腹内脂肪厚度与心血管代谢性疾病危险因素的相关性分析

目的分析腹内脂肪厚度与心血管代谢性疾病危险因素的相关性。方法将我院2010年2月—2012年10月300例体检者根据腹内脂肪厚度分为低腹内脂肪厚度组(腹内脂肪厚度在24mm以下)、中等腹内脂肪厚度组(24～42mm)和高腹内脂肪厚度组(42mm以上),比较3组受检者血压、空腹血糖及总胆固醇水平。结果高腹内脂肪厚度组收缩压、舒张压、空腹血糖和总胆固醇水平均高于低腹内脂肪厚度组,差异有统计学意义(P<0.05)。结论腹部脂肪厚度与心血管代谢性疾病的危险因素存在相关性,有助于预测心血管代谢异常。     

腹内脂肪与代谢综合征

近年认识到,由腹内脂肪堆积形成的中心性肥胖是胰岛素抵抗的标志,是形成代谢综合征的基石[1].尽管胰岛素抵抗和中心性肥胖均与代谢综合征存在相关性,但腹内脂肪含量与代谢综合征的5条诊断标准均存在独立的相关性.由此提出,腹内脂肪堆积是代谢综合征发病的病理生理学基础[2].以下扼要阐述腹内脂肪与皮下脂肪的差异及其在代谢综合征发病中的地位.     

腹内脂肪与代谢综合征

近年认识到，由腹内脂肪堆积形成的中心性肥胖是胰岛素抵抗的标志。是形成代谢综合征的基石。尽管胰岛素抵抗和中心性肥胖均与代谢综合征存在相关性，但腹内脂肪含量与代谢综合征的5条诊断标准均存在独立的相关性。由此提出，腹内脂肪堆积是代谢综合征发病的病理生理学基础。以下扼要阐述腹内脂肪与皮下脂肪的差异及其在代谢综合征发病中的地位。     

腹内型肥胖的代谢特点及合并NIDDM后的变化

应用核磁共振（ＭＲＩ）测量１６例肥胖者，１０例肥胖伴ＮＩＤＤＭ者，及８例正常体重者的腹部皮下、腹内及股部脂肪，观察体脂含量及分布对糖、脂、胰岛素代谢的影响。结果表明：肥胖对糖、脂、胰岛素代谢异常的影响尤以腹内肥胖组为显著，总体脂增加与葡萄糖及游离脂肪酸关系密切；腹内脂肪增加对胰岛素分泌和代谢影响较为显著，胰岛素的清除尚与股部脂肪有关；腹部脂肪与股部脂肪比值是体脂分布对糖、脂、胰岛素代谢影响的较重要     

脂肪细胞中甘油三酯代谢的研究进展

脂肪组织不仅是能量储存器官.而且是参与能最代谢及肥胖相关疾病发生的内分泌器官.脂肪细胞内脂质代谢异常及脂肪组织功能失调与许多疾病的发生、发展密切相关.理解脂肪细胞内脂质代谢的分子过程及调控将为肥胖相关疾病的治疗提供新靶点.现主要从脂滴的结构与功能、脂滴内甘油三酯代谢以及与脂质代谢密切相关的脂肪酶、脂肪细胞因子和信号通路等方面进行综述.     

应用高通量基因表达谱芯片研究替米沙坦对成熟脂肪细胞的影响

目的应用基因表达谱芯片技术筛查替米沙坦独立干预下成熟脂肪细胞的差异表达基因,进而对替米沙坦作用下成熟脂肪细胞的功能变化进行预测。方法将3T3-L1前脂肪细胞诱导为成熟脂肪细胞并进行替米沙坦（0．1mg／L）干预,Trizol一步法提取总RNA并纯化,反转录合成荧光分子（Cy3／Cy5）标记的cDNA探针,分别与含有36000个基因或基因片段的高通量小鼠全基因组寡核苷酸微阵列芯片杂交,杂交信号经扫描和数字化处理,筛选替米沙坦干预组与对照组成熟脂肪细胞间的差异表达基因,进而通过生物信息学数据分析推测替米沙坦独立作用下对于成熟脂肪细胞功能的影响以及可能信号途径。结果共筛选157个差异表达基因,其中表达上调的基因86个,表达下调的基因71个,这些基因涉及脂质代谢、细胞分化及成脂过程以及脂肪细胞分泌,其基因功能可能参与替米沙坦对于脂肪细胞功能的独立影响。通过信号通路的生物信息学分析,包括细胞-细胞受体相互作用、细胞黏附分子、脂肪细胞因子信号途径、氧化应激等与脂肪细胞分泌有关的途径均受到影响。此外,替米沙坦还可能作用于脂肪细胞增殖、分化与成脂过程相关途径如Wnt信号途径、β-catenin相关途径以及Notch信号途径等。结论替米沙坦对成熟脂肪细胞可能具有独立于AT受体的特殊作用,并对细胞脂质合成、代谢产生影响。     

固醇调节元件结合蛋白与脂代谢的基因调控

固醇调节元件结合蛋白(SREBPs)是脂肪合成基因重要的转录调节因子.SREBP-1a、-1c主要调节与脂肪酸代谢相关的酶,SREBP-2主要调控胆固醇代谢.SREBP-1c又称脂肪细胞定向和分化因子(ADD1),在脂肪细胞的分化中发挥重要作用.SREBPs还参与脂肪合成基因的营养调控,并受胰岛素/葡萄糖和瘦素调控,而且是代谢综合征中重要的基因调控连结点.对其调控作用进行全面深入的研究,将对糖尿病、肥胖等代谢综合征的发病机理和临床治疗有更新、更全面的认识.     

促酰基化蛋白的生理及病理生理意义

促酰基化蛋白是从人血浆中分离出的一种小分子蛋白质,它是一种与人类脂肪代谢密切相关的生物活性物质,促酰基化蛋白代谢通路可调控细胞内甘油三酯合成的关键酶———二酰基甘油转酰酶的活性,从而控制脂肪细胞及其他人体组织细胞内甘油三酯的合成,是连接脂肪细胞代谢微循环与脂质代谢循环的桥梁,是调节脂肪功能与脂肪储存的关键因素之一。促酰基化蛋白代谢途径功能失调,会引起一系列脂质代谢紊乱,最终导致肥胖症、糖尿病和心血管疾病。     

Vaspin:一种新的具有胰岛素增敏作用的脂肪因子

腹内脂肪来源的丝氨酸蛋白酶抑制剂(vaspin)是从OLETF(Otsuka Long-Evans Tokushima fatty)大鼠的腹内脂肪分离鉴定出来的一种脂肪因子.人类血清vaspin水平具有性别差异,并与肥胖、胰岛素抵抗指数相关.动物实验表明,vaspin可以改善糖耐量和胰岛素敏感性.因此,vaspin或其类似物有望成为治疗代谢综合征的一种新药.     

肥胖对阻塞性睡眠呼吸暂停综合征及血压的影响

目的探讨肥胖对阻塞性睡眠呼吸暂停综合征（OSAS）及血压的影响。方法测量261例OSAS患者的血压、腰围、腹内脂肪等指标，分析肥胖与睡眠监测相关指标及血压的关系，探讨OSAS者腹内脂肪在其中的作用。结果肥胖的OSAS的患者者高血压检出率明显高于正常体重OSAS患者；腹内脂肪面积≥85cm。组与〈82组比较，患者的收缩压较高，睡眠监测相关指标也有显著差异（P〈0．01）。结论肥胖及腹内脂肪堆积对OSAS及血压有显著影响。     

Metformin induces glucose uptake in human preadipocyte‐derived adipocytes from various fat depots

To evaluate the effect of metformin on basal and insulin‐induced glucose uptake in subcutaneous and visceral preadipocyte‐derived adipocytes from obese and non‐obese patients, preadipocytes were obtained from subcutaneous and visceral fat depots during abdominal surgery. Differentiation efficiency was evaluated by measurement of intracellular triglyceride accumulation. Preadipocyte‐derived adipocytes were treated with metformin (1 mM) for 24 h with or without the addition of insulin (100 nM) for 20 min and glucose uptake was measured. In cells from each donor, intracellular triglyceride accumulation was more abundant in subcutaneous preadipocyte‐derived adipocytes than in visceral preadipocyte‐derived adipocytes (p < 0.001). Insulin stimulated glucose uptake in subcutaneous preadipocyte‐derived adipocytes from both non‐obese and obese patients (p < 0.001 vs. basal). In visceral preadipocyte‐derived adipocytes, insulin did not increase basal glucose uptake. In subcutaneous preadipocyte‐derived adipocytes from non‐obese and obese patients, metformin alone increased glucose uptake to 2.7 ± 0.2 (p < 0.001) and 2.1 ± 0.1 fold (p < 0.001) respectively. Metformin increased glucose uptake in visceral preadipocyte‐derived adipocytes from non‐obese (1.7 ± 0.1 fold vs. basal, p < 0.001) and obese (2.0 ± 0.2 fold vs. basal, p < 0.001) patients. Combined treatment with metformin and insulin increased glucose uptake in subcutaneous preadipocyte‐derived adipocytes from both non‐obese and obese patients (p < 0.001 vs. insulin alone). In preadipocyte‐derived adipocytes glucose uptake is induced by metformin independent of the fat depot origin of the preadipocytes (subcutaneous or visceral) and the obesity state of the patients (non‐obese or obese). In adipocytes, metformin seems to induce glucose uptake independent of insulin suggesting an alternative mechanism of action of this drug.     

Expression of the mRNA coding for 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue from obese patients: an in situ hybridization study

Glucocorticoids play an important role in determining adipose tissue metabolism and distribution. Patients with Cushing's syndrome or receiving corticosteroid therapy develop a reversible visceral obesity. In obese patients, although circulating concentrations of cortisol are not consistently elevated, local conversion of inactive cortisone to active cortisol in adipose tissue, catalyzed by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1), could amplify glucocorticoid signaling. We have studied, using semiquantitative in situ hybridization, 11beta-HSD-1 mRNA expression in the adipocyte and stromal compartments of sc abdominal adipose tissue obtained from 12 lean patients and sc abdominal and visceral adipose tissue obtained from 18 obese patients. 11beta-HSD-1 mRNA was expressed in adipocytes, stroma, and walls of vessels. Localization of 11beta-HSD-1 mRNA did not differ between lean sc and obese sc or visceral adipose tissue. 11beta-HSD-1 mRNA levels were significantly (P = 0.0106) increased in the adipocyte compartment of sc adipose tissue obtained from obese patients as compared with nonobese ones, whereas no significant change (P = 0.446) was found in the stromal compartment. In obese patients, 11beta-HSD-1 mRNA expression was increased (P = 0.0157) in the stromal compartment of visceral compared with sc tissue, whereas no significant change (P = 0.8767) was found in the adipocyte compartment. In summary, our data show that 11beta-HSD-1 mRNA is increased in adipose tissue from obese patients, in the abdominal sc fat in adipocytes and in the visceral fat in both adipocytes and stroma. This observation suggests that an overexpression of 11beta-HSD-1 may explain part of the glucocorticoid-induced metabolic disorders linked to obesity and may promote visceral fat deposition.     

Glucose transport is equally sensitive to insulin stimulation, but basal and insulin-stimulated transport is higher, in human omental compared with subcutaneous adipocytes

Excess visceral fat has been found to correlate more closely with morbidity than subcutaneous fat. We found that isolated adipocytes from omental fat of nondiabetic women expressed significantly more of the insulin-regulated glucose transporter glucose transporter 4 protein and exhibited a higher basal and insulin-stimulated rate of glucose transport, at all concentrations of insulin, than subcutaneous adipocytes from the same individuals. In contrast, dose-response relationships for insulin stimulation of glucose transport demonstrated identical sensitivity to insulin in adipocytes from the 2 locations. The results demonstrate that there is no relative insulin resistance to stimulate glucose uptake in visceral compared with subcutaneous fat cells.     

Fat depot-related differences in gene expression, adiponectin secretion, and insulin action and signalling in human adipocytes differentiated in vitro from precursor stromal cells

Aim/hypothesis The distinct metabolic properties of visceral and subcutaneous adipocytes may be due to inherent characteristics of the cells that are resident in each fat depot. To test this hypothesis, human adipocytes were differentiated in vitro from precursor stromal cells obtained from visceral and subcutaneous fat depots and analysed for genetic, biochemical and metabolic endpoints. Methods Stromal cells were isolated from adipose tissue depots of nondiabetic individuals. mRNA levels of adipocyte-specific proteins were determined by real-time RT-PCR. Insulin signalling was evaluated by immunoblotting with specific antibodies. Glucose transport was measured by a 2-deoxy-glucose uptake assay. Adiponectin secretion in the adipocyte-conditioned medium was determined by a specific RIA. Results With cell differentiation, mRNA levels of PPARG, C/EBPα (also known as CEBPA), AP2 (also known as GTF3A), GLUT4 (also known as SLC2A4) were markedly upregulated, whereas GLUT1 (also known as SLC2A1) mRNA did not change. However, expression of C/EBPα, AP2 and adiponectin was higher in subcutaneous than in visceral adipocytes. By contrast, adiponectin was secreted at threefold higher rates by visceral than by subcutaneous adipocytes while visceral adipocytes also showed two- to threefold higher insulin-stimulated glucose uptake. Insulin-induced phosphorylation of the insulin receptor, IRS proteins, Akt and extracellular signal-regulated kinase-1/2 was more rapid and tended to decrease at earlier time-points in visceral than in subcutaneous adipocytes. Conclusions/interpretation Subcutaneous and visceral adipocytes, also when differentiated in vitro from precursor stromal cells, retain differences in gene expression, adiponectin secretion, and insulin action and signalling. Thus, the precursor cells that reside in the visceral and subcutaneous fat depots may already possess inherent and specific metabolic characteristics that will be expressed upon completion of the differentiation programme. Electronic supplementary material The online versin of this article (doi:) contains supplementary material, which is available to authorised users.     

Biologie des viszeralen Fetts

Visceral obesity is an independent risk factor for the development of cardiovascular diseases and type 2 diabetes. This is likely to be due to biological characteristics of visceral tissue, which are different from those of subcutaneous adipose tissue in terms of decreased insulin sensitivity and increased lipolytic activity. In addition, the anatomical site of visceral fat could be one potential reason for the increased cardio-metabolic risk associated with visceral obesity. Visceral adipose tissue drains into the portal vein and therefore the liver is exposed to the undiluted metabolites and adipokines released from visceral fat. There are profound differences between visceral and subcutaneous adipocytes in the metabolism, expression of specific receptors and secretion of a specific adipokine pattern, which could contribute to the adverse consequences of visceral obesity.     

Somatostatin is expressed and secreted by human adipose tissue upon infection and inflammation

Somatostatin (SRIF) is a well-known neuroendocrine secretion product. SRIF expression and secretion are induced after inflammation in murine macrophages and in endotoxin-injected sheep and pigs. Because adipocytes have been demonstrated to produce numerous cytokines and peptide hormones, we investigated the expression of SRIF and its receptors (SSTR1-5) in human adipose tissue after inflammatory stimulation in vitro and in tissues from patients with septic disease.Preadipocyte-derived adipocytes, mesenchymal stem cell-derived adipocytes, and mature explanted adipocytes expressed SRIF-mRNA after endotoxin [lipopolysaccharide (LPS)] or IL-1beta treatments. LPS- and IL-1beta-mediated SRIF-mRNA induction was blocked by pretreatment with dexamethasone. Using cocultures and quantitative real-time PCR, we demonstrate adipocyte SRIF induction by secretion factors from activated peripheral blood mononuclear cell-derived macrophages. In contrast to basal adipocytes, SRIF protein was detected in culture supernatants of LPS-treated and of combined TNFalpha/IL-1beta/LPS-treated adipocytes. SRIF protein was visualized by immunohistochemistry in explanted minced adipose tissue after overnight incubation in culture medium supplemented with combined IL-1beta and LPS. In septic patients, expression of SRIF-mRNA and SRIF protein was found in visceral, but not in sc, adipose tissue. Adipocyte mRNA abundance of SSTR 1-5 was differentially regulated by inflammatory treatments.Thus, human visceral adipose tissue secretes SRIF during inflammation and sepsis and expresses several SSTRs. It is tempting to speculate that visceral adipose tissue-derived SRIF plays a modulatory role in the immunological and metabolic response to inflammation.     

Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin

Aims/hypothesis Increased visceral white adipose tissue (WAT) is linked to the risk of developing diabetes. Methods/results We showed by fluorescence activated cell sorting analysis that human visceral WAT contains macrophages, the proportion of which increased with obesity. Selective isolation of mature adipocytes and macrophages from human visceral WAT by CD14 immunoselection revealed that macrophages expressed higher levels of chemokines (monocyte chemotactic protein 1, macrophage inflammatory protein 1α, IL-8) and the adipokines resistin and visfatin than did mature adipocytes, as assessed by real-time PCR analysis. Moreover, resistin and visfatin proteins were found to be released predominantly by visceral WAT macrophages. Macrophage-derived secretory products stimulated phosphorylation of protein kinase B in human hepatocytes. Conclusions/interpretation Resistin and visfatin might be considered to be proinflammatory markers. The increased macrophage population in obese human visceral WAT might be responsible for the enhanced production of chemokines as well as resistin and visfatin.     

Is visceral adiposity a significant correlate of subcutaneous adipose cell lipolysis in men?

The aim of the present study was to examine whether site differences in s.c. adipose tissue (AT) lipolysis may be considered a contributing factor to the altered metabolic risk profile of visceral compared to peripheral obese men once the concomitant variation in adipose cell size is taken into account. For this purpose, sc abdominal and femoral fat cell lipolytic responses were investigated in two groups of men (body mass index, 28 +/- 2 kg/m2), aged 36 +/- 3 yr, who were matched for both s.c. abdominal AT area (256 +/- 64 cm2) and s.c. abdominal adipose cell weight (0.55 +/- 0.08 microg lipid/cell) but were characterized by either a high (162 +/- 29 cm2; n = 18) or a low (101 +/- 21 cm2; n = 18) visceral AT deposition. The maximal lipolytic response to epinephrine or to isoproterenol (beta-adrenergic agonist) as well as the maximal antilipolytic effect of either epinephrine or clonidine (alpha2-adrenergic agonist) assessed in s.c. adipocytes were similar among men with low vs. high levels of visceral AT. However, the beta-adrenoceptor sensitivity was increased in s.c. abdominal adipose cells of individuals with a high visceral AT accumulation compared to those with a low intraabdominal fat deposition. Positive relationships were also found between the lipolytic sensitivity of s.c. abdominal adipocytes and plasma insulin concentrations measured in the fasting state and after an oral glucose load. These results suggest that variation in the degree of visceral adiposity in men does not seem to be associated with differences in regional adipose cell maximal lipolytic capacity once fat cell size is taken into account. However, the greater beta-adrenoceptor lipolytic sensitivity of s.c. abdominal adipocytes could be considered a significant correlate of the increased insulinemia observed among men characterized by high levels of visceral AT.     

Alterations of insulin sensitivity by the implantation of 3T3-L1 cells in nude mice. A role for TNF-alpha?

Aims/hypothesis. Visceral adipocytes have different functions than those from the subcutaneous fat area. These differences could contribute to the pathological significance of excessive visceral fat accumulation for accompanying insulin resistance and hyperinsulinaemia. This study addresses this hypothesis and describes a unique method to clarify whether the functional differences between visceral and subcutaneous adipocytes depend on their anatomical location. Methods. 3T3-L1 cells or TNF-α overexpressing CHO cells were implanted into subcutaneous fat area or mesenteric area as visceral fat area in athymic mice of BALB/C strain. Then, serum insulin, glucose, TNF-α, and several markers of lipid metabolism were measured in the fasting condition. OGTT was also analysed. Results. During the course of glucose loading, the mice which had 3T3-L1 cells implanted into mesenteric area but not into subcutaneous fat area showed remarkably increased serum insulin and TMF-α concentrations, compared to the control mice. Moreover, serum insulin concentrations of the mice, implanted with TNF-α overexpressing cells into subcutaneous fat area, were apparently higher than that of control mice. Conclusion/interpretation. This method of implanting adipose cells into subcutaneous or visceral fat area showed high TNF-α concentration and insulin resistance by the adipose cells in visceral area of nude mice. Furthermore, we found that the functional significance of visceral fat accumulation for TNF-α-induced insulin resistance is partly caused by the interaction of adipocytes with surrounding conditions in mesenteric area. [Diabetologia (2002) 45: ▪–▪] Received: 15 February 2001 and in revised form: 21 December 2001