Inmaculada Moreno-Santos

Stearoyl-CoA desaturase-1 is associated with insulin resistance in morbidly obese subjects.

Animal studies have revealed the association between stearoyl-CoA desaturase 1 (SCD1) and obesity and insulin resistance. However, only a few studies have been undertaken in humans. We studied SCD1 in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) from morbidly obese patients and their association with insulin resistance, sterol regulatory element binding protein-1 (SREBP-1) and ATPase p97, proteins involved in SCD1 synthesis and degradation. The insulin resistance was calculated in 40 morbidly obese patients and 11 overweight controls. Measurements were made of VAT and SAT SCD1, SREBP-1 and ATPase p97 mRNA expression and protein levels. VAT and SAT SCD1 mRNA expression levels in the morbidly obese patients were significantly lower than in the controls (P = 0.006), whereas SCD1 protein levels were significantly higher (P < 0.001). In the morbidly obese patients, the VAT SCD1 protein levels were decreased in patients with higher insulin resistance (P = 0.007). However, SAT SCD1 protein levels were increased in morbidly obese patients with higher insulin resistance (P < 0.05). Multiple linear regressions in the morbidly obese patients showed that the variable associated with the SCD1 protein levels in VAT was insulin resistance, and the variables associated with SCD1 protein levels in SAT were body mass index (BMI) and ATPase p97. In conclusion, these data suggest that the regulation of SCD1 is altered in individuals with morbid obesity and that the SCD1 protein has a different regulation in the two adipose tissues, as well as being closely linked to the degree of insulin resistance.

PPARγ Expression After a High-fat Meal Is Associated With Plasma Superoxide Dismutase Activity in Morbidly Obese Persons

Peroxisome proliferator‐activated receptor‐γ (PPARγ) may play a protective role in the regulation of vascular function, partly mediated by its effects on superoxide dismutase (SOD). The aim of this study was to determine the association between PPARγ expression in peripheral blood mononuclear cells (PBMCs) and SOD activity in morbidly obese persons with varying degrees of insulin resistance (IR). We studied in 10 morbidly obese persons (five with no IR and five with high IR) the effect of a high‐fat meal on the plasma activity of various antioxidant enzymes and the mRNA expression of PPARγ in PBMC. The high‐fat meal resulted in a significant decrease in plasma SOD activity, glutathione reductase (GSH‐Rd) activity, and mRNA expression of PPARγ only in the group of morbidly obese persons with high IR. PPARγ expression after the high‐fat meal correlated with the IR levels (r = −0.803, P = 0.009) and the plasma SOD activity (r = 0.903, P = 0.001). Likewise, the reduction in PPARγ expression correlated with the increase in free fatty acids (FFA) (r = 0.733, P = 0.016). In conclusion, the decreased expression of PPARγ in PBMC in morbidly obese persons after a high‐fat meal was associated with the state of IR, the plasma SOD activity, and the changes in the concentration of FFA.

Serum 25-Hydroxyvitamin D and Adipose Tissue Vitamin D Receptor Gene Expression: Relationship With Obesity and Type 2 Diabetes

CONTEXT The relationship between 25-hydroxyvitamin D [25(OH)D] and obesity and type 2 diabetes is not completely understood. Vitamin D receptor (VDR) expression in adipose tissue (AT) is related to obesity and might be regulated by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. OBJECTIVE To analyze serum 25(OH)D and VDR gene expression in AT according to body mass index (BMI) and glycemic status and the effect of 1,25(OH)2D3 on AT according to BMI. DESIGN AND PATIENTS Two cohorts were studied: 1) 118 subjects classified according to their BMI (lean, overweight, obese, or morbidly obese [MO]) and their glycemic status (normoglycemic [NG] and prediabetic and diabetic [P&D]); and 2) 30 obese subjects (BMI > 30 kg/m(2)) classified as NG and P&D. VDR gene expression was analyzed during preadipocyte differentiation and in vitro stimulation with 1,25(OH)2D3 of AT explants from donors with different BMI values. SETTING University Hospital. MAIN OUTCOME MEASURES Serum 25(OH)D, parathyroid hormone (PTH), and AT VDR gene expression. RESULTS 25(OH)D levels were lower in P&D than NG subjects, significantly so in the lean and MO groups (P < .05). 25(OH)D levels correlated negatively with homeostasis model of assessment for insulin resistance (HOMA-IR) (r = -0.200; P = .032) and glucose (r = -0.295; P = .001), but not with BMI. VDR gene expression was higher in MO than in the other BMI groups (P < .05). 1,25(OH)2D3 increased VDR gene expression in AT from obese patients (P < .05) but not from lean subjects. CONCLUSIONS 25(OH)D levels are diminished in P&D compared to NG subjects, independently of BMI, and are closely related to glucose metabolism variables, suggesting that vitamin D deficiency is associated more with carbohydrate metabolism than with obesity. Moreover, AT has a different response to 1,25(OH)2D3 depending on the degree of obesity.

Type 2 diabetes is associated with decreased PGC1α expression in epicardial adipose tissue of patients with coronary artery disease

BackgroundAlthough recent studies indicate that epicardial adipose tissue expresses brown fat-like genes, such as PGC1α, UCP1 and PRDM16, the association of these genes with type 2 diabetes mellitus (DM2) in coronary artery disease (CAD) remains unknown.MethodsPGC1α, UCP1, and PRDM16 mRNAs expression levels were measured by real-time PCR in epicardial and thoracic subcutaneous adipose tissue from 44 CAD patients (22 with DM2 [CAD-DM2] and 22 without DM2 [CAD-NDM2]) and 23 non-CAD patients (NCAD).ResultsThe CAD-DM2 patients had significantly lower PGC1α and UCP1 expression in epicardial adipose tissue than the CAD-NDM2 and NCAD patients. However, PGC1α and UCP1 mRNA trended upward in subcutaneous adipose tissue from CAD-DM2 patients. At multiple regression analysis, age, body mass index, left ventricular ejection fraction, UCP1 expression of epicardial adipose tissue and diabetes came out to be independent predictors of PGC1α levels. Epicardial adipose tissue PGC1α expression was dependent on the number of injured coronary arteries and logistic regression analysis showed that PGC1α expression in epicardial adipose tissue could exert a protective effect against coronary lesions.ConclusionsDM2 is associated with decreased expression of PGC1α and UCP1 mRNA in epicardial adipose tissue of patients with CAD, likely reflecting a loss of brown-like fat features. Decreased expression of PGC1α in human epicardial adipose tissue is associated with higher prevalence of coronary lesions.

Expression of epicardial adipose tissue thermogenic genes in patients with reduced and preserved ejection fraction heart failure

Epicardial adipose tissue has been proposed to participate in the pathogenesis of heart failure. The aim of our study was to assess the expression of thermogenic genes (Uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), and PR-domain-missing 16 (PRDM16) in epicardial adipose tissue in patients with heart failure, stablishing the difference according to left ventricular ejection fraction (reduced or preserved). Among the 75 patients in our study, 42.7% (n=32) had reduced left ventricular ejection fraction. UCP1, PGC1α and PRDM16 mRNA in EAT were significantly lower in patients with reduced left ventricular ejection fraction. Multiple regression analysis showed that age, male gender, body max index, presence of obesity, type-2-diabetes mellitus, hypertension and coronary artery disease and left ventricular ejection fraction were associated with the expression levels of UCP1, PGC1α and PRDM16 mRNA. Thermogenic genes expressions in epicardial adipose tissue (UCP1: OR 0.617, 95%CI 0.103-0.989, p=0.042; PGC1α: OR 0.416, 95%CI 0.171-0.912, p=0.031; PRDM16: OR 0.643, 95%CI 0.116-0.997, p=0.044) were showed as protective factors against the presence of heart failure with reduced left ventricular ejection fraction, and age (OR 1.643, 95%CI 1.001-3.143, p=0.026), presence of coronary artery disease (OR 6.743, 95%CI 1.932-15.301, p<0.001) and type-2-diabetes mellitus (OR 4.031, 95%CI 1.099-7.231, p<0.001) were associated as risk factors. The adequate expression of thermogenic genes has been shown as possible protective factors against heart failure with reduced ejection fraction, suggesting that a loss of functional epicardial adipose tissue brown-like features would participate in a deleterious manner on heart metabolism. Thermogenic genes could represent a future novel therapeutic target in heart failure.

Expression of Sterol Regulatory Element-Binding Proteins in epicardial adipose tissue in patients with coronary artery disease and diabetes mellitus: preliminary study

Objectives: Sterol regulatory element-binding proteins (SREBP) genes are crucial in lipid biosynthesis and cardiovascular homeostasis. Their expression in epicardial adipose tissue (EAT) and their influence in the development of coronary artery disease (CAD) and type-2 diabetes mellitus remain to be determined. The aim of our study was to evaluate the expression of SREBP genes in EAT in patients with CAD according to diabetes status and its association with clinical and biochemical data. Methods: SREBP-1 and SREBP-2 mRNA expression levels were measured in EAT from 49 patients with CAD (26 with diabetes) and 23 controls without CAD or diabetes. Results: Both SREBPs mRNA expression were significantly higher in patients with CAD and diabetes (p<0.001) and were identified as independent cardiovascular risk factor for coronary artery disease in patients with type-2 diabetes (SREBP-1: OR 1.7, 95%CI 1.1-2.5, p=0.02; SREBP-2: OR 1.6, 95%CI 1.2-3, p=0.02) and were independently associated with the presence of multivessel CAD, left main and anterior descending artery stenosis, and higher total and LDL cholesterol levels, and lower HDL cholesterol levels, in patients with CAD and diabetes. Conclusions: SREBP genes are expressed in EAT and were higher in CAD patients with diabetes than those patients without CAD or diabetes. SREBP expression was associated as cardiovascular risk factor for the severity of CAD and the poor lipid control. In this preliminary study we suggest the importance of EAT in the lipid metabolism and cardiovascular homeostasis for coronary atherosclerosis of patients with diabetes and highlight a future novel therapeutic target.

Fibrillin 2 is upregulated in the ascending aorta of patients with bicuspid aortic valve

OBJECTIVES: Bicuspid aortic valve (BAV) is the most prevalent congenital cardiac malformation, frequently associated with aortic dilatation (AD). The molecular mechanisms involved in AD and its aetiological link with BAV formation are poorly understood. Altered fibrillin-1 (FBN1) and metalloprotease-2, -9 (MMP2,9) protein activities have been suggested to be involved in BAV aortopathy. In addition, FBN2 participates in embryonic valve formation, but its possible involvement in BAV-associated AD has never been explored. In this report, we evaluate the expression levels of MMP2,9 and FBN1,2 in the ascending aorta of patients with normal or dilated aortas and with tricuspid aortic valve (TAV) or BAV, using appropriate tissue-specific reference genes. METHODS: Gene expression was quantified by real-time quantitative polymerase chain reaction in 52 patients, using one or three reference genes previously validated in the same patient population. RESULTS: FBN2 expression was significantly increased in the aortas of patients with BAV compared with individuals with TAV (0.178 ± 0.042 vs 0.096 ± 0.021, P = 0.015), whereas differences in FBN1 did not reach statistical significance (1.946 ± 0.228 vs 1.430 ± 0.114, P = 0.090). When four groups of samples were considered, FBN2 expression was significantly higher in patients with BAV and AD compared with patients with TAV and AD (0.164 ± 0.035 vs 0.074 ± 0.027, P = 0.040). No significant differences were found when FBN1/FBN2 ratio, and MMP2 and MMP9 expression levels were analysed. No linear relationship between aortic diameter and gene expression levels were found. CONCLUSIONS: BAV patients have an increased FBN (especially FBN2) gene expression level in the ascending aorta, irrespective of dilatation, whereas MMP expression does not change significantly. These results add a new piece of information to the pathophysiology of BAV disease and point to FBN2 as a new molecular player.

Adipose Tissue LPL Methylation is Associated with Triglyceride Concentrations in the Metabolic Syndrome

BACKGROUND DNA methylation is one of the epigenetic mechanisms that regulate gene expression. DNA methylation may be modified by environmental and nutritional factors. Thus, epigenetics could potentially provide a mechanism to explain the etiology of metabolic disorders, such as metabolic syndrome (MetS). The aim of this study was to analyze the level of DNA methylation of several lipoprotein lipase (LPL)-promoter-CpG dinucleotides in a CpG island region and relate this to the gene and protein expression levels in human visceral adipose tissue (VAT) from individuals with and without MetS. METHODS VAT samples were collected from laparoscopic surgical patients without and with MetS, and levels of LPL mRNA, LPL protein, and LPL DNA methylation were measured by qPCR, western blot, and pyrosequencing. Biochemical and anthropometric variables were analyzed. Individuals included in a subset underwent a dietary fat challenge test, and levels of postprandial triglycerides were determined. RESULTS We found higher levels of DNA methylation in MetS patients but lower gene expression and protein levels. There was a negative association between LPL methylation and LPL gene expression. We found a positive association between LPL methylation status and abnormalities of the metabolic profile and basal and postprandial triglycerides, whereas LPL gene expression was negatively associated with these abnormalities. CONCLUSIONS We demonstrate that LPL methylation may be influenced by the degree of metabolic disturbances and could be involved in triglyceride metabolism, promoting hypertriglyceridemia and subsequent associated disorders, such as MetS.

IGFBP-3 Interacts with the Vitamin D Receptor in Insulin Signaling Associated with Obesity in Visceral Adipose Tissue

Adipose tissue has traditionally only been considered as an energy storage organ. Nevertheless, the importance of this tissue in systemic physiology and, especially, in systemic inflammation has been highlighted in recent years. Adipose tissue expresses proteins related to vitamin D (VD) metabolism, and it has been proposed that it can act as a VD storage tissue. The active form of VD, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is able to modify adipocyte and adipose tissue physiology via the VD receptor (VDR), decreasing the expression of pro-inflammatory cytokines in adipose tissue. Moreover, VD deficiency and VDR has been reported to be associated with obesity and diabetes. However, the results of the different studies are not conclusive. Insulin growth binding proteins (IGFBPs) have been identified in adipose tissue, but their roles are poorly understood. Therefore, the objective of this study was to analyze the plasma levels of VD and the gene expression of VDR in the adipose tissue of subjects with morbid obesity (MO) and with different degrees of insulin resistance (IR), as well as the functionality of direct interaction between IGFBP-3 and VDR, which could explain its inhibitory role in adipogenesis. Our results show a novel role of the VD system in the regulation and activation of IGFBP-3 in visceral adipose tissue (VAT) of patients with MO, as a new and alternative mechanism proposed in the insulin signaling associated with obesity.

Papel de la leptina sérica en la gravedad de la enfermedad coronaria en pacientes con angina estable

BACKGROUND AND OBJECTIVES Leptin is a plasmatic peptide hormone that has been related to cardiovascular homeostasis and atherosclerosis but much is still unknown about its relationship with coronary artery disease. The aim of this study was to evaluate the value of serum leptin in patients with stable angina and its relationship with the severity of coronary disease. PATIENTS AND METHODS 204 patients, 152 with stable angina (coronary artery disease group) and 52 without coronary disease excluded by cardiac computerized tomography (control group) were included. The coronary artery disease group was divided into 2 subgroups according to severity of coronary disease (single or multivessel disease, 46 and 106 patients, respectively). Serum leptin levels were determined by Enzyme-Linked InmunoSorbent Assay. RESULTS Leptin levels were significantly higher in patients with multivessel disease and were independently associated with a greater severity of coronary artery disease when compared with controls (OR 1.14; 95%CI: 1.03-1.27; p=0.014) and with patients with single vessel disease (OR 1.12; 95%CI: 1.01-1.25; p=0.036). Serum leptin was tested as a diagnostic marker of multivessel disease with an area under the curve obtained from Receiver Operating Characteristics of 0.6764 (95%CI 0.5765-0.7657). CONCLUSIONS Serum leptin levels were associated in patients with stable angina with the severity of coronary artery disease, suggesting its value in the development of coronary disease and as a future therapeutic target.