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.  

Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis

Obesity is a risk factor for the development of many severe human diseases such as cardiovascular disorders, diabetes, and cancer, which are tightly linked to angiogenesis. The adipose tissue produces several growth factors/hormones including leptin, tumor necrosis factor alpha, and adiponectin. It has been found that adiponectin levels are reduced in obesity. Here, we report a unique function of adiponectin as a negative regulator of angiogenesis. In vitro, adiponectin potently inhibits endothelial cell proliferation and migration. In the chick chorioallantoic membrane and the mouse corneal angiogenesis assays, adiponectin remarkably prevents new blood vessel growth. Further, we demonstrate that the antiendothelial mechanisms involve activation of caspase-mediated endothelial cell apoptosis. Adiponectin induces a cascade activation of caspases-8, -9, and -3, which leads to cell death. In a mouse tumor model, adiponectin significantly inhibits primary tumor growth. Impaired tumor growth is associated with decreased neovascularization, leading to significantly increased tumor cell apoptosis. These data demonstrate induction of endothelial apoptosis as an unique mechanism of adiponectin-induced antiangiogenesis. Adiponectin, as a direct endogenous angiogenesis inhibitor, may have therapeutic implications in the treatment of angiogenesis-dependent diseases.  

The release of the adipocytokine visfatin is regulated by glucose and insulin

Aims/hypothesis The novel insulin-mimetic adipocytokine visfatin has been linked to the metabolic syndrome, but its regulation has not been characterised to date. Since insulin-mimetic actions of visfatin may be part of the feedback regulation of glucose homeostasis, we hypothesised that visfatin concentrations are influenced by glucose or insulin blood levels in humans.Subjects, materials and methods In this randomised, double-blind, placebo-controlled crossover study, nine healthy male subjects (age 26±6 years) attended three different study days. On each day, systemic glucose concentrations of 5.0, 8.3 and 11.1 mmol/l were attained by stepwise increases in i.v. infusions of glucose, representing fasting and postprandial conditions. Visfatin plasma concentrations were studied during concomitant exogenous hyperinsulinaemia, inhibition of endogenous insulin production by somatostatin infusion, and placebo time control. Additionally, human adipocytes were cultured to study visfatin release and mRNA expression in vitro.Results Glucose concentrations of 8.3 and 11.1 mmol/l increased circulating visfatin from baseline concentrations of 0.5±0.0 ng/ml to 0.9±0.1 and 2.1±0.3 ng/ml, respectively (p<0.01). Glucose-induced elevation of visfatin was prevented by co-infusion of insulin or somatostatin (p<0.05). Cultured subcutaneous and visceral adipocytes released an equivalent amount of visfatin upon glucose-concentration- and time-dependent stimulation. Visfatin secretion involved the phosphatidylinositol 3-kinase (PI3-kinase) and protein kinase B (AKT) pathways. The mRNA expression pattern of visfatin was consistent with this altered protein release.Conclusions/interpretation Circulating visfatin concentrations are increased by hyperglycaemia. This effect is suppressed by exogenous hyperinsulinaemia or somatostatin infusion. Glucose signalling for visfatin release in adipocytes involves the PI3-kinase/AKT pathway.  

腹内脂肪与代谢综合征

腹内脂肪堆积与代谢综合征关系密切。腹内脂肪在受体的分布、脂肪细胞分泌性因子、脂肪细胞内酶的活性等方面与皮下脂肪有显著的差异 ,因此有必要进一步研究不同部位脂肪细胞的差异 ,以更好地揭示脂肪细胞在内分泌及代谢中的作用  

小檗碱对脂肪细胞葡萄糖转运的影响及其机制研究

目的 观察小檗碱对3T3-L1脂肪细胞葡萄糖转运的影响，并探讨其机制。方法 以葡萄糖氧化酶法检测细胞的葡萄糖消耗量，以2-脱氧-^3H-D-葡萄糖摄入法观察葡萄糖的转运率，以免疫共沉淀和蛋白免疫印迹检测蛋白激酶B(protein kinase B，Akt)活性，以Northern印迹检测c-Cbl相关蛋白(CAP)mRNA的表达。结果 0．1-200μmol／L小檗碱显著增加3T3-L1脂肪细胞的葡萄糖消耗，呈剂量依赖效应，其作用不需要胰岛素的存在；0．1～10μmol／L小檗碱显著增加脂肪细胞的葡萄糖转运，在其作用2h后，葡萄糖转运即显著增加，至12h时，其作用趋近最大；免疫共沉淀和蛋白免疫印迹结果显示，小檗碱并未增强Akt激酶活性；Northern印迹结果显示，小檗碱明显降低CAP mRNA的表达。结论 脂肪细胞是小檗碱的重要靶细胞，小檗碱显著增加脂肪细胞的葡萄糖转运和消耗，可能并非通过已知的胰岛素信号转导途径。  

Fatty acid binding protein expression in different adipose tissue depots from lean and obese individuals

Aims/hypothesis: This study investigated the expression of adipose tissue fatty acid binding proteins (FABPs) in subcutaneous and visceral human adipose tissue depots from lean and obese individuals. Methods: Adipocyte lipid binding protein (ALBP) and keratinocyte lipid binding protein (KLBP) expression was quantified by western blot in subcutaneous and omental adipose tissue from 20 obese and 9 lean individuals. RNA expression was quantified by Northern blot in the obese subjects. Results: In the obese subjects, ALBP protein and RNA expression was higher in subcutaneous compared with omental adipose tissue (increases of 31 ± 14 % and 40 ± 13 % respectively, both p < 0.05), whereas in the lean group, KLBP protein levels were 32 ± 9 % lower in subcutaneous fat (p < 0.03). However, the ALBP/KLBP ratio was greater in subcutaneous compared to omental adipose tissue from both lean and obese subjects: increases of 187 ± 71 % (p = 0.01) and 52 ± 23 % (p = 0.17) respectively for the protein ratio, and 21 ± 6 % for RNA (p = 0.01, obese individuals). In lean subjects, insulin concentrations correlated positively with the ALBP/KLBP protein ratio in both depots (both p≤ 0.03). Conclusion/interpretation: There are regional differences in adipose tissue FABP expression, which could be influenced by obesity. However, the ALBP/KLBP ratio is greater in subcutaneous than visceral adipose tissue in lean as well as in obese subjects. Investigation of adipose tissue FABPs could further our understanding of the role of fatty acids in the insulin resistance syndrome. [Diabetologia (2001) 44: 1268–1273] Received: 1 February 2001 and in revised form: 25 June 2001  

Decreased circulating protective adiponectin level is associated with angiographic coronary disease progression in patients with angina pectoris

Adipocyte cytokines regulate glucose metabolism and insulin resistance and adiponectin is thought to have a protective effect against atherosclerosis. Studies have shown that adiponectin expression is decreased in obese subjects and those with metabolic syndrome or diabetes mellitus. The purpose of this study was to investigate the relationship between circulating adipocyte cytokine concentrations and angiographic coronary artery disease (CAD) progression in patients with chest pain. Patients with stable angina pectoris who underwent repeat coronary angiograms and had serum samples at the time of first catheterization between March 1999 and January 2004 were enrolled. A modified Gensini scoring system was used to define angiographic coronary artery progression between the index and follow-up angiograms. Those who had significant angiographic progression of coronary lesions were classified into the progression group (N = 55). Those who did not have CAD progression were classified into the non-progression group (N = 102). Univariate analysis showed that CAD progression was associated with male gender (93% vs. 78%, p = 0.038), higher baseline total cholesterol (187 ± 43 vs. 173 ± 39 mg/dl, p = 0.037) and higher baseline fasting blood glucose (128 ± 57 vs. 110 ± 40 mg/dl, p = 0.037). Patients in the progression group had a significantly lower serum adiponectin level (14.3 ± 7.9 vs. 18.9 ± 13.2 μg/ml, p = 0.007) than, but resistin (28.9 ± 13.4 vs. 34.4 ± 26.0 ng/ml, p = 0.142) and leptin (7.4 ± 4.6 vs. 7.7 ± 6.5 ng/ml, p = 0.675) levels similar to, those in the non-progression group. In a multivariate binary logistic regression model, male gender (odds ratio 4.283, p = 0.015), higher serum cholesterol (odds ratio 1.010, p = 0.032) and lower serum adiponectin (odds ratio 0.959, p = 0.030) were all significant independent predictors of CAD progression. In conclusion, we found that a decreased circulating level of adiponectin is associated with angiographic CAD progression in patients with angina pectoris.  

Upregulation of adiponectin receptor 1 and 2 mRNA and protein in adipose tissue and adipocytes in insulin-resistant women with polycystic ovary syndrome

Aims/hypothesis Polycystic ovary syndrome (PCOS) is a multifaceted metabolic disease linked with insulin resistance (IR) and obesity. Adiponectin, which is lower in IR states, exerts its glucose-lowering and anti-inflammatory effects by activating two receptors, ADIPOR1 and ADIPOR2. There are no data on the relative expression of these receptors in adipose tissue of PCOS women.Methods We investigated the expression of adiponectin receptors from corresponding s.c. and omental (o.m.) adipose tissue in women with PCOS compared with matched non-PCOS women. As there is a disturbance in the steroid milieu in PCOS women, we also assessed the effects of testosterone and oestradiol on adiponectin receptors using adipocytes and adipocyte explants. Real-time RT-PCR and western blotting were used to assess the relative adiponectin receptor mRNA expression and protein production, respectively. Biochemical measurements were performed in our hospital’s laboratory.Results We are the first to describe adiponectin receptor expression and production, in corresponding s.c. and o.m. human adipose tissues at the mRNA and protein level. We demonstrate the upregulation of mRNA expression and protein production of adiponectin receptors in women with PCOS, in s.c. and o.m. adipose tissue. Treatment of adipose tissue explants and adipocytes with testosterone and oestradiol induced the expression of adiponectin receptor mRNA and protein. There was a significant positive association between ADIPOR1/R2 expression and homeostasis model assessment, testosterone, oestradiol and triglycerides and a negative relationship with sex hormone-binding globulin.Conclusions/interpretation The precise reason for the upregulation of adiponectin receptors seen in PCOS women, a pro-diabetic state, is unknown, but it appears that sex steroids may play a role in their regulation in adipose tissue.Electronic supplementary material Supplementary material is available for this article at and is accessible to authorised users.B. K. Tan and J. Chen contributed equally to this work.  

Cholesterol-fed rabbit as a unique model of nonalcoholic, nonobese, non-insulin-resistant fatty liver disease with characteristic fibrosis

Background The number of patients suffering from metabolic syndrome is increasing rapidly. Metabolic syndrome causes severe pathological changes in various organs, including the liver, and its main phenotype is nonalcoholic fatty liver disease (NAFLD). NAFLD has a broad spectrum ranging from simple fatty change to severe steatohepatitis with marked fibrosis. Recently, several experimental animal models for NAFLD have been proposed. However, most were established by rather artificial conditions such as genetic alteration. In the present study, we tried to establish a unique animal model mimicking some of the physiopathological features of NAFLD using high-cholesterol-fed rabbits. Methods Male rabbits fed with standard rabbit food containing 1% cholesterol for 8 weeks and 12 weeks were compared to controls (six rabbits/group). The weight of food was strictly restricted to 100 g/rabbit per day. Results Body weights and fasting plasma insulin levels showed no significant differences among the groups. In contrast, characteristic fine fibrosis was extended from perivenular to pericellular areas, and microvesicular fatty change with ballooning degeneration was observed in perivenular areas in livers of the cholesterol-fed rabbits. Increase of serum cholesterol level, activation of hepatic stellate cells, and exposure to oxidative stress were also recognized. Conclusions Cholesterol-fed rabbits share several physiopathological features of NAFLD. Because this model did not show insulin resistance or obesity, it may be useful for elucidating the mechanism of NAFLD related mainly to hyperlipidemia.