瘦素及其在相关领域的研究进展

瘦素（leptin）是由肥胖基因（ob）编码，由脂肪细胞分泌的一种凋爷机体能量平衡的蛋白类激素，参与机体能量的摄取、贮存和释放。瘦素水平异常与代谢综合征的一系列疾病相关，本义仪就近年来国内外对瘦素及其在防治肥胖胆结石等领域的研究进展作一简介!     

瘦素及其在相关领域的研究进展

瘦素（Leptin）是由肥胖基因（ob）编码，由脂肪细胞分泌的一种调节机体能量平衡的蛋白质类激素．参与机体能量的摄取、贮存和释放。瘦素水平异常与代谢综合征（MS）的一系列疾病相关。本文仅就近年来国内外对瘦素及其在防治肥胖、胆结石等领域的研究进展作一简介。     

瘦素与肥胖、胰岛素抵抗及2型糖尿病

瘦素是肥胖基因(ob基因)的蛋白质产物,由成熟脂肪细胞分泌,作为脂肪组织和中枢神经系统问网络联系的外周信号.可作用于中枢神经系统,影响摄食行为和调整自主神经系统活动,它在摄食、能量平衡.内分泌功能.免疫功能.红细胞生成.骨骼和大脑发育方面有重要的调节功能[1].瘦素与胰岛素都是调节能量代谢的主要激素,研究表明瘦素代谢紊乱是2型糖尿病发生的一个重要因素.瘦素含量过高或过低均会导致2型糖尿病的发生[2],2型糖尿病发病前期多有代谢综合征的表现,而肥胖、胰岛素抵抗是代谢综合征的重要特征,本文分别阐述瘦素与代谢综合征各组成部分的相关性,对瘦素与2型糖尿病的发生发展及治疗方面的关系作一综述.     

瘦素—医学界研究的热门课题

瘦素 (ｌｅｐｔｉｎ)是由肥胖基因 (ｏｂ基因 )编码的一种蛋白质 ,于 1994年由美国学者首先发现并命名。此蛋白质系一种脂源性激素 ,主要来源于脂肪细胞 ,由 146个氨基酸组成 ,分子量为 16ＫＤ ,其主要功能是通过减少能量摄取、增加能量消耗、抑制脂肪合成来调节机体的脂肪储存。晚近的研究显示 ,瘦素与神经内分泌系统之间组成一个复杂的双向闭合环路 ,一方面它作用于下丘脑、胰腺、肾上腺、甲状腺和性腺等靶器官 ,发挥重要的调节功能 ;另一方面 ,它又受这些神经内分泌器官的反馈调节 ,其作用已经远远超出了增加能量消耗和减少摄食的范畴。…     

抵抗素及其启动子-420C/G多态性与肥胖、肥胖伴2型糖尿病的相关性

目的探讨抵抗素水平及其基因多态性位点-420C/G与肥胖、肥胖伴2型糖尿病的相关性。方法选择60例正常对照者、67例单纯肥胖患者、63例肥胖伴2型糖尿病患者,测量身高(H)、体重(W),计算体重指数,测定空腹血糖(FPG)、空腹胰岛素(FINS)、抵抗素和总胆固醇(CHO)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白A(ApoA)、载脂蛋白B(ApoB),计算胰岛素抵抗指数(HOMA-IR),检测抵抗素基因-420C/G位点多态性,并对血清抵抗素水平、抵抗素基因-420C/G多态性与肥胖、肥胖伴2型糖尿病的相关性进行分析。结果 1)单纯肥胖组与肥胖伴2型糖尿病组抵抗素和FINS均高于正常对照组(P值均<0.05);单纯肥胖组与肥胖伴2型糖尿病组的抵抗素和FINS比较,差异均无统计学意义(P>0.05);HOMA-IR 3组间两两比较,差异均有统计学意义(P值均<0.05)。2)抵抗素基因-420C/G位点G等位基因频率3组间两两比较,差异均无统计学意义(P>0.05)。结论单纯肥胖者及肥胖伴2型糖尿病者血清抵抗素水平显著升高,与HOMA-IR呈正相关,抵抗素可能参与胰岛素抵抗的发生,但与胰岛素抵抗的发展及与肥胖至2型糖尿病的发病过程的关系尚待证实。抵抗素-420C/G位点G等位基因频率与胰岛素抵抗的发生无显著相关。     

肥胖—人体健康的重要危险因素

肥胖是全球性的公共卫生问题之一,肥胖一般是由遗传和环境双重因素决定的。肥胖是一种被忽视的疾病,它与非传染病的发病和死亡的增加密切相关。特别是儿童肥胖危害更大。本文就肥胖的定义、诊断、原因、预防和治疗等予以探讨。1 肥胖的定义、分类、诊断 当摄入能量超过能量的消耗时,过剩能量以身体脂肪     

消脂素的研究进展

消脂素 (Leptin)是由肥胖基因编码、脂肪组织分泌的蛋白质类激素。Leptin与下丘脑的受体相互作用以降低食欲 ,增加能耗 ,抑制脂肪合成。多数人类肥胖者血Leptin水平显著高于正常体重者和消瘦者 ,但 2 5 %的肥胖个体仍相对性地缺乏Leptin。提示多数肥胖个体存在内源性Leptin拮抗 ,这可能是人类肥胖的重要原因。部分Leptin相对缺乏的肥胖者将有可能成为Leptin治疗的对象。重组Leptin能使体重正常化 ,恢复肥胖基因缺陷小鼠生育能力。     

瘦素的研究进展及其与胰岛素的关系

瘦素是由脂肪细胞分泌的一种蛋白质激素，它对动物摄食、能量代谢、脂肪存储、免疫水平等有重要的调控作用。同时瘦素功能与胰岛素存在复杂而深刻的联系，1994年底Friedman等成功克隆出肥胖基因（ob gene）及人的同源基因，使这一领域的研究有了突破性进展。现将对瘦素的研究进展及其与胰岛素的关系作一综述。     

瘦素与妇科肿瘤

瘦素(leptin)是肥胖(ob)基因所编码、脂肪细胞分泌的多肽类激素,在多个学科领域中的作用得到了广泛关注.瘦素不仅是机体调节能量的重要物质,而且可以抑制肿瘤细胞凋亡、促进其增殖、增加其对基底膜的侵袭能力及促进血管生成[1,2],与肿瘤的发生密切相关.瘦素在妇科肿瘤发生发展中的作用日益受到关注.     

内脂素与肥胖相关性疾病的研究

脂肪组织不仅能调节能量储存与营养平衡,而且还是活跃的内分泌器官,可分泌多种脂肪细胞因子,如瘦素、抵抗素、脂联索、网膜素等,这些脂肪因子具有广泛的内分泌及心血管活性作用.肥胖时随着脂肪的堆积以及脂肪细胞体积的增大,脂肪因子分泌失调,可引起多种代谢紊乱,如高脂血症、胰岛素抵抗、糖尿病、代谢综合征等.内脂素(visfatin)是新近发现的主要由内脏脂肪组织分泌的一种脂肪细胞因子,具有类胰岛素活性,降低血糖、调节糖脂代谢、参与炎性反应及免疫应答等多种生物学功能.现有研究表明,vifatin可能与冠心病、高血压、糖尿病等一系列肥胖相关性疾病密切相关.本文简述visfatin生物学效应及其在肥胖及肥胖相关性疾病中的研究进展.     

Emerging antiobesity drugs

The healthcare burden that the obesity epidemic now poses is highly significant, in part due to increased risk of secondary chronic diseases such as hypertension. A lack of physical activity and high fat diets are major factors contributing to this condition. However, increasingly apparent is the genetic predisposition of individuals and ethnic groups to obesity. Present treatment strategies are currently inadequate and unlikely to have a major effect on the future prevalence of obesity. To slow the obesity epidemic, the source needs to be tackled now through fundamental research into the mechanisms by which obesity is manifest, and education on the risks and how to prevent it. This article will describe current and emerging treatments for obesity and review the recent advances in research that may provide the antiobesity treatments of the future. Research into obesity has escalated at considerable pace, catalysed by the discovery of the obese gene product leptin. Leptin is secreted by adipose tissue and acts via specific receptors in the brain to engage central neural pathways involved in regulating energy homeostasis. Since this discovery, numerous significant advances have been made in our understanding of how the brain integrates and responds to central and peripheral signals involved in maintaining energy homeostasis, and how disruption of these signalling mechanisms can manifest as obesity. As a consequence of these findings, numerous potential sites for therapeutic intervention into this condition have and are materialising. The aim of this review is to highlight current treatment strategies for obesity, recent advances in our understanding of the central neural control of energy balance, and what the authors consider to be the most promising targets for the development of novel antiobesity drugs in the future. Thus, the review focuses on leptin, neuropeptide Y, melanocortin and ghrelin signalling at the level of the CNS, and strategies targeting the sympathetic innervation of fat cells at the periphery.     

Obesity and the hepatic control of feeding behavior

Despite its well-established role in the control of food intake, the liver has not been a target for the development of drugs to modulate appetite and treat obesity. This paper provides an overview of the hepatic control of food intake and focuses in particular on how it may play a part in overeating and body weight gain. Signals from the liver that control feeding behavior are triggered in response to changes in liver energy status and are carried to the brain by vagal sensory neurons. Consumption of diets rich in fat and carbohydrate is a major contributing cause of overeating and obesity, and susceptibility to such diet-induced obesity is associated with a reduced capacity for fat oxidation. Inhibition of fatty acid oxidation in the liver stimulates food intake by decreasing liver ATP production, suggesting that low liver energy status may contribute to diet-induced overeating and obesity. These findings raise the possibility that liver energy production, the mechanisms that transduce changes in hepatic energy status into neural signals or hepatic vagal afferent activity may provide new targets for the development of drugs for appetite control and obesity.     

Emerging antiobesity drugs

The healthcare burden that the obesity epidemic now poses in highly significant, in part due to increased risk of secondary chronic diseases such as hypertension. A lack of physical activity and high fat diets are major factors contributing to this condition. However, increasingly apparent is the genetic predisposition of individuals and ethnic groups to obesity. Present treatment strategies are currently inadequate and unlikely to have a major effect on the future prevalence of obesity. To slow the obesity epidemic, the source needs to be tackled now through fundamental research into the mechanisms by which obesity is manifest, and education on the risks and how to prevent it. This article will describe current and emerging treatments for obesity and review the recent advances in research that may provide the antiobesity treatments of the future. Research into obesity has escalated at considerable pace, catalysed by the discovery of the obese gene product leptin. Leptin is secreted by adipose tissue and acts via specific receptors in the brain to engage central neural pathways involved in regulating energy homeostasis. Since this discovery, numerous significant advances have been made in our understanding of how the brain integrates and responds to central and peripheral signals involved in maintaining energy homeostasis, and how disruption of these signalling mechanisms can manifest as obesity. As a consequence of these findings, numerous potential sites for therapeutic intervention into this condition have and are materializing. The aim of this review is to highlight current treatment strategies for obesity, recent advances in our understanding of the central neural control of energy balance, and what the authors consider to be the most promising targets for the development of novel antiobesity drugs in the future. Thus, the review focuses on leptin, neuropeptide Y, melanocortin and ghrelin signalling at the level of the CNS, and strategies targeting the sympathetic innervation of fat cells at the periphery.     

Aquaporin-7 and glycerol permeability as novel obesity drug-target pathways

Advances in determining the mechanisms that underlie the control of energy balance in mammals have recently been provided by the discovery and characterization of aquaporin-7 (AQP7), a water-glycerol transporter that is present in the plasma membrane of fat-storing cells (adipocytes). Recent studies have shown that the absence of AQP7 expression in fat cells increases glycerol kinase activity, boosting triacylglycerol synthesis and ultimately leading to obesity. Thus, AQP7 operates as a glycerol channel in vivo, whereby adipocyte glycerol permeability has a key role in the regulation of fat accumulation.     

Lipogenic enzymes as therapeutic targets for obesity and diabetes

Since storage of excess fat in peripheral tissues is a contributing factor leading to obesity and type II diabetes, many investigators are studying the key lipid metabolizing enzymes found in adipose tissue as drug targets to reduce excess fat. The availability of cultured cell lines and primary stem cells, preadipocyetes, and adipocytes has facilitated therapeutic approaches aimed at targeting fat storage. This includes developing inhibitors for enzymes regulating lipogenesis in these cells, such as acetyl-CoA carboxylase, fatty acid synthase, diacylgycerol acyl transferase, and stearoyl CoA desaturase. High level expression of each protein is often used to confirm stem cells have undergone adipogenesis. Inhibition of these enzymes often leads to reduced fat cell fat differentiation and lipid synthesis and may also contribute to increased fat oxidation and energy expenditure. This article reviews developments in pharmaceutical research on these enzymes, with particular emphasis on the role of the enzymes in adipose tissue metabolism.     

Natural inhibitors of pancreatic lipase as new players in obesity treatment

Obesity is a multifactorial disease characterized by an excessive weight for height due to an enlarged fat deposition such as adipose tissue, which is attributed to a higher calorie intake than the energy expenditure. The key strategy to combat obesity is to prevent chronic positive impairments in the energy equation. However, it is often difficult to maintain energy balance, because many available foods are high-energy yielding, which is usually accompanied by low levels of physical activity. The pharmaceutical industry has invested many efforts in producing antiobesity drugs; but only a lipid digestion inhibitor obtained from an actinobacterium is currently approved and authorized in Europe for obesity treatment. This compound inhibits the activity of pancreatic lipase, which is one of the enzymes involved in fat digestion. In a similar way, hundreds of extracts are currently being isolated from plants, fungi, algae, or bacteria and screened for their potential inhibition of pancreatic lipase activity. Among them, extracts isolated from common foodstuffs such as tea, soybean, ginseng, yerba mate, peanut, apple, or grapevine have been reported. Some of them are polyphenols and saponins with an inhibitory effect on pancreatic lipase activity, which could be applied in the management of the obesity epidemic.     

Human genomics and obesity: finding appropriate drug targets

The increasing prevalence of obesity worldwide has prompted the World Health Organization (WHO) to classify it as a global epidemic. Around the globe, more than a half billion people are overweight, and the chronic disease of obesity represents a major threat to health care systems in developed and developing countries. The major health hazards associated with obesity are the risks of developing diabetes, cardiovascular disease, stroke, osteoarthritis and some forms of cancer. In this paper, we review the prevalence of obesity and its cost to health care systems and present the relative contribution of environmental conditions and genetic makeup to the development of obesity in people. We also discuss the concept of “essential” obesity in an “obesigenic” environment. Though weight gain results from a sustained imbalance between energy intake and energy expenditure, it is only recently that studies have identified important new mechanisms involved in the regulation of body weight. The etiology of the disease is presented as a feedback model in which afferent signals inform the central controllers in the brain as to the state of the external and internal environment and elicit responses related to the regulation of food intake and energy metabolism. Pharmaceutical agents may intervene at different levels of this feedback model, i.e., reinforce the afferent signals from the periphery, target the central pathways involved in the regulation of food intake and energy expenditure, and increase peripheral energy expenditure and fat oxidation directly. Since obesity results from genetic predisposition, combined with the proactive environmental situation, we discuss new potential targets for generation of drugs that may assist people in gaining control over appetite as well as increasing total energy expenditure and fat oxidation.     

Recent advances in human brown fat physiology

Of the two variants of adipose tissue, white fat is traditionally known as a lipid rich tissue which undergoes pathological expansion in obese conditions. To counter the excess accumulation of white fat in states of energy imbalance, the second and unique type of brown fat plays a key role by burning extra energy into heat through a special metabolic pathway. In addition brown fat also plays a vital role in thermoregulation in animals and newborn humans and infants. Recent progress in research areas of these two types of fat tissue has provided compelling evidence to show that they secrete a large number of chemicals that play an important role in body weight control that involves several mechanisms. Brown fat was considered absent in the adult humans until recently. But new techniques have provided ample support for its active existence. Based on the very recent data it has been suggested that brown fat can be a target organ in the treatment of obesity which can lead to exciting and informative outcomes in the future.     

The discovery of drugs for obesity,the metabolic effects of leptin and variable receptor pharmacology: perspectives from β<Subscript>3</Subscript>-adrenoceptor agonists

Although beta3-adrenoceptor (beta3AR) agonists have not become drugs for the treatment of obesity or diabetes, they offer perspectives on obesity drug discovery, the physiology of energy expenditure and receptor pharmacology. beta3AR agonists, some of which also stimulate other betaARs in humans, selectively stimulate fat oxidation in rodents and humans. This appears to be why they improve insulin sensitivity and reduce body fat whilst preserving lean body mass. Regulatory authorities ask that novel anti-obesity drugs improve insulin sensitivity and reduce mainly body fat. Drugs that act on different targets to stimulate fat oxidation may also offer these benefits. Stimulation of energy expenditure may be easy to detect only when the sympathetic nervous system is activated. Leptin resembles beta3AR agonists in that it increases fat oxidation, energy expenditure and insulin sensitivity. This is partly because it raises sympathetic activity, but it may also promote fat oxidation by directly stimulating muscle leptin receptors. The beta1AR and beta2AR can, like the beta3AR, display atypical pharmacologies. Moreover, the beta3AR can display variable pharmacologies of its own, depending on the radioligand used in binding studies or the functional response measured. Studies on the beta3AR demonstrate both the difficulties of predicting the in vivo effects of agonist drugs from in vitro data and that there may be opportunities for identifying drugs that act at a single receptor but have different profiles in vivo.     

Novel effects of macrostemonoside A, a compound from Allium macrostemon Bung, on hyperglycemia, hyperlipidemia, and visceral obesity in high-fat diet-fed C57BL/6 mice

Macrostemonoside A, a newly found compound, is derived from Allium macrostemon Bung. However, investigation into its nature is lacking. In this study, the effects of macrostemonoside A on hyperglycemia, hyperlipidemia, visceral fat accumulation, and related enzyme activities in high-fat diet-fed C57BL/6 mice are examined. The results showed that mice fed with a high-fat diet had a significant increase in fasting blood glucose, liver glycogen, serum total cholesterol, and visceral fat accumulation, but were mildly or moderately inhibited by macrostemonoside A at a dose of 4 mg/kg/d after 30 days of treatment. This hypoglycemic effect might be associated with the potential increase in insulin sensitivity and visfatin expression, although it needs further validation in future studies. Its anti-obesity effect might be associated with elevated total lipase activity in visceral adipose cells. The up-regulation in the expression of peroxisome proliferators-activated receptor gamma 2 might be responsible for the increased lipase activity in visceral adipose cells. Furthermore, we supposed that its action mechanisms might promote energy metabolism in muscles. Macrostemonoside A, with its steroid-like structure, has no significant cortisone-like side effects on the immune system but has potential cardiovascular protective effects. These results suggested that a potential compound to treat hyperglycemia, hyperlipidemia, and visceral obesity could be developed. However, its underlying mechanisms need further investigation in future studies.