抵抗素与2型糖尿病及合并冠心病研究进展

2型糖尿病是一种受多因子影响的复杂性疾病,常合并心血管病变。近年来的研究表明,脂肪组织具有旺盛的内分泌功能。现已发现人脂肪细胞分泌几十种脂肪细胞因子及蛋白质因子。这些脂肪细胞因子具有广泛的生物学特性。近年来研究发现众多细胞因子如瘦素、抵抗素、脂联素、白介素、肿瘤坏死因子等可能对胰岛素敏感性、糖代谢、2型糖尿病及其大血管并发症的发生、发展有一定的作用。     

非酒精性脂肪性肝炎发病机制的研究进展

非酒精性脂肪性肝炎(NASH)是以肝细胞丧失、脂肪变性、气球样变、炎性坏死及纤维化形成为特征的病理状态.NASH常见于2型糖尿病、高血压、高脂血症及肥胖患者.新近的一些研究着重于胰岛素抵抗、氧应激及脂质过氧化损伤、促炎症细胞因子、脂肪细胞因子以及线粒体功能障碍在NASH发生发展中的作用.本文系统阐述了胰岛素抵抗、氧应激及脂质过氧化损伤、炎症细胞因子、抵抗素、瘦素、脂联素、PPAR-α等脂肪因子,细胞凋亡、NF-κB、SREBP-1c、肠源性内毒素血症以及铁超载等在NASH发病机制中的作用.NASH的致病机制主要与胰岛素抵抗、氧应激及脂质过氧化损伤有关,而脂肪细胞因子通过其内分泌和旁分泌间的复杂相互作用也在NASH的发病机制中起重要作用.这些发病机制的最新进展为NASH的针对性治疗提供了新的思路.     

脂肪细胞因子的临床和基础研究

脂肪组织具有旺盛的内分泌功能。其分泌的细胞因子可分为脂肪组织特异表达的脂肪因子如瘦素、脂联素和非特异表达的脂肪因子如多种炎症因子。近年新的脂肪因子不断被发现如内脏脂肪素等,同时已肯定脂肪因子参与体内多种代谢活动,尤其是与胰岛素抵抗的发生等密切相关。此外,脂肪因子的新的功能也不断被挖掘,其在体内的作用越来越重要。本文将结合本课题组对脂肪因子的临床和基础研究,介绍脂肪内分泌功能和脂肪因子作用等的进展。     

2型糖尿病家系一级亲属脂肪细胞因子变化特点及影响因素的研究进展

脂肪细胞因子是脂肪组织产生的一系列具有生物活性的细胞因子,参与体内能量代谢、免疫、内分泌等生理活动,在代谢平衡的调控过程中起到重要作用。2型糖尿病家系一级亲属作为糖尿病的高危人群,常伴有脂肪细胞因子分泌异常,本文就其体内脂肪细胞因子变化特点及影响因素的研究进展作一综述。     

脂肪细胞因子的临床和基础研究

脂肪组织具有旺盛的内分泌功能。其分泌的细胞因子可分为脂肪组织特异表达的脂肪因子如瘦素、脂联素和非特异表达的脂肪因子如多种炎症因子。近年新的脂肪因子不断被发现如内脏脂肪素等，同时已肯定脂肪因子参与体内多种代谢活动，尤其是与胰岛素抵抗的发生等密切相关。此外，脂肪因子的新的功能也不断被挖掘，其在体内的作用越来越重要。本文将结合本课题组对脂肪因子的临床和基础研究，介绍脂肪内分泌功能和脂肪因子作用等的进展。     

细胞因子与脂肪性肝炎

脂肪性肝炎 (ｓｔｅａｔｏｈｅｐａｔｉｔｉｓ)是一种继发于肝脂肪变性和细胞损伤的炎症和纤维化状态。按其病因分为非酒精性脂肪性肝炎 (ｎｏｎａｌｃｏｈｏｌｉｃｓｔｅａｔｏｈｅｐａｔｉｔｉｓ ,ＮＡＳＨ)和酒精性肝炎 (ａｌｃｏｈｏｌｉｃｈｅｐａｔｉｔｉｓ ,ＡＨ)。其病因及发病机制比较复杂 ,至今尚未完全阐明。近来细胞因子 (ＣＫ )在肝脏疾病中的作用已受到密切关注 ,从肝细胞脂肪变性到脂肪性肝炎、肝纤维化及肝硬化的进展中 ,细胞因子都起重要作用[1] 。参与肝脏疾病的细胞因子主要有 :①致炎ＣＫ ,如ＴＮＦ α、ＩＬ 1、ＩＬ 1…     

脂肪细胞因子与胰岛素抵抗

脂肪细胞因子是指从脂肪组织分离的生物活性分子,包括细胞因子、生长因子、炎性蛋白等,与肥胖、胰岛素抵抗等密切相关.胰岛素与靶细胞膜上特异受体结合后发挥正常的信号转导作用,而该转导途径直接或者间接地受大部分脂肪细胞因子的负件调节,导致机体出现胰岛素抵抗及其相父疾病.本文综述了胰岛素信号转导作用、代谢综合征患者血浆脂肪细胞因子水平的变化以及脂肪细胞因子调节胰岛素信号转导的机制.     

内脏脂肪素在心血管系统的研究进展

脂肪组织作为一个内分泌器官,可以分泌诸多的脂肪细胞因子,如脂联素和瘦素等。内脏脂肪素(Visfatin)是最近新发现的一个脂肪细胞因子,作用于胰岛素受体而发挥类胰岛素样作用。参与氧化、内皮功能紊乱、血管再生、冠状动脉粥样硬化(AS)和缺血再灌注损伤等心血管系统的病理生理过程,并与高血压、糖脂代谢紊乱和肥胖等密切相关,可能作为代谢综合征和心血管疾病的枢纽。现就其在此方面的研究进展综述如下。     

胰岛素抵抗的炎症机制

研究证明胰岛素抵抗是一个慢性亚临床炎症过程 ,细胞因子肿瘤坏死因子 (TNF)α和白介素 (IL) 6都能减低机体组织细胞对胰岛素的敏感性 ,来自脂肪等组织的细胞因子和炎症敏感蛋白如IL 8、抵抗素、脂联素、C反应蛋白和纤溶酶原激活物抑制剂 (PAI) 1等对胰岛素抵抗的发生也有重要作用。另一方面 ,在胰岛素抵抗时脂肪组织、骨骼肌细胞、肝脏和动脉血管组织都不同程度地增加一些细胞因子的表达 ,这些细胞因子通过内分泌、旁分泌和自分泌机制进一步减低组织细胞对胰岛素的敏感性。通过对胰岛素抵抗炎症机制的认识 ,有助于对这些代谢性疾病的发生和发展进行预测、动态观察和干预治疗。     

Chemerin:一个新的脂肪细胞因子

Chemerin(趋化素)是新发现的脂肪细胞因子,它可由脂肪细胞分泌,通过自分泌途径作用于自身受体CMKLR1,促进脂肪细胞分化及葡萄糖转运,并可通过旁分泌途径作用于炎性反应细胞(如巨噬细胞).从而对脂肪组织及脂质代谢产生一系列影响,提示chemerin可能在肥胖及胰岛素抵抗中起重要作用.本文就chemerin及其受体CMKLR1的结构、分布及产生作用的可能机制进行综述.     

A role for novel adipose tissue‐secreted factors in obesity‐related carcinogenesis

Obesity, a pandemic disease, is caused by an excessive accumulation of fat that can have detrimental effects on health. Adipose tissue plays a very important endocrine role, secreting different molecules that affect body physiology. In obesity, this function is altered, leading to a dysfunctional production of several factors, known as adipocytokines. This process has been linked to various comorbidities associated with obesity, such as carcinogenesis. In fact, several classical adipocytokines with increased levels in obesity have been demonstrated to exert a pro‐carcinogenic role, including leptin, TNF‐α, IL‐6 and resistin, whereas others like adiponectin, with decreased levels in obesity, might have an anti‐carcinogenic function. In this expanding field, new proteomic techniques and approaches have allowed the identification of novel adipocytokines, a number of which exhibit an altered production in obesity and type 2 diabetes and thus are related to adiposity. Many of these novel adipocytokines have also been identified in various tumour types, such as that of the breast, liver or endometrium, thereby increasing the list of potential contributors to carcinogenesis. This review is focused on the regulation of these novel adipocytokines by obesity, including apelin, endotrophin, FABP4, lipocalin 2, omentin‐1, visfatin, chemerin, ANGPTL2 or osteopontin, emphasizing its involvement in tumorigenesis.     

Adiponectin and hypertension

Adipose tissue secretes a variety of bioactive molecules, also known as adipocytokines or adipokines. Obesity, in particular, visceral fat accumulation, is implicated in the dysregulated secretion of adipocytokines, which can contribute to the development of metabolic syndrome and cardiovascular diseases. Adiponectin is an adipocytokine that is exclusively secreted from adipose tissue, but its plasma levels are reduced in obese subjects, especially those with visceral fat accumulation. Adiponectin has a variety of protective properties against obesity-linked complications, such as hypertension, metabolic dysfunction, atherosclerosis, and ischemic heart disease. Adiponectin exerts the beneficial effects on vascular disorders by directly affecting components of vascular tissue. This review will discuss clinical and experimental findings that examine the role of adiponectin in regulation of hypertension and vascular function.     

The emerging role of adipocytokines as inflammatory mediators in inflammatory bowel disease

Anorexia, malnutrition, altered body composition and development of mesenteric obesity are well known features of inflammatory bowel disease (IBD). Recent data suggest that dysregulation of protein secretion by white adipose tissue is involved in these manifestations of patients with IBD. Adipocytes are recently recognized as endocrine cells that secrete a variety of bioactive substances known as adipocytokines. There is evidence that adipocytokines are involved in inflammatory and metabolic pathways in human beings. Overexpression of adipocytokines such as leptin, adiponectin and resistin in mesenteric adipose tissue of operated patients with Crohn's disease has recently been reported, suggesting that mesenteric adipocytes in IBD may act as immunoregulating cells. Therefore, it could be suggested that adipocytokines play an important role in the disease pathogenesis. Moreover, modulators of mesenteric adipose function have been suggested as potential therapeutic drugs in IBD. In this review, the importance of white adipose tissue function and adipocytokines, is discussed with respect to IBD.     

Obesity as a risk factor for Alzheimer’s disease: the role of adipocytokines

Alzheimer’s disease is the leading cause of dementia and the most prevalent neurodegenerative disease. It is an aging-related multi-factorial disorder and growing evidence support the contribution of metabolic factors to what was formerly thought to be a centrally mediated process. Obesity has already been recognized as an important player in the pathogenesis of this type of dementia, independently of insulin resistance or other vascular risk factors. Although the exact underlying mechanisms are still unknown, adipocyte dysfunction and concomitant alteration in adipocyte-derived protein secretion seem to be involved, since these adipocytokines can cross the blood–brain barrier and influence cognitive-related structures. Very few studies have assessed the role of adipocytokines dysfunction on cognitive impaired patients and yielded contradictory results. Interestingly, extensive research on the central effects of leptin in Alzheimer’s disease-transgenic mice has demonstrated its capacity to enhance synaptic plasticity and strength, as well as to prevent beta-amyloid deposition and tau phosphorylation. In addition, adiponectin, the most abundant adipocytokine whose levels are inversely correlated to adiposity, has shown to be neuroprotective to hippocampal cells. Many other adipose-derived cytokines have mainly pro-inflammatory properties, being able to trigger and/or enhance central inflammatory cascades and also to influence the secretion of other adipocytokines involved in cognition. This paper pretends to review the existing evidence on the contribution of adipocytokines dysfunction to the increased risk of dementia associated with mid-life obesity, unraveling its insulin-independent effects on cognition.     

Association of digestive organ disease with metabolic syndrome: role of adipocytokine and its molecular mechanisms

Recently, lifestyle-related disease due to excess nutrition and insufficient physical exercise has been increasing in developed countries, including Japan. Metabolic syndrome is related to visceral fat accumulation in individuals with upper body obesity. Adipose tissue is an endocrine organ that secretes adipocytokines such as adiponectin, leptin, and TNF-α. Obesity alters the secretion of adipocytokines, leading to insulin resistance and various other metabolic disorders. Little is known about how altered regulation of adipocytokines is related to the development and progression of digestive organ disease. Clarification of the mechanisms whereby such altered adipocytokine secretion participates in pathophysiology of digestive organ disease could lead to the development of preventive and therapeutic measures.     

Chronic ethanol-induced insulin resistance is associated with macrophage infiltration into adipose tissue and altered expression of adipocytokines

BACKGROUND: Chronic ethanol consumption disrupts glucose homeostasis and is associated with the development of insulin resistance. While adipose tissue and skeletal muscle are the two major organs utilizing glucose in response to insulin, the relative contribution of these two tissues to impaired glucose homeostasis during chronic ethanol feeding is not known. As other models of insulin resistance, such as obesity, are characterized by an infiltration of macrophages into adipose tissue, as well as changes in the expression of adipocytokines that play a central role in the regulation of insulin sensitivity, we hypothesized that chronic ethanol-induced insulin resistance would be associated with increased macrophage infiltration into adipose tissue and changes in the expression of adipocytokines by adipose tissue. METHODS: Male Wistar rats were fed a liquid diet containing ethanol as 36% of calories or pair-fed a control diet for 4 weeks. The effects of chronic ethanol feeding on insulin-stimulated glucose utilization were studied using the hyperinsulinemic-euglycemic clamp technique, coupled with the use of isotopic tracers. Further, macrophage infiltration into adipose tissue and expression of adipocytokines were also assessed after chronic ethanol feeding. RESULTS: Hyperinsulinemic-euglycemic clamp studies revealed that chronic ethanol feeding to rats decreased whole-body glucose utilization and decreased insulin-mediated suppression of hepatic glucose production. Chronic ethanol feeding decreased glucose uptake in epididymal, subcutaneous, and omental adipose tissue during the hyperinsulinemic-euglycemic clamp, but had no effect on glucose disposal in skeletal muscle. Chronic ethanol feeding increased the infiltration of macrophages into epididymal adipose tissue and changed the expression of mRNA for adipocytokines: expression of mRNA for monocyte chemoattractant protein 1, tumor necrosis factor alpha, and interleukin-6 were increased, while expression of mRNA for retinol binding protein 4 and adiponectin were decreased in epididymal adipose tissue. CONCLUSIONS: These data demonstrate that chronic ethanol feeding results in the development of insulin resistance, associated with impaired insulin-mediated suppression of hepatic glucose production and decreased insulin-stimulated glucose uptake into adipose tissue. Chronic ethanol-induced insulin resistance was associated with increased macrophage infiltration into adipose tissue, as well as changes in the expression of adipocytokines by adipose tissue.     

Role of adipose tissue as an inflammatory organ in human diseases

Reviews on the inflammatory role of adipose tissue outside the field of metabolism are rare. There is increasing evidence provided by numerous basic research studies from nearly all internal medicine subspecializations that adipocytes and adipocytokines are involved in primary inflammatory processes and diseases. Therefore, it is the aim of the present review to discuss and to summarize the current knowledge on the inflammatory role of adipocytokines and special types of regional adipocytes such as retroorbital, synovial, visceral, subdermal, peritoneal, and bone marrow adipocytes in internal medicine diseases. Future clinical and therapeutic implications are discussed.     

Adipocytokines and metabolic syndrome

Recently, adipocytes have been shown to be endocrine cells that secrete a variety of bioactive substances-the so-called adipocytokines. Among adipocytokines, tumor necrotizing factor alpha, plasminogen activator inhibitor 1, and heparin-binding epidermal growth factor-like growth factor are produced in adipocytes as well as already known organs, and they contribute to the development of vascular diseases. Visfatin is a very recently discovered visceral fat-specific protein that may be related to the development of obesity-related diseases such as diabetes mellitus and cardiovascular disease. In contrast to these adipocytokines, adiponectin, also a newfound adipose tissue-specific collagen-like protein, has been noted recently as an important antiatherogenic as well as antidiabetic protein. The function of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysfunction of adipocytes including oversecretion of tumor necrotizing factor alpha, plasminogen activator inhibitor 1, and heparin-binding epidermal growth factor-like growth factor, as well as hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, including adiponectin, is discussed with respect to atherosclerosis.     

Therapy Insight: adipocytokines in metabolic syndrome and related cardiovascular disease

Abdominal fat accumulation has been shown to play crucial roles in the development of metabolic syndrome. Visceral fat accumulation particularly is closely correlated to the development of cardiovascular disease and obesity-related disorders such as diabetes mellitus, hyperlipidemia and hypertension. Given these clinical findings, the functions of adipocytes have been intensively investigated in the past 10 years, and have been revealed to act as endocrine cells that secrete various bioactive substances termed adipocytokines. Among adipocytokines, tumor-necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin-binding epidermal growth factor-like growth factor are produced in adipocytes as well as other organs, and contribute to the development of vascular diseases. Visfatin has been identified as a visceral-fat-specific protein that might be involved in the development of obesity-related diseases, such as diabetes mellitus and cardiovascular disease. In contrast to these adipocytokines, adiponectin, which is an adipose-tissue-specific, collagen-like protein, has been noted as an important antiatherogenic and antidiabetic protein, or as an anti-inflammatory protein. The functions of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysregulation of adipocyte functions, including oversecretion of tumor-necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin-binding epidermal growth factor-like growth factor, and hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, particularly adiponectin, is discussed with respect to cardiovascular diseases.     

高脂喂养对ApoE-/-小鼠脂肪细胞因子的影响

目的 探讨高脂诱导胰岛素抵抗(IR)对ApoE-/-小鼠内脂素(Visfatin)和脂联素的影响.方法 健康雄性ApoE-/-小鼠,随机分为普食组(NF)和高脂喂养组(HF),共喂养16 w.采用以3-H3葡萄糖为示踪剂的高胰岛素-正糖钳夹评价糖代谢变化.用实时荧光定量PCR测定肝和脂肪组织细胞因子Visfatin和脂联素mRNA表达水平,采用Western印迹法测定肝、脂肪组织及血浆Visfatin蛋白水平.结果 HF组小鼠空腹血糖、血浆胰岛素、胆固醇、游离脂肪酸、甘油三酯、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)水平明显升高(均P<0.01).胰岛素钳夹术中,HF组葡萄糖输注率(GIR)明显低于NF组,肝糖生成率(HGP)明显高于NF组(均P<0.01).HF组小鼠肝脏Visfatin和脂联素mRNA表达水平以及脂肪组织Visfatin mRNA表达水平明显低于NF组(P<0.01和P<0.05);HF组血浆、肝脏和脂肪组织Visfatin蛋白表达也显著降低均(均P<0.01).结论 高脂喂养的ApoE-/-小鼠具备明显的IR基本特征,可能与脂肪细胞因子的改变有关.