Adipose tissue lipoprotein lipase in chronic hemodialysis: role in plasma triglyceride metabolism.

The role of adipose tissue lipoprotein lipase (LPL) in the pathogenesis of hypertriglyceridemia in uremic patients receiving maintenance hemodialysis was evaluated. The fasting level of adipose tissue LPL activity was reduced below normal (3.4 +/- 2.5 microU/106 cells; n = 23; mean +/- SD) in hypertriglyceridemic dialysis patients (1.5 +/- 0.8; P less than 0.01; n = 15) and did not differ from normal in normotriglyceridemic dialysis patients (2.5 +/- 2.4; P = NS; n = 13). The enzyme activity increased as a function of relative body weight in normotriglyceridemic hemodialysis patients (r = 0.21; P less than 0.05) but not in the hypertriglyceridemic group (r = 0.21; P = NS). There was an abnormal response of LPL to feeding in the hypertriglyceridemic dialysis patients. The postprandial level of LPL was significantly lower in hypertriglyceridemic dialysis patients (2.2 +/- 1.0; n = 9) than in normotriglyceridemic dialysis patients (3.9 +/- 1.9; P less than 0.05; n = 10) or normal controls (4.8 +/- 1.8; P less than 0.01; n = 12). Whereas the postprandial change in LPL was inversely related to the fasting enzyme activity in normotriglyceridemic dialysis patients (r = 0.74; P less than 0.02; n = 10) and in normal controls (r = 0.58; P less than 0.05; n = 12), no such relationship existed in hypertriglyceridemic dialysis patients (r = 0.17; P = NS; n = 9). Furthermore, fasting plasma triglyceride levels in the entire group of dialysis patients were a function of the postprandial level of LPL activity (rs = 0.574; P less than 0.02; n = 19). Since the level of LPL 1) is below normal in both the fasted and fed state in the hypertriglyceridemic hemodialysis patients, 2) is normal in both the fasted and fed state in the normotriglyceridemic hemodialysis patients, and 3) in the fed state is inversely correlated with the fasting plasma triglyceride concentration in the entire group of hemodialysis patients, it is proposed that adipose tissue LPL plays a role in the etiology of hypertriglyceridemia in hemodialysis patients.     

脂肪甘油三酯脂肪酶:一种新的脂肪分解基因

脂肪是人体重要的能量储存组织,脂肪组织的脂质代谢紊乱与高甘油三酯血症、2型糖尿病、肥胖密切相关.脂肪组织中脂肪代谢基因调控着脂肪生成和分解的平衡.以前脂肪生成基因研究很多,但是对脂肪分解基因的认识仅仅限于激素敏感性脂肪酶(hormone-sensitive lipase,HSL),随着2000年HSL敲除小鼠的诞生[1],发现它并无肥胖或仅有甘油二酯的沉积,说明应该有更重要的酶控制着脂肪的水解.     

Adipose tissue cellularity in human obesity.

All human obesity is characterised by adipocyte hypertrophy and when body weight exceeds 170 per cent of ideal, a maximum cell size of roughly twice normal is achieved. With greater severity, hyperplasia becomes increasingly manifest and when body weight exceeds 170 per cent of ideal, the degree of hyperplasia is well correlated with severity. Although severity and hypercellularity are often found in those with early onset of obesity, individuals can be found who are hypercellular but have had a later onset of obesity. Until the details of cellular development in man are more fully understood, the precise timing of 'critical' periods for cellular development must remain speculative.     

Adipose triglyceride lipase gene expression in human visceral obesity.

In comparison to subcutaneous (SC) fat, visceral adipose tissue is more sensitive to catecholamine-induced lipolysis and less sensitive to the antilipolytic effects of insulin. Variation in the expression of lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) have been reported. We therefore hypothesized that expression of adipose triglyceride lipase (ATGL) is different in visceral and SC depot and investigated whether ATGL mRNA expression is related to obesity, fat distribution and insulin sensitivity. ATGL, LPL, and HSL mRNA expression was measured in 85 paired samples of omental and subcutaneous adipose tissue in normal glucose tolerant lean and obese individuals. In addition, we included a subgroup of obese (BMI >30 kg/m2) individuals with either impaired or preserved insulin sensitivity determined by euglycemic-hyperinsulinemic clamps. ATGL mRNA levels are significantly decreased in insulin resistant obese subjects. Independently of body fat mass, omental ATGL mRNA correlates with fasting insulin concentration, glucose uptake during the steady state of the clamp and HSL mRNA expression. In obese, but not in lean subjects, LPL and HSL mRNA expression was significantly higher in omental compared to SC fat. In both depots, HSL mRNA was significantly lower in obese individuals. Visceral HSL mRNA expression is closely related to adipocyte size and fasting plasma insulin concentrations, whereas visceral fat area significantly predicts visceral LPL mRNA expression. ATGL mRNA expression is not significantly different between omental and SC fat. HSL, but not ATGL mRNA expression is closely related to individual and regional differences in adipocyte size. Impaired insulin sensitivity was associated with decreased ATGL and HSL mRNA expression, independently of body fat mass and fat distribution.     

Adipose tissue lipoprotein-lipase activity in obesity

The activity of lipoprotein-lipase in heparin-eluates of adipose tissue (AT-LPLA) of three body regions was measured in 22 obese and 18 nonobese females under basal conditions. AT-LPLA in the obese women both before and after 10 d of caloric restriction was also measured. Basal LPLA correlated well with plasma insulin values and reduced significantly after caloric restriction. Relative body weight, body fat, fasting and glucose-stimulated insulin levels, triglycerides, total cholesterol, but not high-density lipoprotein cholesterol, significantly decreased after caloric restriction. Variation of insulin levels after caloric restriction was the best explanatory variable correlating with AT-LPLA variations. These results are consistent with a primary role of insulin in regulating AT-LPLA.     

Adipose tissue lipoprotein lipase activity in type III hyperlipoproteinemia.

An impairment in the catabolism of chylomicron and very low density lipoprotein remnants appears to cause the lipid abnormalities in type III hyperlipoproteinemia. A reduction in the activity of lipoprotein lipase (LPL) has been suggested as the catabolic defect. Results in this study indicate that the activity of adipose tissue LPL measured in the fasted and fed states are in the normal range in type III hyperlipoproteinemia (fasted: type III = 2.7 +/- 1.8 mU/10(6) cells, N = 8; normals = 3.4 +/- 2.5, N = 23, p, not significant; fed: type III = 3.6 +/- 2.1, N = 7; normals = 4.8 +/- 1.8, N = 12, p, not significant). This suggests that perhaps another mechanism, such as the interaction between LPL and its lipid substrate, is abnormal, or that the activity of LPL derived from another tissue source is deficient.     

The gastro-entero-pancreatic hormone secretion after a mixed meal in normal subjects before and after a 72 hour period of starvation.

The responses of plasma gastro-entero-pancreatic (GEP) hormones and free fatty acids (FFA) to a standard mixed meal before and after starvation have been measured. Raised insulin, glucose and FFA levels were found following refeeding after starvation and levels of secretin and C-terminal glucagon-like-immunoreactivity (C-GLI), raised by starvation, were rapidly suppressed on refeeding. The responses of gastrin and N-terminal glucagon-like-immunoreactivity (N-GLI) to a standard mixed meal were not altered by starvation. Although this study does not directly support that secretin and glucagon are responsible for the hyperglycaemia or hyperinsulinaemia of starvation diabetes, a role for both hormones in the raised FFA levels is proposed, as well as a role for glucagon in the initial hyperglycaemic response to a meal after starvation.     

Adipose tissue in obesity and obstructive sleep apnoea

A European Respiratory Society research seminar on "Metabolic alterations in obstructive sleep apnoea (OSA)" was jointly organised in October 2009 together with two EU COST actions (Cardiovascular risk in the obstructive sleep apnoea syndrome, action B26, and Adipose tissue and the metabolic syndrome, action BM0602) in order to discuss the interactions between obesity and OSA. Such interactions can be particularly significant in the pathogenesis of metabolic abnormalities and in increased cardiovascular risk in OSA patients. However, studying the respective role of OSA and obesity is difficult in patients, making it necessary to refer to animal models or in vitro systems. Since most OSA patients are obese, their management requires a multidisciplinary approach. This review summarises some aspects of the pathophysiology and treatment of obesity, and the possible effects of sleep loss on metabolism. OSA-associated metabolic dysfunction (insulin resistance, liver dysfunction and atherogenic dyslipidaemia) is discussed from the perspective of both obesity and OSA in adults and children. Finally, the effects of treatment for obesity or OSA, or both, on cardio-metabolic variables are summarised. Further interdisciplinary research is needed in order to develop new comprehensive treatment approaches aimed at reducing sleep disordered breathing, obesity and cardiovascular risk.     

Adipose tissue inflammation in glucose metabolism

Obesity is now recognised as a low grade, chronic inflammatory disease that is linked to a myriad of disorders including cancer, cardiovascular disease and type 2 diabetes (T2D). With respect to T2D, work in the last decade has revealed that cells of the immune system are recruited to white adipose tissue beds (WAT), where they can secrete cytokines to modulate metabolism within WAT. As many of these cytokines are known to impair insulin action, blocking the recruitment of immune cells has been purported to have therapeutic utility for the treatment of obesity-induced T2D. As inflammation is critical for host defence, and energy consuming in nature, the blockade of inflammatory processes may, however, result in unwanted complications. In this review, we outline the immunological changes that occur within the WAT with respect to systemic glucose homeostasis. In particular, we focus on the role of major immune cell types in regulating nutrient homeostasis and potential initiating stimuli for WAT inflammation.     

Adipose tissue metabolism in benign symmetric lipomatosis

Type 2 benign symmetric lipomatosis (BSL) is characterized by abnormal growth of adipose tissue in the upper back, deltoid region, upper arms, hips, and upper thigh region. Studies of lipomatous tissue in vitro have suggested that defective lipolysis may account for excess fat accumulation; however, in vivo adipose tissue metabolism has not been evaluated. We measured systemic adipose tissue lipolysis and regional adipose tissue fatty acid uptake in a patient with type 2 BSL scheduled for elective brachioplasty. We found increased, rather than decreased, rates of systemic free fatty acid release coupled with normal fatty acid oxidation. The uptake of fatty acids was 19% greater in deltoid region lipomatous tissue than in abdominal sc fat, whereas in control studies the relative uptake of fatty acids in deltoid fat averaged 29% less than that in abdominal fat. Adipocyte size was smaller than expected in lipomatous tissue. These results suggest that type 2 BSL is a hyperplastic adipose tissue abnormality that does not impair systemic lipolysis. The pathophysiology appears similar to what has been termed hyperplastic obesity. A better understanding of this condition could lead to insights into the mechanisms of hyperplastic obesity.     

Adipose tissue metabolism in young and middle-aged men after control for total body fatness

The aim of this study was to compare the sc adipose tissue metabolism of young (29 +/- 4 yr) vs. middle-aged men (57 +/- 5 yr), once the concomitant variation in total adiposity was taken into account. For this purpose, sc abdominal and femoral adipose tissue lipoprotein lipase activities, as well as fat cell lipolytic responses, were investigated in 2 groups of 16 men, differing in age but displaying similar adipose tissue mass (within 2 kg) and sc abdominal adipose tissue area, measured by computed tomography (within 15 cm2). No difference was observed in adipose tissue lipoprotein lipase activity of young vs. middle-aged subjects, regardless of the adipose region considered. Epinephrine induced antilipolysis at low concentrations (10(-9) to 10(-7) mol/L) and a net lipolytic response at higher doses (10(-6) to 10(-5) mol/L), regardless of the subjects' age and the anatomic location of fat. In addition, the selective alpha2-adrenergic agonist, UK-14304, promoted a similar antilipolytic response in sc abdominal and femoral adipose cells from both groups. However, maximal lipolysis induced by isoproterenol (beta-adrenergic agonist) or by postadrenoceptor agents such as dibutyryl-cAMP, forskolin, and theophylline were lower in both adipose regions of middle-aged (as compared with young) men. No difference in the beta- or the alpha2-adrenoceptor sensitivity of sc adipose cells was observed between groups. These results indicate that there is, with age, a selective decrease in the lipolytic capacity to beta-adrenergic agonist, which seems to be caused by postadrenoceptor impairments. Because subjects in the 2 age-groups displayed similar body fatness, these alterations are independent from the age-expected increase in total adiposity.     

Adipose tissue fatty acid metabolism in insulin-resistant men

AIMS/HYPOTHESIS: Increased NEFA production and concentrations may underlie insulin resistance. We examined systemic and adipose tissue NEFA metabolism in insulin-resistant overweight men (BMI 25-35 kg/m2). METHODS: In a cohort study we examined NEFA concentrations in men in the upper quartile of fasting insulin (n = 124) and in men with fasting insulin below the median (n = 159). In a metabolic study we examined NEFA metabolism in the fasting and postprandial states, in ten insulin-resistant men and ten controls. RESULTS: In the cohort study, fasting NEFA concentrations were not significantly different between the two groups (median values: insulin-resistant men, 410 micromol/l; controls, 445 micromol/l). However, triacylglycerol concentrations differed markedly (1.84 vs 1.18 mmol/l respectively, p < 0.001). In the metabolic study, arterial NEFA concentrations again did not differ between groups, whereas triacylglycerol concentrations were significantly higher in insulin-resistant men. Systemic NEFA production and the release of NEFA from subcutaneous adipose tissue, expressed per unit of fat mass, were both reduced in insulin-resistant men compared with controls (fasting values by 32%, p = 0.02, and 44%, p = 0.04 respectively). 3-Hydroxybutyrate concentrations, an index of hepatic fat oxidation and ketogenesis, were lower (p = 0.03). CONCLUSIONS/INTERPRETATION: Adipose tissue NEFA output is not increased (per unit weight of tissue) in insulin resistance. On the contrary, it appears to be suppressed by high fasting insulin concentrations. Alterations in triacylglycerol metabolism are more marked than those in NEFA metabolism and are indicative of altered metabolic partitioning of fatty acids (decreased oxidation, increased esterification) in the liver.     

Adipose tissue, insulin action and vascular disease: inflammatory signals

Insulin resistance, both in nondiabetic and diabetic subjects, is frequently associated with obesity, particularly an excess of central fat. Many of the features that have been ascribed to the metabolic or insulin-resistance syndrome are also more commonly found in obese subjects. These phenotypes include diabetic dyslipidaemia, elevation of levels of plasminogen activator inhibitor-1, microalbuminuria and endothelial dysfunction. More recently, features of acute-phase activation and low-grade inflammation, including elevated levels of fibrinogen, C-reactive protein and interleukin-6, have been associated with (central) obesity. Adipose tissue generation of cytokines has been shown in vitro and in vivo, and a number of novel cytokine-like molecules, collectively termed adipocytokines, have been identified as adipocyte products. While several of these, such as tumour necrosis factor-alpha, may act predominantly in autocrine or paracrine fashion, others are released into the systemic circulation, acting as signalling molecules to remote tissues, including liver, skeletal muscle and endothelium. A clearer understanding of adipose tissue signalling, and its contribution to the state of low-grade inflammation of obesity, will require physiological, as well as cellular and molecular, studies.     

Adipose tissue lipolysis after long-term overfeeding in identical twins.

Ten pairs of young male sedentary, non-obese, monozygotic (MZ) twins, aged 21 +/- 2 years (mean +/- s.d.), were overfed for a period of 100 days during which they ingested 4.2 MJ (1000 kcal) per day above their individual energy needs, 6 days per week. There was a mean 8.4 kg increase in body weight and the average gain in body fat reaches 5.6 kg (P less than 0.0001). A biopsy of subcutaneous abdominal fat was performed, before and after the treatment, to determine fat cell weight as well as basal and catecholamine stimulated lipolyses from collagenase isolated adipocytes. Although analysis of variance revealed an increase in abdominal fat cell weight, no significant changes were noted in basal and catecholamine-stimulated lipolyses, due to large variation among individuals, results being expressed either per cell number or corrected for cell surface area. However, significant intrapair resemblance was observed in the changes of basal and epinephrine stimulated lipolyses (ri of about 0.60 in both cases), suggesting a concordant within-pair response, despite large between-pair variation. These results support the notion that the genotype may play an important role in regulating the response of abdominal adipose cells lipolytic activity to caloric excess.     

Adipose tissue NK cells manifest an activated phenotype in human obesity

ObjectiveAdipose tissue inflammation is a cause of obesity-related metabolic disease. Natural killer (NK) cells are an understudied cell type in the context of obesity. The goal of this study was to determine the phenotype of human adipose tissue NK cells.MethodsWe used flow cytometry phenotyping to study adipose tissue and peripheral blood NK cells from obese and lean humans.ResultsHuman adipose tissue NK cells, relative to peripheral blood NK cells, express increased levels of activation markers. Adipose tissue NK cells also demonstrate an activated phenotype in obese relative to lean subjects, with increased expression of the activating receptor NKG2D.ConclusionsThese data are the first detailed phenotypic characterization of human adipose tissue NK cells, and suggest a role for NK cells in adipose tissue inflammation in obesity.