Inflammation and metabolic disorders

Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.     

单纯性肥胖的主要原因与运动减肥原理

单纯性肥胖是一种现代“     

代谢综合症的运动干预

随着社会的发展和人们生活方式的改变,代谢综合症(MS)从1999年命名至今,发病率逐年升高。MS会并发T2DM、心血管疾病、肥胖等疾病,严重影响人们的生活质量甚至危及生命。MS治疗的基本策略是以改善IR为基础的心血管危险因素的综合防治。包括生活方式干预、饮食控制和运动治疗,无效时考虑药物治疗。运动作为MS的重要干预手段,对MS有着显著的影响,本文就MS与运动之间的关系做一综述。     

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.     

Functional interactions between the gut microbiota and host metabolism

The link between the microbes in the human gut and the development of obesity, cardiovascular disease and metabolic syndromes, such as type 2 diabetes, is becoming clearer. However, because of the complexity of the microbial community, the functional connections are less well understood. Studies in both mice and humans are helping to show what effect the gut microbiota has on host metabolism by improving energy yield from food and modulating dietary or the host-derived compounds that alter host metabolic pathways. Through increased knowledge of the mechanisms involved in the interactions between the microbiota and its host, we will be in a better position to develop treatments for metabolic disease.     

代谢综合征左心功能研究进展

 简述了代谢综合征(metalbolic syndrome,MS)的定义及临床诊断标准,综述了高血压(EH)、肥胖、血糖异常、血脂异常等危险因素与左室心功能间的关系,分析了多种危险因素聚集一体的MS 的心功能变化特点。MS 患者的左室功能降低是由多个心血管危险因素引起,会导致多个复杂的代谢反应,影响心肌的结构和代谢环境,也改变了心肌功能和心肌能量。因此MS 患者在有症状的心力衰竭发展之前,可能存在一段时间亚临床的左心室功能障碍。     

肥胖的风险与平板运动心电图诊断(综述)

通过文献资料法、实践观察法等研究方法研究了肥胖引起的合并症、肥胖患者在运动中存在的风险、以及肥胖的治疗和预防。研究结果发现,近年来肥胖的现象在全球越来越普遍,由于生活习惯等因素的改变,出现很大一部分超重或者肥胖的人群。这些人群可能出现冠心病、Ⅱ型糖尿病、胰岛素抵抗、高胰岛素血症、脂肪肝等各种合并症,并且在运动中存在潜在危险。平板运动心电图试验是诊断冠心病、评价心功能和运动耐力的简便有效的方法,通过试验可以诱发心律失常状况,或加重心血管疾病的某些症状,从而发现具有运动风险的人群,并对其运动负荷和持续时间提供指导。治疗和预防肥胖需要家庭、学校、工作场所、社区等多方面的支持。     

Dynamics of fat cell turnover in humans

Obesity is increasing in an epidemic manner in most countries and constitutes a public health problem by enhancing the risk for cardiovascular disease and metabolic disorders such as type 2 diabetes. Owing to the increase in obesity, life expectancy may start to decrease in developed countries for the first time in recent history. The factors determining fat mass in adult humans are not fully understood, but increased lipid storage in already developed fat cells (adipocytes) is thought to be most important. Here we show that adipocyte number is a major determinant for the fat mass in adults. However, the number of fat cells stays constant in adulthood in lean and obese individuals, even after marked weight loss, indicating that the number of adipocytes is set during childhood and adolescence. To establish the dynamics within the stable population of adipocytes in adults, we have measured adipocyte turnover by analysing the integration of 14C derived from nuclear bomb tests in genomic DNA. Approximately 10% of fat cells are renewed annually at all adult ages and levels of body mass index. Neither adipocyte death nor generation rate is altered in early onset obesity, suggesting a tight regulation of fat cell number in this condition during adulthood. The high turnover of adipocytes establishes a new therapeutic target for pharmacological intervention in obesity.     

Human metabolic individuality in biomedical and pharmaceutical research

Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.     

Obesity as a medical problem

Obesity is now so common within the world's population that it is beginning to replace undernutrition and infectious diseases as the most significant contributor to ill health. In particular, obesity is associated with diabetes mellitus, coronary heart disease, certain forms of cancer, and sleep-breathing disorders. Obesity is defined by a body-mass index (weight divided by square of the height) of 30 kg m(-2) or greater, but this does not take into account the morbidity and mortality associated with more modest degrees of overweight, nor the detrimental effect of intra-abdominal fat. The global epidemic of obesity results from a combination of genetic susceptibility, increased availability of high-energy foods and decreased requirement for physical activity in modern society. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals, but an epidemic that threatens global well being.     

The search for new cardiovascular biomarkers

Despite considerable advances in the treatment of cardiovascular disease, it remains the leading cause of death in developed countries. Assessment of classic cardiovascular risk factors--including high blood pressure, diabetes and smoking--has a central role in disease prevention. However, many individuals with coronary heart disease (a narrowing of the blood vessels that supply the heart) have only one, or none, of the classic risk factors. Thus, new biomarkers are needed to augment the information obtained from traditional indicators and to illuminate disease mechanisms.     

游泳运动综合干预对肥胖青少年脑代谢的影响

研究游泳运动综合干预对肥胖青少年脑代谢的改善性作用,可以预防和治疗肥胖相关的消化系统疾病,改善肥胖青少年的膳食功能。通过测定青少年肥胖患者脑代谢和肺活量指数血压指数、采用荧光滴定的方法测定Gn-NA(n=1~3)在甲醇/DMSO的含量进行脑代谢特征分析,最后通过K-center算法构建全方位(holo-directed)和半方位(hemi-directed)的肥胖患者的碳酸酐酶水链,建立了游泳运动综合干预下肥胖患者的脑代谢功能改善的相关因素模型。实验结果表明:通过分析游泳运动综合干预对肥胖青少年脑代谢的影响,准确把握了肥胖人群的青少年肥胖患者脑代谢变化水平。模型中青少年肥胖患者脑代谢分布速率收敛,通过游泳运动有效增加脂肪燃烧速率,保证了身体健康,预防了相关的肥胖综合症疾病的发生,在临床实践中具有重要的指导意义。     

Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet the causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models reveal that inflammasome-deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic tumour-necrosis factor (TNF)-α expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders.     

肠道菌群调控脂质代谢的分子机制

人类肠道菌群基因组又被称为“人类第二基因组” ,其在人体脂肪的分解合成过程中起到了重要的调控作用。 体内肠道菌群的失调,会引起肥胖、糖尿病等在内的代谢综合症的发生。 本文从肠道菌群通过调控在脂质代谢中 起重要作用的酶类和调控因子从而为机体提供能量、减脂和改善健康状况的研究进展方面进行了综述。     

Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring

The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic. Having either parent obese is an independent risk factor for childhood obesity. Although the detrimental impacts of diet-induced maternal obesity on adiposity and metabolism in offspring are well established, the extent of any contribution of obese fathers is unclear, particularly the role of non-genetic factors in the causal pathway. Here we show that paternal high-fat-diet (HFD) exposure programs β-cell 'dysfunction' in rat F(1) female offspring. Chronic HFD consumption in Sprague-Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time, and normal adiposity. Paternal HFD altered the expression of 642 pancreatic islet genes in adult female offspring (P?相似文献   

The hormone resistin links obesity to diabetes

Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.     

Variations in DNA elucidate molecular networks that cause disease

Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors.     

基于核磁共振的肾虚痰瘀型2型糖尿病患者血清代谢组学研究

 利用核磁共振技术(Nuclear Magnetic Resonance,NMR)探讨肾虚痰瘀型2型糖尿病患者的血清代谢变化及发生机制。对33例肾虚痰瘀型2型糖尿病患者和50例健康人血清进行核磁共振氢谱检测,通过分段积分后运用正交偏最小二乘判别(OPLS-DA)分析所采集的图谱。结果显示,肾虚痰瘀型2型糖尿病患者与健康人相比血清中多种氨基酸显著降低,包括异亮氨酸、亮氨酸、缬氨酸、丙氨酸、谷氨酸、组氨酸、酪氨酸、苯丙氨酸、1-甲基组氨酸,差异有统计学意义(P<0.05)。此外,乳酸、柠檬酸、肌酸及肌酸酐也较健康人显著降低,差异有统计学意义(P<0.05)。同时,肾虚痰瘀型2型糖尿病患者血清中α-葡萄糖及β-葡萄糖较健康人增加,差异有统计学意义(P<0.05)。由此得出结论,肾虚痰瘀型2型糖尿病患者代谢成分与健康人存在显著差异,肾虚痰瘀型2型糖尿病患者体内的三羧酸循环及糖酵解途径被抑制,蛋白质代谢异常,支链氨基酸代谢增强。     

Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2

Adipocyte fatty-acid-binding protein, aP2 (FABP4) is expressed in adipocytes and macrophages, and integrates inflammatory and metabolic responses. Studies in aP2-deficient mice have shown that this lipid chaperone has a significant role in several aspects of metabolic syndrome, including type 2 diabetes and atherosclerosis. Here we demonstrate that an orally active small-molecule inhibitor of aP2 is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. In macrophage and adipocyte cell lines with or without aP2, we also show the target specificity of this chemical intervention and its mechanisms of action on metabolic and inflammatory pathways. Our findings demonstrate that targeting aP2 with small-molecule inhibitors is possible and can lead to a new class of powerful therapeutic agents to prevent and treat metabolic diseases such as type 2 diabetes and atherosclerosis.