Genetics, postprandial lipemia and obesity.

It has been shown that a number of candidate gene loci (APOA1, APOA4, APOC3, APOB, APOE, CETP, LPL and FABP2) explain a significant, although still rather small, proportion of interindividual variability in fasting dietary responses. Other loci code for products that play a major role in lipoprotein metabolism and are prime candidate for future studies (i.e., CYP7, ABCA1, SRBI). Some of these loci also affect postprandial lipemic responses, and the interactions between genetic and dietary factors may be further modulated by body mass index. The deleterious phenotypic associations observed with some of the genotypes of candidate genes may therefore only be expressed in subjects with a high BMI. This question requires more careful research, the findings of which may contribute towards the drafting of specific dietary recommendations for the primary and secondary prevention of coronary heart disease.     

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.     

Intermuscular adipose tissue rivals visceral adipose tissue in independent associations with cardiovascular risk

BACKGROUND: The metabolic implications of intermuscular adipose tissue (IMAT) are poorly understood compared to those of visceral adipose tissue (VAT) even though the absolute quantities of both depots are similar in many individuals. OBJECTIVE: The aim was to determine the independent relationship between whole-body IMAT and cardiovascular risk factor parameters. DESIGN: Whole body magnetic resonance imaging (MRI) was used to quantify total skeletal muscle (SM), total adipose tissue (TAT) of which IMAT, defined as the AT visible by MRI within the boundary of the muscle fascia, is a sub-component. Fasting serum measures (n=262) of glucose, total cholesterol (T-Chol), high-density lipoprotein cholesterol (HDL-Chol), triglycerides (TG), protein bound glucose (PBG, n=206) and insulin (n=119) were acquired in healthy African-American (AA, n=78) and Caucasian (Ca, n=109) women (body mass index (BMI) 26.5+/-5.7 kg/m(2); 44.4+/-16.4 years) and men (39 AA, 62 Ca; BMI 25.6+/-3.5 kg/m(2); 45.6+/-17.4 years). General linear models identified the independent effects of IMAT after covarying for SM, VAT, TAT, race, sex and two-way interactions. RESULTS: Significant independent associations were observed for IMAT with glucose (P<0.001), PBG (P<0.001) and T-Chol (P<0.05). The association of IMAT with cholesterol differed by race in such a manner that for a unit increase in IMAT, T-Chol increased more rapidly in Ca compared to AA (P<0.05). TG, HDL-Chol and insulin had no independent association with IMAT. CONCLUSION: The strong independent associations of IMAT with fasting glucose and PBG suggest that IMAT may be related to glucose metabolism; however, IMAT is also associated with T-Chol in Ca.     

Update on genetics of postprandial lipemia

The relationship between alimentary lipemia and coronary disease is of great interest in view of the epidemiological and experimental evidence that underlies it. The modulation of such phenomena is influenced by both genetic and environmental factors, thus explaining their extraordinary individual variance. Over the last two decades there has been an explosion of research in this area, with often conflicting findings reported in the literature. In this study we have presented the current evidence linking a number of candidate genes (APOA1/C3/A4/A5 cluster, ABCA1, CETP, GCKR, HL, IL-6, LPL, PLIN, and TCF7L2) to the modulation of the postprandial lipid metabolism. Increased knowledge of how these and other genes influence postprandial response should increase the understanding of personalised nutrition.     

Local androgen inactivation in abdominal visceral adipose tissue

We examined the expression and activity of two enzymes from the aldoketoreductase (AKR) family 1C, namely type 5 17beta-hydroxysteroid dehydrogenase (17beta-HSD-5, AKR1C3) and type 3 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD-3, AKR1C2) in female sc and omental adipose tissue and in preadipocyte primary cultures. 17beta-HSD-5 preferentially synthesizes testosterone from the inactive adrenal precursor androstenedione, whereas 3alpha-HSD-3 inactivates dihydrotestosterone. mRNAs of both enzymes were detected in adipose tissue from the omental and sc compartments. Real-time PCR quantification indicated a 3-fold higher 3alpha-HSD-3 expression compared with 17beta-HSD-5, and the expression of both enzymes tended to be higher in the sc vs. the omental depot. Accordingly, dose-response and time-course experiments performed in preadipocyte primary cultures indicated that 3alpha-HSD activity was higher than 17beta-HSD activity (13-fold maximum velocity difference). We measured 3alpha-HSD activity in omental and sc adipose tissue samples of 32 women for whom body composition and body fat distribution were evaluated by dual-energy x-ray absorptiometry and CT, respectively. We found that androgen inactivation in omental adipose tissue through 3alpha-HSD activity was significantly higher in women with elevated vs. low visceral adipose tissue accumulation (1.7-fold difference; P < 0.05). Moreover, omental adipose tissue 3alpha-HSD activity was positively and significantly associated with CT-measured visceral adipose tissue (r = 0.43; P < 0.02) and omental adipocyte diameter (r = 0.42; P < 0.02). These results indicate that local androgen inactivation is a predominant reaction in female abdominal adipose tissue, with the greatest conversion rates observed in the presence of abdominal visceral obesity. Increased androgen inactivation in omental adipose tissue of abdominally obese women may impact locally on the regulation of adipocyte metabolism.     

Effect of carbohydrate ingestion on postprandial lipemia

Summary The present study shows that the degree of postprandial lipemia may be decreased by all factors which increase carbohydrate metabolism, such as glucose and glucagon, and increased by factors inhibiting CHO metabolism, such as fasting and epinephrine. The intensity of the lipemia is not, therefore, necessarily an indication merely of fat absorption. Attention is called to the fact that existing knowledge of fat tolerance has usually been based on the effects of test meals containing little or no carbohydrate in relation to the amount of fat.Presented at the Joint Meeting of the Subsection on Gastroenterology, American Federation for Clinical Research, and the Gastroenterology Research Group, Atlantic City, N. J., April 29, 1956.Supported in part by grants from the American Cancer Society and from the United States Public Health Service.     

Recent findings in the study of postprandial lipemia

The study of postprandial metabolism is in the early stages compared with other areas of atherosclerosis research. Recent advances in postprandial research have included improvements in methodology and the investigation of factors that modulate the lipemic response to a meal. Enough studies have now been performed that normal ranges have been identified for blood triacylglycerol (TAG) concentrations that occur after a healthy patient consumes a standardized-mixed meal or a high-fat shake designed to elicit lipemia. Typical postprandial concentrations of other metabolites, such as apolipoproteins B48 and B100 or gastrointestinal hormones (eg, cholecystokinin), have not been studied sufficiently to be able to qualify what represents a standard postprandial response. The method of data analysis is also a key point to consider. Data from children are now becoming available, and the specific effects of ethnicity have just begun to be explored. New areas of study include the effects of different fatty acids (monosaturates or polyunsaturates), the sources of chylomicron lipids (dietary TAG and cholesterol versus that newly synthesized in the body), and the effects of alcoholic beverages consumed with the meal. Variables that can also affect the results of a meal test are under investigation. These include the type of food that is consumed the day before the meal test, the time of day the test is performed, and the palatability of the food. Given solid evidence that delayed postprandial lipemia is an independent risk factor for coronary heart disease, future scientific investigation in the area of post-prandial metabolism is likely to yield discoveries that will significantly contribute to advancements in disease treatment.     

非肥胖2型糖尿病大鼠腹腔脂肪组织基因差异表达的鉴定

目的 研究非肥胖2型糖尿大鼠腹腔脂肪组织基因差异表达。方法 基因差异表达筛查使用代表性差异分析(cDNA RDA)技术；最终的差异产物经亚克隆、测序及生物信息学分析；半定量RT—PCR对筛查到的已知基因表达量进行初步的鉴定。结果 在大鼠脂肪组织中，发现7个高表达的表达序列标签(ESTs)，6个为新的ESTs，1个为已知基因[脂蛋白脂酶(LPL)基因]，其中1个EST与小鼠肌肉ERA-like GTPase(Era)基因部分相似(相似性约15％)。LPL基因在非肥胖2型糖尿病及高脂饮食组大鼠腹腔脂肪组织表达上调。结论 在大鼠腹腔脂肪组织中发现6个新的ESTs和1个已知基因高表达，其中1个EST与小鼠肌肉ERA—like GTPase(Era)基因部分相似。LPL基因表达上调可能与高脂饮食、高血脂、胰岛素抵抗及非肥胖2型糖尿大鼠分子发病机制相关。     

Subcutaneous and visceral adipose tissue: structural and functional differences

Obesity is a heterogeneous disorder. Obese individuals vary in their body fat distribution, their metabolic profile and degree of associated cardiovascular and metabolic risk. Abdominal obesity carries greater risk of developing diabetes and future cardiovascular events than peripheral or gluteofemoral obesity. There are differences between adipose tissue present in subcutaneous areas (SCAT) and visceral adipose tissue (VAT) present in the abdominal cavity. These include anatomical, cellular, molecular, physiological, clinical and prognostic differences. Anatomically, VAT is present mainly in the mesentery and omentum, and drains directly through the portal circulaion to the liver. VAT compared with SCAT is more cellular, vascular, innervated and contains a larger number of inflammatory and immune cells, lesser preadipocyte differentiating capacity and a greater percentage of large adipocytes. There are more glucocorticoid and androgen receptors in VAT than in SCAT. VAT adipocytes are more metabolically active, more sensitive to lipolysis and more insulin-resistant than SCAT adipocytes. VAT has a greater capacity to generate free fatty acids and to uptake glucose than SCAT and is more sensitive to adrenergic stimulation, while SCAT is more avid in absorption of circulating free fatty acids and triglycerides. VAT carries a greater prediction of mortality than SCAT.     

Impact of visceral adipose tissue on liver metabolism and insulin resistance. Part II: Visceral adipose tissue production and liver metabolism

Excess visceral adipose tissue is associated with anomalies of blood glucose homoeostasis, elevation of plasma triglycerides and low levels of high-density lipoprotein cholesterol that contribute to the development of type-2 diabetes and cardiovascular syndromes. Visceral adipose tissue releases a large amount of free fatty acids and hormones/cytokines in the portal vein that are delivered to the liver. The secreted products interact with hepatocytes and various immune cells in the liver. Altered liver metabolism and determinants of insulin resistance associated with visceral adipose tissue distribution are discussed, as well as, determinants of an insulin-resistant state promoted by the increased free fatty acids and cytokines delivered by visceral adipose tissue to the liver.     

Surgical removal of visceral adipose tissue: Effects on insulin action

Many studies have demonstrated that excess of visceral fat has deleterious effects on insulin action. Mainly, it has been shown to be associated with a decrease in hepatic and peripheral insulin sensitivity, which results in a clinical condition also known as insulin resistance. This report describes a novel experimental method that we employed in order to analyze the particular effects of visceral fat on insulin activity. By extracting visceral fat we were able to distinguish the specific role that it plays in insulin action, and to analyze its effects on the gene expression of a variety of fat-derived peptides, which may be considered to be (at least partially) mediators in the development of the metabolic syndrome and possibly diabetes mellitus.     

The impact of postprandial lipemia in accelerating atherothrombosis

Several clinical studies have shown that the magnitude and duration of postprandial lipemia is positively related to the pathogenesis and progression of coronary heart disease. Postprandial lipid metabolism refers to the series of metabolic events that occur following the ingestion of a meal containing fat. Dietary fat is principally composed of triacylglycerol, postprandial lipaemia therefore being characterized by an increase in plasma triacylglycerol concentration. This review will describe the nature of the postprandial response and show the direct and indirect pro-atherogenic effects of triacylglycerol-rich lipoprotein metabolism. An elevated postprandial lipemic response precipitates a number of adverse metabolic events, including the production of atherogenic chylomicron remnants, the formation of the highly atherogenic small, dense low-density lipoprotein particles, and a reduction in the concentration of the cardioprotective high-density lipoprotein fraction. Postprandial lipemia also interacts with the process of thrombosis, in that an elevated postprandial triacylglycerol-rich lipoprotein concentration has the ability to activate the coagulation factor VII and plasminogen activator inhibitor. In the light of the potential impact of an elevated postprandial lipemia on atherothrombosis, the genetic determinants of the magnitude of the postprandial response will be identified. Finally, the nutritional factors that modulate the postprandial response will also be discussed.     

内脏脂肪组织与心肌纤维化研究进展

肥胖与心肌纤维化关系密切,尤其是内脏脂肪组织与心肌纤维化的相关性,引起了医学界的重视。既往有众多研究证实内脏脂肪组织通过分泌瘦素、脂联素等多种脂肪细胞因子参与心肌纤维化,其作用机制较为复杂。而最近研究表明内脏脂肪组织还能通过产生骨桥蛋白促进心肌纤维化。新兴起的测定内脏脂肪组织的生物电阻抗分析法亦将为其进一步的临床应用及研究奠定基础。文章就内脏脂肪组织参与心肌纤维化机制及其测定方法作一综述。     

Anger, hostility, and visceral adipose tissue in healthy postmenopausal women.

Central obesity is an important risk factor for chronic disease. Its etiology remains unclear. We examined whether anger and hostility, ie, psychological attributes that influence cardiovascular morbidity and mortality, prospectively predict central visceral obesity across 13 years. Visceral adipose tissue (VAT) was determined by x-ray computed tomography (CT) at the L4-L5 disc space in a population-based sample of 157 postmenopausal Healthy Women Study participants. Standardized tests were completed to measure separately trait anger (anger frequency and intensity), style of anger expression (holding anger in and expressing it outwardly), and hostile (mistrustful) attitudes. The higher the VAT score, the higher the trait anger and anger-out scores measured 13 years earlier (Ps < .04) and the higher the concurrent hostile attitudes score (P < .02). Moreover, the higher the VAT score, the greater the increase in trait anger over the study period (P < .03). Trait anger and hostility predicted VAT independent of fasting insulin levels, although both predicted an increase in fasting insulin over time. Women were categorized into three groups according to the distribution of the average percent increase in trait anger and in weight across the study period, respectively. The mean VAT scores increased with the likelihood of being in the highest tertile of increasing trait anger (means: 129.1, 131.1, and 155.8, P < .048) and in the highest tertile of increasing weight (means: 122.4, 131.1, and 162.2, P < .003). The association between a high trait anger score and VAT remained significant, controlling for weight gain. We conclude that hostile attributes, fasting insulin, and weight gain in midlife may contribute to the development of VAT in healthy Caucasian women.     

Associations between circulating free fatty acids, visceral adipose tissue accumulation, and insulin sensitivity in postmenopausal women

The aims of the study were to evaluate the contribution of visceral adipose tissue (AT) accumulation and insulin sensitivity to the determination of circulating free fatty acid (FFA) concentrations measured during a 2-hour euglycemic-hyperinsulinemic clamp and to verify whether elevated FFAs are associated with other components of the metabolic syndrome in postmenopausal women. This cross-sectional study included 115 postmenopausal women (46-68 years old). Visceral AT was estimated by computed tomography. Insulin sensitivity was assessed by a 2-hour euglycemic-hyperinsulinemic clamp. Free fatty acid concentration was measured in the fasting state and every 30 minutes during the clamp. Fasting plasma glucose and 2-hour plasma glucose were measured by an oral glucose tolerance test. Visceral AT was associated positively and insulin sensitivity negatively with FFA area under the curve (AUC) measured during the clamp. Women with high visceral AT accumulation and low insulin sensitivity had higher FFA AUC than women with high visceral AT accumulation and high insulin sensitivity or women with low visceral AT combined with either low or high insulin sensitivity. Free fatty acid AUC was positively associated with triglyceride (r = 0.25, P < .05), fasting plasma glucose (r = 0.26, P < .01), 2-hour plasma glucose (r = 0.27, P < .01), and diastolic blood pressure (r = 0.21, P < .05) independently of visceral AT and insulin sensitivity. In postmenopausal women, the presence of both high visceral AT and low insulin sensitivity is needed to observe an elevated FFA AUC. Moreover, FFA AUC is associated with some components of the metabolic syndrome, independently of visceral AT and insulin sensitivity.     

Novel aspects of postprandial lipemia in relation to atherosclerosis

Postprandial hyperlipidemia is considered to be a substantial risk factor for atherosclerosis. Interestingly, this concept has never been supported by randomized clinical trials. The difficulty lies in the fact that most interventions aimed to reduce postprandial lipemia, will also affect LDL-C levels. The atherogenic mechanisms of postprandial lipids and lipoproteins can be divided into direct lipoprotein-mediated and indirect effects; the latter, in part, by inducing an inflammatory state. Elevations in postprandial triglycerides (TG) have been related to the increased expression of postprandial leukocyte activation markers, up-regulation of pro-inflammatory genes in endothelial cells and involvement of the complement system. This set of events is part of the postprandial inflammatory response, which is one of the recently identified potential pro-atherogenic mechanisms of postprandial lipemia. Especially, complement component 3 levels show a close correlation with postprandial lipemia and are also important determinants of the metabolic syndrome. In clinical practice, fasting TG are frequently used as reflections of postprandial lipemia due to the close correlation between the two. The use of serial capillary measurements in an out-of-hospital situation is an alternative for oral fat loading tests. Daylong TG profiles reflect postprandial lipemia and are increased in conditions like the metabolic syndrome, type 2 diabetes and atherosclerosis. Studies are needed to elucidate the role of postprandial inflammation in atherogenesis and to find new methods in order to reduce selectively the postprandial inflammatory response. Future studies are needed to find new methods in order to reduce selectively the postprandial inflammatory response.