The concept of metabolic syndrome: contribution of visceral fat accumulation and its molecular mechanism

Although abdominal obesity or visceral obesity is considered to be one of the components of metabolic syndrome and to have an important role in a cluster of cardiovascular risks, there is no consensus about the definition and diagnostic criteria for this syndrome, probably because there is considerable disagreement about the location and definition of abdominal obesity or visceral obesity.In this review article, the important role of visceral fat accumulation in the development of a variety of lifestyle-related diseases is shown, including cardiovascular disease based on our clinical studies using CT scans, and the mechanism of these disorders is discussed, focusing on adipocytokines, especially adiponectin.The importance of diagnosing metabolic syndrome, in which visceral fat accumulation plays an essential role in the development of multiple risk factors, should be emphasized because lifestyle modification for the reduction of visceral fat may be very effective for the reduction of risks of this type, namely metabolic syndrome in the narrow sense.     

替米沙坦上调内脏脂肪组织的脂联素表达并改善胰岛素抵抗

目的 探讨替米沙坦对体外原代培养的人前脂肪细胞和OLETF大鼠脂肪组织中脂联素表达以及胰岛素敏感性的影响.方法 提取人腹部皮下和内脏的前脂肪细胞,原代培养并传代后接种于无血清培养基,分为对照组（H-N）、吡格列酮组（H-P）和替米沙坦（H-T）组.葡萄糖消耗试验测定细胞的胰岛素敏感性,实时荧光定量PCR（RT-PCR）技术测定细胞脂联素mRNA的表达,放射免疫法测定培养基上清脂联素的分泌量.4周龄雄性OLETF大鼠28只,初始体重150～180 g.高脂喂养,分为对照组（O-HFD组,10只）、吡格列酮组（O-P组,8只）和替米沙坦组（O-T组,10只）.口服葡萄糖耐量实验和高胰岛素-正糖钳夹实验检测胰岛素抵抗指数和60 ～ 120 min葡萄糖输注速度以测定大鼠胰岛素抵抗水平,RT-PCR和Western blotting技术检测大鼠皮下和内脏脂肪组织脂联素的mRNA和蛋白表达.计量资料均数比较应用单因素方差分析.结果 H-T组和H-P组内脏前脂肪细胞的葡萄糖消耗量较之H-N组明显升高[分别为（5.6±1.6）、（4.4±1.6）、（2.0±0.8）mmol/L,F=20.240,P＜0.05].O-T和O-P组大鼠高胰岛素-正糖钳夹实验得到的60 ～ 120 min葡萄糖输注速度明显高于O-HFD组大鼠[分别为（18±5）、（20±4）、（10±3） mg·kg-1·min-1,F=8.136,P＜0.05].O-T和O-P组大鼠的HOMA胰岛素抵抗指数也显著低于O-HFD组大鼠（分别为10.0±8.6、5.5±2.0、17.8±10.1,F=5.784,P＜0.05）.替米沙坦可降低高脂饲养OLETF大鼠升高的腹围、内脏脂肪系数和血清游离脂肪酸水平,并改善大鼠的空腹高血糖,差别有统计学意义[分别为（24.0±2.0）比（26.5±2.7） cm、5.8％±2.4％比8.6％±2.4％、（2.8±0.7）比（5.3±1.8）μg/L、（10±6）比（15±7） mmoL/L,均P＜0.05].H-T较之H-N组原代培养人前脂肪细胞和O-T较之O-HFD组大鼠脂肪组织脂联素的mRNA表达和蛋白分泌量均明显上调（均P＜0.05）.H-T较之H-P组人内脏脂肪细胞和O-T较之O-P组大鼠内脏脂肪组织脂联素mRNA和蛋白表达水平均升高或有上升的趋势（分别为59.9±2.0比6.0±1.6、1.807±0.297比1.332±0.112、4.43±2.57比1.71±0.57、2.6±0.9比1.9±0.5,均P＜0.05）.结论 替米沙坦具有提高OLETF大鼠与人前脂肪细胞胰岛素敏感性、缓解大鼠的内脏性肥胖和改善大鼠糖脂代谢功能紊乱的作用,并很可能通过上调脂肪尤其是内脏脂肪的脂联素表达来完成.     

A polymorphism in the adiponectin gene influences adiponectin expression levels in visceral fat in obese subjects

OBJECTIVE: Reduced serum adiponectin levels have been found in obesity and type 2 diabetes and variations in the adiponectin gene (APM1) have been associated with type 2 diabetes and features of the metabolic syndrome in different populations. STUDY DESIGN: Here, we investigated the expression of APM1 in adipose tissue and studied the relationship between variation in APM1 expression, the APM1 G276T polymorphism, the common PPARG Pro12Ala polymorphism and clinical features of 36 morbidly obese (body mass index (BMI) 41.5 +/- 4.9 kg/m2) nondiabetic subjects. RESULTS: APM1 mRNA expression in visceral fat was correlated with serum adiponectin levels (r = 0.54, P = 0.012). In visceral, but not in subcutaneous, adipose tissue APM1 mRNA level was 38% higher among carriers of the APM1 G276T T allele (G/T and T/T) than among carriers of the G/G genotype (0.91 +/- 0.06 for G/T and T/T carriers vs 0.66 +/- 0.09 for G/G carriers, P = 0.013). Carriers of the T allele also had significantly higher body fat percent compared to G/G carriers (65 +/- 6 vs 56 +/- 10%, P = 0.011).Conclusion:Our results indicate that genetic variation in APM1 influences the expression of the gene in visceral adipose tissue and suggest a potential role for such variation in regulation of body fat accumulation in obese subjects.     

Impact of sleep-disordered breathing, visceral fat accumulation and adiponectin levels in patients with night-time onset of acute coronary syndrome

Acute coronary syndrome (ACS) during sleep occurs at a relatively low frequency and the pathogenic background remains uncertain. The aim of the present study was to determine the significance of sleep-disordered breathing (SDB) and excess visceral fat with nocturnal dysregulation of adipocytokines in night-time onset of ACS. SDB, visceral fat area (VFA), and changes in circulating adipocytokine levels were assessed in 109 consecutive patients with ACS. SDB and VFA were assessed by cardiorespiratory monitoring and computed tomographic scan, respectively. Visceral fat accumulation was more common in patients with (12 to 7 a.m.) than without (7 to 12 a.m.) night-time onset of ACS (p <0.05). In patients with night-time onset of ACS, those with excess visceral fat were significantly more likely to have SDB and nocturnal dysregulation of adiponectin than those without such accumulation (p <0.05), but there was no difference between those with and without excess visceral fat (VFA cutoff 100 cm(2)) in patients with non-night-time onset of ACS. In conclusion, night-time onset of ACS is associated with excess visceral fat and SDB (referred as to "syndrome Z"). SDB and excess visceral fat are treatable risk factors. Decrease of excess visceral fat and treatment of SDB could be beneficial in in preventing nocturnal cardiac events.     

Ultrasonography for the evaluation of visceral fat and the metabolic syndrome

Association between abdominal obesity and cardiovascular disease has been related with visceral adiposity, through the predisposition of developing type 2 diabetes mellitus and metabolic syndrome (MS). Sonography is a simple and reliable method to measure both subcutaneous and visceral fat. To analyze the relationship of anthropometric measurements with abdominal adiposity measured by sonography and to analyze the utility of sonography in the prediction of insulin resistance (IR) and the other components of MS. Visceral fat measurements by sonography correlated better with components of MS than did subcutaneous fat measurements. Preperitoneal circumference (PC) was strongly correlated with all components of MS and with IR expressed as a homeostasis model assessment (HOMA) index for IR. PC was better than waist circumference (WC) in predicting triglyceride levels, apolipoprotein B levels, and HOMA index, but WC was better than PC in predicting high-density lipoprotein cholesterol levels. The area under the receiver operating characteristic curve was 0.699 for PC and 0.684 for WC, in subjects with body mass index 25 kg/m2 or greater (P=.024 and .015, respectively). PC and WC showed good correlation with HOMA index (Spearman correlation coefficient=0.306, P<.001 and .206, P<.001, respectively). Abdominal visceral fat is better correlated with MS than subcutaneous fat; sonography is a useful method to evaluate the abdominal fat; PC is the best sonography parameter correlated with components of MS, and in overweight and obese subjects, PC is better than WC at predicting components of the MS.     

女性内脏脂肪指数与代谢综合征的关系

目的探讨北京沙河镇女性内脏脂肪指数与代谢综合征的关系。方法 2009年9月～10月纳入北京市昌平区（25～70）岁妇女2228名,采用生物电阻抗分析方法测量内脏脂肪指数,并调查其代谢综合征发病情况及体重、血压、血脂、血糖指标与内脏脂肪指数的关系。结果入组调查对象平均年龄（45.1±7.1）岁,内脏脂肪指数中位数为8（1～30）,代谢综合征患病率为33.3%;内脏脂肪指数与代谢综合征及体重、血压、血脂、血糖都存在相关性（P〈0.001）。将内脏脂肪指数用三分位数法划分为低、中、高指数组（分别对应1～7分,7～10分,10～30分）。各组间代谢综合征患病率和代谢指标发生风险均有统计学差异（P〈0.001）;Logistic回归分析显示内脏脂肪指数与代谢综合征具有相关性,经年龄调整后,中、高指数组的OR值分别为7.47（5.25～10.62）和32.34（22.74～45.98）。结论内脏脂肪指数检测方法且与代谢综合征具有显著相关性,可作为代谢综合征的筛查手段。     

Systemic oxidative stress is associated with visceral fat accumulation and the metabolic syndrome.

BACKGROUND: The metabolic syndrome (MetS) is a major target for prevention of atherosclerotic cardiovascular diseases and visceral fat accumulation is an underlying component of MetS. The aim of this study was to investigate the association of systemic oxidative stress with visceral fat accumulation and MetS. METHODS AND RESULTS: The study group consisted of Japanese men (n=44; 51.2+/-11.4 years) and women (n=61; 55.4 +/-13.4 years). Urinary 8-epi-prostaglandin F2alpha (8-epi-PGF2 alpha) concentration, a biomarker of systemic oxidative stress, was significantly high in the subjects with MetS. As the urinary concentration of 8-epi-PGF2alpha increased, the number of criteria for MetS were significantly met (abdominal obesity, hypertriglyceridemia, low high-density lipoprotein-cholesterol, hypertension, and high fasting glucose). Among parameters associated with MetS, the correlation coefficient of visceral fat area (VFA) with urinary 8-epi-PGF2alpha concentration was the highest (r=0.636, p<0.0001). In non-obese subjects, the correlation coefficient of VFA with urinary 8-epi-PGF2alpha concentration was higher (r=0.728, p<0.0001), although there was no significant correlation between subcutaneous fat area and urinary 8-epi-PGF2 alpha. Stepwise multiple regression analysis identified VFA as the strongest and independent determinant of urinary 8-epi-PGF2 alpha (p<0.0001) followed by adiponectin (p=0.0212) and, high sensitive C-reactive protein (p=0.0365). CONCLUSIONS: Systemic oxidative stress, as measured by urinary 8-epi-PGF2alpha , is strongly associated with visceral fat accumulation and MetS.     

Enhanced intra-abdominal visceral fat accumulation in patients with Werner's syndrome.

OBJECTIVE: Studies were made on the abnormality of glucose and lipid metabolism and its cause in four patients with Werner's syndrome to infer the reason for accelerated atherogenesis in this syndrome. RESULTS: Of these four patients, hypercholesterolemia was found in three, hypertriglyceridemia in four, hypoalphalipoproteinemia in two and hypertension in two. All the patients had insulin-resistant diabetes mellitus and three of them had apparent hyperinsulinemia. Abdominal computed tomography revealed that all of them had visceral fat obesity, namely augumented intra-abdominal adipose tissue. CONCLUSION: The clinical features of these patients resemble those recently designated as insulin resistant syndrome (syndrome X) or visceral fat syndrome. The metabolic abnormality may be one of important factors in the accelerated atherogenesis in this syndrome.     

Serum levels of retinol-binding protein 4 and adiponectin in women with polycystic ovary syndrome: associations with visceral fat but no evidence for fat mass-independent effects on pathogenesis in this condition

CONTEXT: Insulin resistance, which associates with levels of retinol-binding protein 4 (RBP4) and adiponectin, is implicated in the development of polycystic ovary syndrome (PCOS). OBJECTIVE: The objective of the study was to explore the potential contribution of RBP4 and adiponectin in the etiology of PCOS and their relationships with specific fat depot measurements. DESIGN: This was a cross-sectional study. SETTING AND PARTICIPANTS: Serum RBP4 and adiponectin levels were compared between 50 PCOS cases and 28 female controls (including 22 body mass index/fat mass-matched pairs) and correlated with specific fat depot (including visceral) axial magnetic resonance imaging cross-sectional area measurements. All subjects were of U.K. British/Irish origin. MAIN OUTCOME MEASURE(S): Serum levels of RBP4 (automated immunonephelometric assay) and adiponectin [immunoassay: total and high molecular weight (HMW)]. Data are reported as geometric mean (sd, range) and optionally adjusted for fat mass and age. RESULTS: Between the 50 PCOS cases and 28 controls, serum RBP4 levels were indistinguishable [39.0 microg/ml (31.0, 49.0) vs. 41.6 microg/ml (32.7, 52.9), respectively, unadjusted P = 0.24; adjusted P = 0.55]. Total (and HMW) adiponectin levels were lower in PCOS cases [total adiponectin 19.9 microg/ml (14.2, 27.8) vs. 25.8 microg/ml (17.7, 37.7), respectively, unadjusted P = 2.4 x 10(-3); adjusted P = 0.10]. For the paired-sample analyzes, there were no differences in RBP4 (P = 0.09), total adiponectin (P = 0.06), HMW adiponectin (P =0.19), or HMW to total adiponectin ratio (P = 0.98). In PCOS cases, L4-visceral fat area was associated positively with RBP4 (r(2) = 0.34, P = 0.01) and negatively with HMW to total adiponectin ratio (r(2) = -0.44, P = 1.3 x 10(-3)). Controls showed similar relationships. CONCLUSIONS: Although associated with visceral fat, serum RBP4 and adiponectin levels do not play important, fat-mass-independent primary roles in the development of PCOS.     

Waist circumference,visceral abdominal fat thickness and three components of metabolic syndrome

ObjectiveThe relationships between the waist circumference (WC), visceral adipose tissue (VAT) thickness and three components of metabolic syndrome (MetS) were explored to verify which of the obesity indices might be superior.MethodsA cross-sectional study was conducted of 1256 subjects (840 males and 416 females) aged 26–89 years, who were individuals undergoing intensive health checkup. The three components of MetS examined were high blood pressure, glucose intolerance and dyslipidemia. Receiver-operating characteristic (ROC) curve analysis and multiple logistic regression analysis were used for the analyses.ResultsThe mean values of the WC and VAT thickness were significantly higher in the subject group positive for each of the metabolic syndrome components than in the subject group that was negative for all the components (p < 0.001). ROC curve analysis showed that the WC showed an advantage over the VAT thickness only for predicting high blood pressure in men. Logistic regression analysis revealed increase of the odds ratios of the WC for glucose intolerance (p < 0.001), high blood pressure (p < 0.001) and dyslipidemia (p < 0.01) in men. In contrast, the odds ratio of the VAT thickness was significantly increased only for dyslipidemia (p < 0.01) in men. In women, the odds ratios of the WC for glucose intolerance (p < 0.01) and dyslipidemia (p < 0.001) were significantly increased, and odds ratio of the VAT thickness for high blood pressure (p < 0.01) was significantly increased.ConclusionThis survey presented an advantage of WC over VAT thickness as an obesity index for identifying all the three components of metabolic syndrome, although sex differences in the study outcomes were found.     

代谢综合征患者腹部内脏脂肪厚度测量的价值

目的 探讨代谢综合征(MS)患者内脏脂肪厚度(VFT)测量的价值.方法 选择2007年9月到2009年1月在我院住院的166例代谢综合征患者为研究对象,代谢综合征采用2005年国际糖尿病联盟MS全球共识定义中国标准,其中男性85例,平均年龄(58±11)岁,女性81例,平均年龄(60±13)岁.记录所有患者的身高、体重、腰围、血压等,检测受试者的血脂、空腹血糖(FPG)、尿酸、肾功能等指标,同时应用超声测量腹部内脏脂肪厚度(VFT)和颈动脉内膜中层厚度(IMT).结果 男性组IMT与年龄、甘油三酯、尿酸、高血压病、糖尿病、腹部内脏脂肪呈正相关.女性组IMT值与年龄、低密度脂蛋白胆固醇、2型糖尿病及腹部内脏脂肪呈正相关,与高密度脂蛋白胆固醇呈负相关.校正腰围后,VFT仍然是IMT的独立危险因素.在代谢综合征患者中,无论男女,随着VFT的增加,IMT逐渐增加,高血压病、糖尿病、冠心病的发病率明显增高,差异有统计学意义.结论 代谢综合征患者VFT与颈动脉粥样硬化及心血管疾病发病率明显相关,VFT测量可以作为代谢综合征患者心血管疾病危险评估的有用指标.     

Usefulness of differentiating metabolic syndrome into visceral fat type and subcutaneous fat type using ultrasonography in Japanese males

Background  

Although metabolic syndrome (MS) is likely to be associated with nonalcoholic fatty liver disease (NAFLD), visceral fat type MS and subcutaneous fat type MS have not been distinguished. In this study, we divided persons with MS into those with visceral and subcutaneous fat types by ultrasonography (US), and elucidated differences between these types of MS in Japanese males.     

IASO AWARD IN POPULATION SCIENCE AND PUBLIC HEALTHAW0008Defining the risk of weight gain and limiting its impact

Our 1976 UK obesity report based ‘normal’ weights on recalculated prewar US insurance data using BMIs despite their limited validity in females. Obesity's public health implications were then compared and distinguished from smoking in the Royal College Physicians (London) 1983 report. We established the 1985 UN's energy requirements of children and adults based on energy expenditure, not purported intakes and then developed a new classification of underweight with the lower normal BMI as 18.5 not 20. In 1986 our first WHO Europe report on diet, deficiencies and chronic diseases led to the global WHO 797 report with the first universal population dietary goals including 400g/head/d of vegetables and fruit. Our lithium tracer technique for dietary salt sources also emphasised the importance of processed food composition. We then established the IOTF 10 years ago, developed and spearheaded the WHO obesity report, highlighted the unusual needs of Asians, defined the classification of childhood obesity and produced the UN Millennium nutrition report highlighting the significance of low birth weight, maternal weight and childhood stunting in a life cycle approach to health. Our 2002 WHO global burden analyses established excess weight gain (BMI ≥ 21) as globally hazardous and our new Mexican analyses suggest the need to extend our concepts of Asian vulnerability. The new Global Prevention Alliance now demands novel socio‐economic thinking if we are to combat effectively the chronic disease epidemic.     

Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat

BACKGROUND: Concurrent with the rise in obesity, nonalcoholic fatty liver disease is recognized as the leading cause of serum aminotransferase elevations in obese youth. Nevertheless, the complete metabolic phenotype associated with abnormalities in biomarkers of liver injury and intrahepatic fat accumulation remains to be established. METHODS: In a multiethnic cohort of 392 obese adolescents, alanine aminotransferase (ALT) levels were related with parameters of insulin sensitivity, glucose, and lipid metabolism as well as adipocytokines and biomarkers of inflammation. A subset of 72 adolescents had determination of abdominal fat partitioning and intrahepatic fat accumulation using magnetic resonance imaging. FINDINGS: Elevated ALT (> 35 U/liter) was found in 14% of adolescents, with a predominance of male gender and white/Hispanic race/ethnicity. After adjusting for potential confounders, rising ALT was associated with reduced insulin sensitivity and glucose tolerance as well as rising free fatty acids and triglycerides. Worsening of glucose and lipid metabolism was already evident as ALT levels rose into the upper half of the normal range (18-35 U/liter). When hepatic fat fraction was assessed using fast magnetic resonance imaging, 32% of subjects had an increased hepatic fat fraction, which was associated with decreased insulin sensitivity and adiponectin, and increased triglycerides, visceral fat, and deep to superficial sc fat ratio. The prevalence of the metabolic syndrome was significantly greater in those with fatty liver. INTERPRETATION: Deterioration in glucose and lipid metabolism is associated even with modest ALT elevations. Hepatic fat accumulation in childhood obesity is strongly associated with the triad of insulin resistance, increased visceral fat, and hypoadiponectinemia. Hence, hepatic steatosis may be a core feature of the metabolic syndrome.     

Telmisartan treatment decreases visceral fat accumulation and improves serum levels of adiponectin and vascular inflammation markers in Japanese hypertensive patients.

Hypertension contributes to the occurrence and progression of cardiovascular diseases. The angiotensin II type 1 receptor blocker telmisartan is reported to activate the peroxisome proliferator-activated receptor gamma and improve insulin sensitivity. We investigated the effects of telmisartan treatment on visceral fat, serum adiponectin and vascular inflammation markers in Japanese hypertensive patients. This was an open-label, non-controlled study. Twenty-eight essential hypertensive patients (22 men and 6 women; age 60.6+/-1.9 years; body mass index [BMI] 25.5+/-0.6 kg/m(2)) participated. Fat area was assessed with computerized tomography. All the subjects were started on telmisartan 40 mg/day, which was increased to 80 mg/day to achieve the blood pressure target of less than 130/80 mmHg. We assessed the visceral and subcutaneous fat areas, serum adiponectin levels, and vascular inflammation markers at baseline and 24 weeks of telmisartan treatment. There were significant reductions in visceral fat area (from 103.1+/-7.9 to 93.3+/-8.4 cm(2), p<0.01) and pulse wave velocity (from 1,706+/-52 to 1,587+/-51 cm/s, p<0.01) at 24 weeks. In contrast, significant increases in serum high-density lipoprotein cholesterol (from 5.06+/-0.15 to 5.32+/-0.13 mmol/L, p<0.05) and adiponectin levels (from 8.27+/-0.76 to 9.13+/-0.81 microg/mL, p<0.05) were observed. Also, there were reductions in the interleukin-6 level (from 2.26+/-0.27 to 1.60+/-0.14 pg/mL, p<0.01). We also conducted these investigations in male subjects alone and similar findings were obtained for all of these parameters. In conclusion, telmisartan treatment was associated with an improvement of vascular inflammation, reductions in visceral fat and increases in serum adiponectin.     

腹部内脏脂肪沉积的老年非代谢综合征患者脂联素瘦素比值的变化

目的 观察体质指数正常、腹部内脏脂肪沉积的非代谢综合征老年男性患者血清脂联素、瘦素水平及脂联素瘦素比值的变化.方法 将入选的老年非代谢综合征男性患者109例分为2组,内脏无脂肪沉积组67例,内脏脂肪沉积组42例.采用CT方法测定内脏脂肪面积,当腹部内脏脂肪面积≥100cm2,为内脏脂肪沉积;采用LINCO公司提供的放射免疫试剂盒测定空腹血脂联素、瘦素水平;代谢综合征的诊断采用2004年中国糖尿病学会制定的标准.结果 (1)脂肪沉积组与无脂肪沉积组比较,体质指数、内脏脂肪面积均显著升高,体质指数分别为(22.94±1.35)kg/m2对(21.38±2.55)kg/m2(P＜O.001),内脏脂肪面积(135.6±31.7)cm2对(68.6±22.6)cm2(P＜O.001);脂联素瘦素比值降低.分别为2.17±1.77对4.54±7.00(P=0.031);而脂联素、瘦素水平在两者间差异无统计学意义;(2)脂联素瘦素比值与体质指数(r=-0.552,P＜0.001)、腰围(r=-0.390,P＜0.001)、腹部内脏脂肪面积(r=-0.311,P＜0.001)呈负相关.结论 体质指数正常有内脏脂肪沉积与无内脏脂肪沉积的老年男性比较.脂联素瘦素比值明显下降.并与腹部脂肪面积显著负相关.提示血清脂联素瘦素比值可能可用于筛选体质指数正常有腹部内脏脂肪肪沉积的患者.