Adipokine在肥胖症及胰岛素抵抗中的作用（综述）

从Adipokines与胰岛素抵抗的关系,Adipokines与肥胖者脂肪组织巨噬细胞浸润,炎症与胰岛素抵抗信号转导,内质网应激与胰岛素抵抗等方面综述了Adipokines在肥胖症及胰岛素抵抗中的作用;并着重探讨了肥胖,adipokines,炎症,胰岛素抵抗四者之间的关系。     

脂肪组织功能紊乱与肥胖和糖尿病

脂肪组织是机体的重要器官,主要负责能量的储存和代谢,同时分泌多种激素和细胞因子,参与机体生理功能的调控。近年来的研究表明脂肪组织的功能紊乱与肥胖和糖尿病密切相关,为进一步探讨两者的关系,综述了脂肪组织的生理和内分泌功能以及脂肪组织功能紊乱与胰岛素抵抗、肥胖和糖尿病发生、发展的关系。     

脂联素受体与2型糖尿病

脂联素（Adiponectin）是脂肪组织分泌的一种脂肪细胞因子,具有增加脂肪酸氧化、提高葡萄糖摄取量、改善胰岛素抵抗、调控血管内皮的炎症反应等作用。正常人血浆中脂联素浓度与体质量指数（BMI）、腰臀比、空腹血糖、空腹胰岛素、甘油三酯、尿酸和瘦素呈负相关。脂联素还与肥胖、胰岛素抵抗、2型糖尿病和心血管疾病密切相关。     

中等负荷运动对胰岛素抵抗大鼠脾脏DC影响的研究

通过运动干预高脂饮食诱发的胰岛素抵抗大鼠,了解运动对其树突状细胞形态和功能的影响,旨在探讨运动在免疫中的作用,为运动免疫提供理论支持。结果显示:较长周期的中等负荷的运动干预可以使高脂饮食诱发的胰岛素抵抗大鼠树突状细胞形态结构和功能得到一定恢复;其机理可能是通过运动降低血糖水平、改善降低胰岛素抵抗,减少机体脂肪组织,降低低度炎症,提高机体免疫力的结论。     

美科学家发现抑制肥胖新方法

正人体内的白色脂肪储存过多热量,与肥胖密切相关;而棕色脂肪燃烧卡路里以产生热量,已成为消除肥胖的潜在手段。美国布朗大学科学家发现一种叫做SNRK的酶能够抑制白色脂肪中的炎症,同时提高棕色脂肪代谢,SNRK成为抑制肥胖的研究对象。研究人员认为,如果能找到一种方法来提高脂肪组织SNRK的含量,那么可能会有双重好处——减少白色脂肪中的炎症可以缓解相关的并发症,如胰岛素抵抗,而增加棕色脂肪代谢可有助于减轻体重,但还须进一步人体研究来证实这些可能性。研究论文发表在《糖尿病》杂志上。     

Chemerin、肥胖与运动研究进展

Chemerin主要由脂肪细胞分泌的新型脂肪细胞因子,具有多种生物学功能,在肥胖和胰岛素抵抗中发挥一定生理效应。本文主要从Chemerin与肥胖、胰岛素抵抗、2型糖尿病、炎症的关系及运动对Chemerin的影响进行综述,为肥胖及肥胖相关疾病的运动治疗提供理论依据。     

高热量日粮与胰岛素抵抗动物模型

胰岛素抵抗（IR）是指胰岛素作用的靶器官、组织（主要是肝脏、骨骼肌、脂肪组织）对胰岛素的敏感性降低的一种异常状态,即需要高于正常剂量的胰岛素才能产生正常的生理效应。IR在代谢综合症中的核心作用已得到广泛认可。它不仅与肥胖、高血压、动脉硬化、脂代谢异常等代谢性疾病的发生、发展有密切联系,同时也存在于妊娠、肿瘤、感染、炎症、应激等多种生理或病理状态。     

肥胖抵抗现象及其机制研究

随着肥胖症在全球迅速蔓延,国内外学者对肥胖的研究也逐渐深入,食源性肥胖抵抗（diet-induced obesity resistance,DIO-R）表现为肥胖易感程度低,与肥胖机体相比能量代谢状况较好,是机体能量代谢研究中较新的研究方向。本研究探讨了现阶段国内外肥胖抵抗大鼠的主要筛选方法,就食源性肥胖抵抗与食源性肥胖（diet-induced obesity,DIO）机体代谢差异最新研究成果进行综述,从瘦素敏感性、胰岛素敏感性、脂联素水平、食物利用率等方面分析了肥胖抵抗现象的发生机制,并从运动生理生化的角度提出现阶段肥胖抵抗研究存在的问题,对肥胖抵抗大鼠代谢及机制差异的研究前景进行展望。     

小麦烷基间苯二酚对3T3-L1脂肪细胞胰岛素抵抗改善作用及机制

低度慢性炎症状态是肥胖导致机体胰岛素抵抗的重要原因之一。小麦烷基间苯二酚(alkylresorcinols, ARs)是全麦食品膳食的生物标记物和重要的活性功能成分。利用体外炎症因子诱导,建立3T3-L1成熟脂肪细胞胰岛素抵抗模型,通过检测脂肪细胞脂质分解和葡萄糖吸收与利用情况,探讨小麦ARs在炎症状态下对脂肪细胞胰岛素抵抗的保护机制。研究结果表明:不同浓度小麦ARs(5~20μmol/L)干预能够剂量依赖性地改善炎症因子诱导的3T3-L1脂肪细胞胰岛素抵抗,脂肪细胞对葡萄糖利用率分别提升了4.3%、10.2% 和24.0%;小麦ARs可以显著缓解炎症因子导致的脂肪细胞脂质分解。进一步机制解析发现:炎症因子显著降低了脂肪细胞糖代谢两个关键蛋白Akt的磷酸化(p-Akt)及其下游GLUT4蛋白表达,导致其葡萄糖利用障碍,而ARs干预显著提升了这两个蛋白的表达;采用PI3K抑制剂(LY294002)预处理脂肪细胞后,ARs 对于脂肪细胞p-Akt及GLUT4表达的增加被抑制,相应的对于葡萄糖吸收的改善作用也被显著降低,脂肪细胞脂质分解增加,表明ARs通过特异性激活p-Akt/GLUT4信号通路改善了3T3-L1脂肪细胞胰岛素抵抗。最后,研究了小麦ARs的5种主要单体成分分别对于脂肪细胞胰岛素抵抗的改善作用,结果表明,十七烷基间苯二酚是小麦ARs发挥生理功能的主要活性物质。     

肥胖大鼠低氧训练中羟自由基与胰岛素抵抗相关性研究

为明确不同模式的低氧训练对肥胖大鼠自由基代谢的影响，探讨低氧训练过程中自由基代谢与胰岛素敏感性的关系，构建肥胖大鼠模型，进行4周的低氧训练干预，定期称量，实验末称量并统计其体脂，测定血清胰岛素、血糖、羟自由基和过氧化氢酶水平，统计各实验组胰岛素抵抗指数。实验结果表明，低氧暴露有利于机体胰岛素敏感性的提高，抗氧化酶的活性的降低可能与机体胰岛素敏感性有一定关系。     

Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance

Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.     

PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells

Obesity and type-2 diabetes have increased markedly over the past few decades, in parallel. One of the major links between these two disorders is chronic, low-grade inflammation. Prolonged nutrient excess promotes the accumulation and activation of leukocytes in visceral adipose tissue (VAT) and ultimately other tissues, leading to metabolic abnormalities such as insulin resistance, type-2 diabetes and fatty-liver disease. Although invasion of VAT by pro-inflammatory macrophages is considered to be a key event driving adipose-tissue inflammation and insulin resistance, little is known about the roles of other immune system cell types in these processes. A unique population of VAT-resident regulatory T (Treg) cells was recently implicated in control of the inflammatory state of adipose tissue and, thereby, insulin sensitivity. Here we identify peroxisome proliferator-activated receptor (PPAR)-γ, the 'master regulator' of adipocyte differentiation, as a crucial molecular orchestrator of VAT Treg cell accumulation, phenotype and function. Unexpectedly, PPAR-γ expression by VAT Treg cells was necessary for complete restoration of insulin sensitivity in obese mice by the thiazolidinedione drug pioglitazone. These findings suggest a previously unknown cellular mechanism for this important class of thiazolidinedione drugs, and provide proof-of-principle that discrete populations of Treg cells with unique functions can be precisely targeted to therapeutic ends.     

Mechanisms linking obesity to insulin resistance and type 2 diabetes

Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes. In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance. When insulin resistance is accompanied by dysfunction of pancreatic islet beta-cells - the cells that release insulin - failure to control blood glucose levels results. Abnormalities in beta-cell function are therefore critical in defining the risk and development of type 2 diabetes. This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention.     

Mechanisms linking obesity with cardiovascular disease

Obesity increases the risk of cardiovascular disease and premature death. Adipose tissue releases a large number of bioactive mediators that influence not only body weight homeostasis but also insulin resistance - the core feature of type 2 diabetes - as well as alterations in lipids, blood pressure, coagulation, fibrinolysis and inflammation, leading to endothelial dysfunction and atherosclerosis. We are now beginning to understand the underlying mechanisms as well as the ways in which smoking and dyslipidaemia increase, and physical activity attenuates, the adverse effects of obesity on cardiovascular health.     

Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver

The earliest defect in developing type 2 diabetes is insulin resistance, characterized by decreased glucose transport and metabolism in muscle and adipocytes. The glucose transporter GLUT4 mediates insulin-stimulated glucose uptake in adipocytes and muscle by rapidly moving from intracellular storage sites to the plasma membrane. In insulin-resistant states such as obesity and type 2 diabetes, GLUT4 expression is decreased in adipose tissue but preserved in muscle. Because skeletal muscle is the main site of insulin-stimulated glucose uptake, the role of adipose tissue GLUT4 downregulation in the pathogenesis of insulin resistance and diabetes is unclear. To determine the role of adipose GLUT4 in glucose homeostasis, we used Cre/loxP DNA recombination to generate mice with adipose-selective reduction of GLUT4 (G4A-/-). Here we show that these mice have normal growth and adipose mass despite markedly impaired insulin-stimulated glucose uptake in adipocytes. Although GLUT4 expression is preserved in muscle, these mice develop insulin resistance in muscle and liver, manifested by decreased biological responses and impaired activation of phosphoinositide-3-OH kinase. G4A-/- mice develop glucose intolerance and hyperinsulinaemia. Thus, downregulation of GLUT4 and glucose transport selectively in adipose tissue can cause insulin resistance and thereby increase the risk of developing diabetes.     

Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by a paucity of adipose (fat) tissue which is evident at birth and is accompanied by a severe resistance to insulin, leading to hyperinsulinaemia, hyperglycaemia and enlarged fatty liver. We have developed a mouse model that mimics these features of CGL: the syndrome occurs in transgenic mice expressing a truncated version of a nuclear protein known as nSREBP-1c (for sterol-regulatory-element-binding protein-1c) under the control of the adipose-specific aP2 enhancer. Adipose tissue from these mice was markedly deficient in messenger RNAs encoding several fat-specific proteins, including leptin, a fat-derived hormone that regulates food intake and energy metabolism. Here we show that insulin resistance in our lipodystrophic mice can be overcome by a continuous systemic infusion of low doses of recombinant leptin, an effect that is not mimicked by chronic food restriction. Our results support the idea that leptin modulates insulin sensitivity and glucose disposal independently of its effect on food intake, and that leptin deficiency accounts for the insulin resistance found in CGL.     

基因芯片研究小檗碱对胰岛素抵抗卵巢颗粒细胞基因表达的影响

应用基因芯片技术研究小檗碱对胰岛素抵抗卵巢颗粒细胞基因表达谱的影响。方法采用胰岛素信号转导通路调节糖代谢的关键分子——PI-3K的特异性阻断剂沃漫青霉素作用于猪卵巢颗粒细胞,人工诱导胰岛素抵抗(IR)的细胞模型;同时应用小檗碱作用在细胞模型上,作用48h后提取细胞总RNA,应用猪全基因组单通道芯片对样本基因进行筛查,得出差异表达基因数据并进行分析。结果显示,中药小檗碱作用模型细胞后差异表达基因42个。差异表达基因主要涉及的功能有:物质代谢、炎症与免疫反应、信号转导等。由此可得出结论:小檗碱可通过多种途径在基因水平上对胰岛素抵抗卵巢颗粒细胞起作用。     

Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.