimulatory effect. Moreover, there is little information on the responses of human islets in vitro to fatty acids. We have therefore studied the acute effects of a range of fatty acids on insulin secretion from rat and human islets of Langerhans at different glucose concentrations. Fatty acids (0.5 mM) acutely stimulated insulin release from rat islets of Langerhans in static incubations in a glucose-dependent manner. The greatest effect was seen at high glucose concentration (16.7 mM) and little or no response was elicited at 3.3 or 8.7 mM glucose. Long-chain fatty acids (palmitate and stearate) were more effective than medium-chain (octanoate). Saturated fatty acids (palmitate, stearate) were more effective than unsaturated (palmitoleate, linoleate, elaidate). Stimulation of insulin secretion by fatty acids was also studied in perifused rat islets. No effects were observed at 3.3 mM glucose but fatty acids markedly potentiated the effect of 16.7 mM glucose. The combination of fatty acid plus glucose was less effective when islets had been first challenged with glucose alone. The insulin secretory responses to fatty acids of human islets in static incubations were similar to those of rat islets. In order to examine whether the responses to glucose and to fatty acids could be varied independently we used an animal model in which lactating rats are fed a low-protein diet during early lactation. Islets from rats whose mothers had been malnourished during lactation were still able to respond effectively to fatty acids despite a lowered secretory response to glucose. These data emphasise the complex interrelationships between nutrients in the control of insulin release and support the view that fatty acids play an important role in glucose homeostasis during undernutrition.     

Leptin controls the fate of fatty acids in isolated rat white adipocytes

Leptin directly increases the rate of exogenous glucose and fatty acids oxidation in isolated adipocytes. However, the effects of leptin on fatty acid metabolism in white adipose tIssue have not been examined in detail. Here, we report that in adipocytes incubated for 6 h in the presence of leptin (10 ng/ml), the insulin-stimulated de novo fatty acid synthesis was inhibited by 36% (P<0.05), while the exogenous oxidation of acetic and oleic acids was increased by 50% and 76% respectively. Interestingly, leptin did not alter the oxidation of intracellular fatty acids. Leptin-incubated cells presented a 16-fold increase in the incorporation of oleic acid into triglyceride (TG) and a 123% increase in the intracellular TG hydrolysis (as measured by free fatty acids release). Fatty acid-TG cycling was not affected by leptin. By employing fatty acids radiolabeled with (3)H and (14)C, we could determine the concomitant influx of fatty acids (incorporation of fatty acids into TG) and efflux of fatty acids (intracellular fatty acids oxidation and free fatty acids release) in the incubated cells. Leptin increased by 30% the net efflux of fatty acids from adipocytes. We conclude that leptin directly inhibits de novo synthesis of fatty acids and increases the release and oxidation of fatty acids in isolated rat adipocytes. These direct energy-dissipating effects of leptin may play an important role in reducing accumulation of fatty acids into TG of rat adipose cells.     

Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation

We have studied mechanisms by which leptin overexpression, which reduces body weight via anorexic and thermogenic actions, induces triglyceride depletion in adipocytes and nonadipocytes. Here we show that leptin alters in pancreatic islets the mRNA of the genes encoding enzymes of free fatty acid metabolism and uncoupling protein-2 (UCP-2). In animals infused with a recombinant adenovirus containing the leptin cDNA, the levels of mRNAs encoding enzymes of mitochondrial and peroxisomal oxidation rose 2- to 3-fold, whereas mRNA encoding an enzyme of esterification declined in islets from hyperleptinemic rats. Islet UCP-2 mRNA rose 6-fold. All in vivo changes occurred in vitro in normal islets cultured with recombinant leptin, indicating direct extraneural effects. Leptin overexpression increased UCP-2 mRNA by more than 10-fold in epididymal, retroperitoneal, and subcutaneous fat tissue of normal, but not of leptin–receptor-defective obese rats. By directly regulating the expression of enzymes of free fatty acid metabolism and of UCP-2, leptin controls intracellular triglyceride content of certain nonadipocytes, as well as adipocytes.     

Serum leptin and habitual fatty acid dietary intake in patients with type 1 diabetes mellitus

OBJECTIVE: To study the contribution of a normal intake of nutrients to the variability of serum leptin concentrations in persons with type 1 diabetes mellitus. DESIGN: We studied the relation between serum leptin and nutrient intake in a cross-sectional study. METHODS: Serum leptin measured by radioimmunoassay, nutritional data determined by a self-administered 7-day nutritional questionnaire, and the fatty acid composition of the serum phospholipids (measured by thin layer chromatography and gas chromatography) were determined in 60 patients with type 1 diabetes mellitus. Correlation and regression analyses were performed between serum leptin and dietary fatty acids and serum phospholipid fatty acids. RESULTS: In the prediction models for the concentrations of serum leptin in men with type 1 diabetes mellitus, the dietary fatty acids displaced the anthropometric variables, and were independent of the serum testosterone concentrations. This fact remained when the prediction was made on the basis of indirect markers of the intake, such as the serum phospholipid fatty acids. In the women, the fatty acids from the diet or from the serum phospholipids also partly explained the variation in serum leptin, although not displacing the anthropometric variables. CONCLUSIONS: Our data suggest that, in non-experimental conditions, the concentrations of serum leptin in men with type 1 diabetes mellitus and, to a lesser extent, those in women with diabetes, may be influenced by the composition of the habitual diet, especially the type of dietary fat.     

The short-term effect of fatty acids on glucagon secretion is influenced by their chain length, spatial configuration, and degree of unsaturation: studies in vitro

The influence of fatty acids on beta cell function has been well established whereas little is known about the role of fatty acids on alpha cell function. The aim of our study was to investigate the short-term effects of chain length, spatial configuration, and degree of unsaturation of fatty acids on glucagon secretion from isolated mouse islets and alpha tumor cell 1 clone 6 cells (alpha TC1-6 cells). Glucagon release was measured with different saturated and unsaturated fatty acids as well as cis and trans isomers of fatty acids at low and high glucose. Palmitate (0.1-0.5 mmol/L) immediately stimulated glucagon release in a dose-dependent manner from both isolated islets and alpha TC 1-6 cells. The longer chain length of saturated fatty acids, the higher glucagon responses were obtained. The average fold increase in glucagon to saturated fatty acids (0.3 mmol/L) compared to control was octanoate 1.5, laurate 2.0, myristate 2.9, palmitate 5.4, and stearate 6.2, respectively. Saturated fatty acids were more effective than unsaturated fatty acids in stimulating glucagon secretion. At an equimolar concentration, trans-fatty acids were more potent than their cis isomers. Fatty acids immediately stimulate glucagon secretion from isolated mouse islets pancreatic alpha cells. The chain length, spatial configuration, and degree of unsaturation of fatty acids influence the glucagonotropic effect.     

The impact of dietary fat composition on serum leptin concentrations in healthy nonobese men and women

The recently discovered hormone leptin is primarily secreted by adipose tissue and serves as an internal signal indicating the size of body fat stores. The aim of the present study was to investigate the impact of the dietary fatty acid composition on serum leptin concentrations. Therefore, serum leptin levels were measured by RIA in healthy nonobese men (n = 30) and women (n = 25). First, all participants received a baseline high-fat diet, rich in saturated fat, for 2 wk and were then randomly assigned to one of three high-fat dietary treatments, which contained refined olive oil (rich in monounsaturated fatty acids, n = 19), rapeseed oil [rich in monounsaturated fatty acids and alpha-linolenic acid (18:3n-3), n = 17], or sunflower oil (rich in n-6-polyunsaturated fatty acids, n = 19) as the principal source of fat for 4 wk. On the rapeseed oil diet, serum leptin concentrations increased slightly in men [+0.25 ng/ml, T(9) = -2.778, P = 0.021], but decreased distinctly in women [-4.70 ng/ml, T(6) = 5.083, P = 0.002]. Both the olive oil and the sunflower oil diet did not affect serum leptin concentrations. Thus, it is proposed that serum leptin levels were affected by the high amount of alpha-linolenic acid in rapeseed oil. However, questions remain as to why this diet differently affected serum leptin in men and women.