Metabolic syndrome and adipose tissue: New clinical aspects and therapeutic targets

The metabolic syndrome is a long-term process, explained by the interaction of genetic and environmental factors, that starts early in life and is involved in the pathophysiology of a large percentage of cases with type 2 diabetes and atherosclerosis. A number of clinical studies have demonstrated the importance of fat distribution and especially the contribution of visceral fat accumulation to the development of metabolic disorders. Visceral adipose tissue can be studied through different imaging techniques. The accumulation of visceral adipose tissue, as opposed to subcutaneous fat, increases the risk of developing metabolic disease and cardiovascular diseases (CVD). Visceral adipocytes secrete a variety of cytokines known as adipocytokines suggesting that adipose tissue is an endocrine organ that may affect the function of other organs. Weight loss, particularly a reduction in waist circumference, improves insulin sensitivity, lipid profile, and serum adipocytokines, reducing the risk of developing chronic disease and CVD. Waist circumference is a required component of metabolic syndrome under the International Diabetes Federation (IDF) criteria, rather than an optional component as used by other previous classifications. Studies have shown that using a lower waist circumference threshold within the context of metabolic syndrome increases the prevalence, but decreases the risk of mortality and type 2 diabetes. It is possible that waist circumference acts as a marker for other risk factors. These findings reinforce the notion that reductions in visceral adipose tissue should be a primary aim of strategies designed to reduce health risks associated with metabolic syndrome. © 2007 Bentham Science Publishers Ltd

Small, dense low-density lipoprotein and C-reactive protein in obese subjects with and without other criteria for the metabolic syndrome

Although obesity is an important cardiovascular risk factor, growing evidence shows that a substantial portion of obese subjects can be considered metabolically healthy but obese (MHO). However the extent to which obese subjects manifest small, dense low-density lipoprotein (LDL) particles without other characteristics of the metabolic syndrome (MS) remains unknown. The purpose of this study was to determine the difference between MHO (only meeting the obesity criteria) and obese subjects meeting all the criteria for the MS with regard to LDL size and high-sensitivity C-reactive protein (hs-CRP), as a biomarker of inflammation. Two hundred obese subjects (168 women, mean age 36.5 ± 5 years [range, 20–60]; mean body mass index [BMI; calculated as kg/m2] 39 ± 5 [range, 30–80.4]) were studied for LDL particles size and hs-CRP levels. Of 200 enrolled obese subjects, 55 were defined MHO subjects meeting only obesity criteria. The other 145 met all five criteria and were defined as having MS. Although MHO and MS subjects had similar BMI, MHO subjects had a lower percentage of small LDL particles (8% vs 29%, P < 0.001), higher average LDL diameter (274 ± 5 vs 270 ± 7 Å, P < 0.001), and lower hs-CRP levels (P < 0.05) than MS patients. The major finding of this study is that MHO subjects compared to equally obese subjects meeting the criteria of the MS have statistically significant differences in size of LDL and concentration of hs-CRP. However, the absolute differences are very small and of uncertain clinical significance

Relation between epicardial adipose tissue and left ventricular mass

Visceral adiposity is a cardiovascular risk factor of growing interest. This study sought to evaluate the hypothesis of a relation between epicardial adipose tissue, the visceral adipose tissue deposited around the heart, and left ventricular morphology in healthy subjects with a wide range of adiposity. We found for the first time that an increase in epicardial fat is significantly related to an increase in left ventricular mass

Prevalence of uncomplicated obesity in an Italian obese population

The existence of healthy obese subjects has been suggested but not clearly reported. We sought to address the prevalence of uncomplicated obesity and adverse risk factors in a large Italian obese population. This was a cross-sectional study of a population of consecutive Italian obese subjects. We studied 681 obese subjects (514 women and 167 men), with a mean age of 41.1+/-13.9 years (range, 16 to 77 years), mean BMI of 40.2+/-7.6 kg/m2 (range, 30 to 89.8 kg/m2), and a history of obesity for 20.5+/-7 years (range, 10.5 to 30 years). Anthropometric, metabolic, cardiac, and obesity-related risk factors were evaluated. The prevalence of uncomplicated subjects was 27.5%, independent of BMI and duration of obesity. The youngest group of obese subjects showed a higher, but not statistically significantly higher, prevalence of uncomplicated obesity. No statistical difference for the prevalence of impaired fasting glucose, glucose intolerance, high triglycerides, high total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol among BMI categories (from mild to extremely severe obesity degree) was found. Obese subjects with BMI>50 kg/m2 showed a higher prevalence of high blood pressure only when they were compared with the group with a BMI of 30 to 35 kg/m2 (p40 kg/m2 showed a higher prevalence of hyperinsulinemia than subjects with BMI 30 to 35 kg/m2 (p<0.01). This study shows that a substantial part of an Italian obese population has uncomplicated obesity, and the prevalence of adverse risk factors in this sample is unexpectedly low and partially independent of obesity degree. Uncomplicated obesity could represent a well-defined clinical entity

Adapted changes in left ventricular structure and function in severe uncomplicated obesity

A massive amount of fat tissue, as that observed in obese subjects with BMI over 50 kg/m(2), could affect cardiac morphology and performance, but few data on this issue are available. We sought to evaluate cardiac structure and function in uncomplicated severely obese subjects. We studied 55 uncomplicated severely obese patients, 40 women, 15 men, mean age 35.5 +/- 10.2 years, BMI 51.2 +/- 8.8 kg/m(2), range 43 to 81 kg/m(2), with a history of fat excess of at least 10 years, and 55 age-matched normal-weight subjects (40 women, 15 men, mean BMI 23.8 +/- 1.2 kg/m(2)) as a control group. Each subject underwent an echocardiogram to evaluate left ventricular (LV) mass and geometry and systolic and diastolic function. Severely obese subjects showed greater LV mass and indexed LV mass than normal-weight subjects (p or = 50 kg/m(2) and those with BMI or = 50 kg/m(2) and those with BMI < or = 50 kg/m(2) was seen. Our data show that uncomplicated severe obesity, despite the massive fat tissue amount, is associated largely with adapted and appropriate changes in cardiac structure and function

Acute insulin infusion decreases plasma ghrelin levels in uncomplicated obesity

Background: Plasma ghrelin levels have been shown to decrease after insulin infusion in lean subjects. Nevertheless, the mechanism of the suggested inhibitory effect of insulin on ghrelin is still unclear and no data about the effect of acute insulin infusion on plasma ghrelin concentration in obese subjects are available. Objective: We sight to evaluate plasma ghrelin concentration during an hyperinsulinemic euglycemic clamp in uncomplicated obese subjects. Methods: 35 uncomplicated obese subjects, body mass index (BMI) 43.3 +/- 10.1 kg/m(2), 33 women and 2 men, mean age 34.9 +/- 10, with a history of excess fat of at least 10 years underwent euglycemic hyperinsulinemic clamp. Blood samples for ghrelin were performed at baseline and steady state of euglycemic insulin clamp. Results: Ghrelin concentrations decreased over time to 10.6 +/- 15% (range 2-39%) of baseline, from a mean of 205.53 +/- 93.79 pg/ml to 179.03 +/- 70.43 pg/ml during the clamp (95% Cl, 10.69 to 36.44, P<0.01). In a univariate linear regression analysis baseline plasma ghrelin levels were inversely correlated to BMI (r = - 0.564, P = 0.04). A linear positive trend between whole body glucose utilization (M-FFMkg index) and ghrelin reduction during the clamp was found (chi(2) 3.05, p = 0.05). Conclusions: Our data seem to suggest that hyperinsulinemia during a euglycemic clamp is able to suppress plasma ghrelin concentrations in uncomplicated obesity. This effect appears to be positively related to insulin sensitivity. (C) 2004 Elsevier B.V. All rights reserved

Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth

Glioblastoma multiforme (GBM) is the most frequent and aggressive form of primary brain tumor in the adult population; its high recurrence rate and resistance to current therapeutics urgently demand a better therapy. Regulation of protein stability by the ubiquitin proteasome system (UPS) represents an important control mechanism of cell growth. UPS deregulation is mechanistically linked to the development and progression of a variety of human cancers, including GBM. Thus, the UPS represents a potentially valuable target for GBM treatment. Using an integrated approach that includes proteomics, transcriptomics and metabolic profiling, we identify praja2, a RING E3 ubiquitin ligase, as the key component of a signaling network that regulates GBM cell growth and metabolism. Praja2 is preferentially expressed in primary GBM lesions expressing the wild-type isocitrate dehydrogenase 1 gene (IDH1). Mechanistically, we found that praja2 ubiquitylates and degrades the kinase suppressor of Ras 2 (KSR2). As a consequence, praja2 restrains the activity of downstream AMP-dependent protein kinase in GBM cells and attenuates the oxidative metabolism. Delivery in the brain of siRNA targeting praja2 by transferrin-targeted self-assembling nanoparticles (SANPs) prevented KSR2 degradation and inhibited GBM growth, reducing the size of the tumor and prolonging the survival rate of treated mice. These data identify praja2 as an essential regulator of cancer cell metabolism, and as a potential therapeutic target to suppress GBM growth