Wifredo Ricart - Academia.edu (original) (raw)

Papers by Wifredo Ricart

Research paper thumbnail of Adiponectin is independently associated with insulin sensitivity in women with polycystic ovary syndrome

Clinical Endocrinology, 2004

In humans, adiponectin has been demonstrated to circulate in inverse proportion to the degree of ... more In humans, adiponectin has been demonstrated to circulate in inverse proportion to the degree of insulin resistance. To investigate the association between adiponectin and glycosylated haemoglobin (HbA1c) in a population-based study. Two hundred and ninety-seven individuals aged 30-75 years were enrolled in a cross-sectional study. They included patients with type 2 (non-insulin-dependent) diabetes mellitus and stable, good metabolic control (n=32) and individuals with glucose intolerance (n=54). Adiponectin was measured using a sandwich enzyme-linked immunosorbent assay (intra-assay and interassay coefficients of variation 3.3 and 7.4% respectively). Adiponectin correlated with age (r=0.161; P=0.006), body mass index (r=-0.197; P=0.001), diastolic blood pressure (r=-0.181; P=0.005), fasting glucose and HbA1c (r=-0.251 and r=-0.22 respectively; P<0.0001), high-density lipoprotein cholesterol (r=0.442; P<0.001) and serum triglycerides (r=-362; P<0.001). In multiple regression analysis, sex, age, fasting and post-load glucose, and adiponectin independently contributed to 40% of the variance in HbA1c. Among individuals with normal glucose tolerance, fasting glucose (P=0.0033), post-load glucose (P=0.0015), age (P=0.001) and adiponectin (P=0.0083) independently contributed to 21% of the variance in HbA1c. Adiponectin is significantly associated with altered glucose metabolism and independently contributes to the variance of HbA1c in a population-based manner.

Research paper thumbnail of The relevance of EGFR, ErbB receptors and neuregulins in human adipocytes and adipose tissue in obesity

Biomedicine & Pharmacotherapy

To investigate the potential role of EGFR, ErbBs receptors and neuregulins in human adipose tissu... more To investigate the potential role of EGFR, ErbBs receptors and neuregulins in human adipose tissue physiology in obesity. Methods: Gene expression analysis in human subcutaneous (SAT) and visceral (VAT) adipose tissue in three independent cohorts [two cross-sectional (N = 150, N = 87) and one longitudinal (n = 25)], and in vitro gene knockdown and overexpression experiments were performed. Results: While both SAT and VAT ERBB2 and ERBB4 mRNA increased in obesity, SAT EGFR mRNA was negatively correlated with insulin resistance, but did not change in obesity. Of note, both SAT and VAT EGFR mRNA were significantly associated with adipogenesis and increased during human adipocyte differentiation. In vitro experiments revealed that EGFR, but not ERBB2 and ERBB4, gene knockdown in preadipocytes and in fully differentiated human adipocytes resulted in decreased expression of adipogenic-related genes. ERBB2 gene knockdown also reduced gene expression of fatty acid synthase in fully differentiated adipocytes. In addition, neuregulin 2 (NRG2) mRNA was associated with expression of adipogenic genes in human adipose tissue and adipocytes, and its overexpression increased expression of EGFR and relevant adipogenic genes. Conclusions: This study demonstrates the association between adipose tissue ERBB2 and obesity, confirms the relevance of EGFR on human adipogenesis, and suggests a possible adipogenic role of NRG2.

Research paper thumbnail of Serum neuregulin 4 is negatively correlated with insulin sensitivity in humans and impairs mitochondrial respiration in HepG2 cells

Frontiers in Physiology

Neuregulin 4 (NRG4) has been described to improve metabolic disturbances linked to obesity status... more Neuregulin 4 (NRG4) has been described to improve metabolic disturbances linked to obesity status in rodent models. The findings in humans are controversial. We aimed to investigate circulating NRG4 in association with insulin action in humans and the possible mechanisms involved. Insulin sensitivity (euglycemic hyperinsulinemic clamp) and serum NRG4 concentration (ELISA) were analysed in subjects with a wide range of adiposity (n = 89). In vitro experiments with human HepG2 cell line were also performed. Serum NRG4 was negatively correlated with insulin sensitivity (r = −0.25, p = 0.02) and positively with the inflammatory marker high-sensitivity C reative protein (hsCRP). In fact, multivariant linear regression analyses showed that insulin sensitivity contributed to BMI-, age-, sex-, and hsCRP-adjusted 7.2% of the variance in serum NRG4 (p = 0.01). No significant associations were found with adiposity measures (BMI, waist circumference or fat mass), plasma lipids (HDL-, LDL-choles...

Research paper thumbnail of A microRNA Cluster Controls Fat Cell Differentiation and Adipose Tissue Expansion By Regulating SNCG

Advanced Science, 2021

The H19X‐encoded miR‐424(322)/503 cluster regulates multiple cellular functions. Here, it is repo... more The H19X‐encoded miR‐424(322)/503 cluster regulates multiple cellular functions. Here, it is reported for the first time that it is also a critical linchpin of fat mass expansion. Deletion of this miRNA cluster in mice results in obesity, while increasing the pool of early adipocyte progenitors and hypertrophied adipocytes. Complementary loss and gain of function experiments and RNA sequencing demonstrate that miR‐424(322)/503 regulates a conserved genetic program involved in the differentiation and commitment of white adipocytes. Mechanistically, it is demonstrated that miR‐424(322)/503 targets γ‐Synuclein (SNCG), a factor that mediates this program rearrangement by controlling metabolic functions in fat cells, allowing adipocyte differentiation and adipose tissue enlargement. Accordingly, diminished miR‐424(322) in mice and obese humans co‐segregate with increased SNCG in fat and peripheral blood as mutually exclusive features of obesity, being normalized upon weight loss. The dat...

Research paper thumbnail of Inflammation triggers specific microRNA profiles in human adipocytes and macrophages and in their supernatants

Clinical Epigenetics, 2015

Research paper thumbnail of Inflammation and insulin resistance exert dual effects on adipose tissue tumor protein 53 expression

International journal of obesity (2005), 2014

The purpose of this study was to investigate the expression of human adipose tissue protein 53 (p... more The purpose of this study was to investigate the expression of human adipose tissue protein 53 (p53) in subjects who varied widely in terms of obesity and insulin resistance. We also analyzed different in vivo and in vitro models to try to comprehend the associations found in humans. p53 was analyzed in human adipose and isolated adipocytes, in high fat-fed and GLP-1R KO mice, during in vitro adipogenesis, and in adipocytes after high glucose, rosiglitazone and inflammatory conditions. The effects of surgery-induced weight loss and ex vivo metformin were also evaluated. Omental (OM) p53 gene expression (+27%, P=0.001) and protein (+11%, P=0.04) were increased in obese subjects and high fat diet-induced obese mice (+86%, P=0.018). Although the obesity-associated inflammatory milieu was associated with increased OM p53, this was negatively related to insulin resistance and glycated hemoglobin, and positively with biomarkers for insulin sensitivity. Multiple linear regression analyses ...

Research paper thumbnail of LIGHT is associated with hypertriglyceridemia in obese subjects and increased cytokine secretion from cultured human adipocytes

International journal of obesity (2005), 2010

LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry... more LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells) is a member of the tumor necrosis factor (TNF) family, primarily expressed in lymphocytes, which was associated with the induction of pro-inflammatory cytokines and alterations of lipid homeostasis in animal models. We aimed to analyze whether LIGHT has a role in the human obesity-associated inflammatory status. The association between circulating LIGHT concentrations and clinical variables was studied in 190 subjects with different degrees of obesity and glucose tolerance. The expression and release of 21 different cytokines, and the expression of genes involved in lipid metabolism were also evaluated after stimulation with LIGHT in cultured human differentiated adipocytes. Serum LIGHT concentrations positively associated with body mass index (BMI), fat mass, glycated hemoglobin and fasting triglycerides, and negatively with high-density lipoprotein cholesterol. Circulating...

Research paper thumbnail of Thyroid hormone responsive Spot 14 increases during differentiation of human adipocytes and its expression is down-regulated in obese subjects

International Journal of Obesity, 2009

Context: Very limited information is available regarding the function of human thyroid hormone re... more Context: Very limited information is available regarding the function of human thyroid hormone responsive Spot 14 (human S14, hS14) in adipogenesis and human adiposity. Objective: To evaluate hS14 levels during differentiation of human pre-adipocytes, in human fat depots and isolated fat cells. Design: This was a cross-sectional study. Subjects: A total of 161 omental (OM) and 87 subcutaneous (SC) adipose tissue samples obtained during elective surgical procedures from a population who varied widely in terms of obesity. Measurements: hS14 gene expression and protein levels during adipogenesis were assessed by RT-PCR, western blot, and using an automated confocal imaging approach. Results: hS14 gene expression levels were decreased in OM adipose tissue from overweight (À42.0%) and obese subjects (À56.5%) compared with lean subjects (Po0.05 and Po0.0001, respectively). hS14 mRNA (but not hS14-related) was inversely associated with obesity measures such as body mass index (P ¼ 0.001), percent fat mass (P ¼ 0.001), waist-to-hip ratio (P ¼ 0.020), and systolic blood pressure (P ¼ 0.031). hS14 gene expression and protein levels were up-regulated at the early stages of differentiation of human pre-adipocytes as well as for 3T3-L1 cells. That observation was most prominent in those individual cells exhibiting the more marked differentiation features. hS14 gene expression levels increased by B45 000-fold in mature adipocytes. Increased hS14 levels were also found in stromal-vascular cells/pre-adipocytes (3.8-fold, Po0.05) and in adipose tissue samples (1.9-fold, Po0.0001) from SC compared with OM fat depots. Conclusions: These results suggest that hS14 is involved in human adipogenesis, but inversely related to obesity and OM fat accumulation.

Research paper thumbnail of The lung innate immune gene surfactant protein-D is expressed in adipose tissue and linked to obesity status

International Journal of Obesity, 2013

BACKGROUND: Surfactant protein-D (SFTPD) is a component of the lung innate immunity that enhances... more BACKGROUND: Surfactant protein-D (SFTPD) is a component of the lung innate immunity that enhances clearance of pathogens and modulates inflammatory responses. An inverse association of putative, lung-derived circulating SFTPD with obesity has been reported but no information is available concerning possible SFTPD gene expression in human adipose tissue. METHODS: SFTPD gene expression was analyzed in human omental (OM; n ¼ 156) and subcutaneous (SC; n ¼ 106) adipose tissue, and in isolated fat cells (n ¼ 12) in association with measures of obesity and glucose tolerance. RESULTS: SFTPD gene was expressed in human adipose tissue and adipocytes. This expression was decreased in OM and SC adipose tissue from obese subjects with (À 47%, Po0.0001; and À 37%, P ¼ 0.048) and without (À 34%, P ¼ 0.001; and À 22%, P ¼ 0.08; respectively) type 2 diabetes when compared with the control group. Indeed, OM SFTPD was inversely associated with body mass index (r ¼ À 0.33, Po0.0001), percent fat mass (r ¼ À 0.36, Po0.0001), waist perimeter (r ¼ À 0.26, P ¼ 0.002), diastolic blood pressure (r ¼ À 0.21, P ¼ 0.018) and fasting glucose (r ¼ À 0.21, P ¼ 0.012); and positively linked to the expression of insulin receptor substrate 1 (IRS1; r ¼ 0.25, P ¼ 0.004), perilipin A (PLIN; r ¼ 0.38, P ¼ 0.007) and fatty acid synthase (FASN; r ¼ 0.36, Po0.0001). Accordingly, increased SFTPD (4.5-fold, P ¼ 0.02) was detected in isolated adipocytes when compared with the stromalvascular cell fraction, in parallel to IRS1, FASN and PLIN. CONCLUSIONS: Both OM and SC adipose tissue (mainly mature adipocytes) express SFTPD. This expression decreases with obesity and impaired glucose tolerance.

Research paper thumbnail of Circulating soluble transferrin receptor concentration decreases after exercise-induced improvement of insulin sensitivity in obese individuals

Int J Obes (Lond), 2009

Background: Circulating soluble transferrin receptor (sTfR) has been recently found to be associa... more Background: Circulating soluble transferrin receptor (sTfR) has been recently found to be associated negatively with insulin sensitivity. Objective: To evaluate circulating sTfR concentration after changing insulin sensitivity in obese individuals. Design: Circulating sTfR concentration was evaluated after diet-induced weight loss in obese women (diet (D) group, n=8); after diet-induced weight loss plus resistance training (D+RT group, n=11); and after follow-up without weight loss (control (C) group, n=7). Results: After 16 weeks, insulin sensitivity (HOMA (Homeostasis Model Assessment) value) significantly improved in parallel to weight loss (-7.3%) and reduced total fat mass (evaluated using magnetic resonance imaging) in the D group. Thigh muscle mass decreased significantly (P=0.03). Serum sTfR concentration did not change significantly. In the D+RT group, weight loss (-8.7%) and improvement of insulin sensitivity were of similar magnitude. Thigh muscle mass was preserved (P=0.8). Serum sTfR concentration decreased significantly (P=0.001). Interestingly, higher the thigh muscle volume after weight loss, higher the decrease in circulating sTfR concentration. We also found that higher the increases in leg force at week 16, higher the decrease in circulating sTfR concentration in all individuals as a whole. No significant changes were observed in insulin sensitivity, sTfR concentration or thigh muscle mass in the C group. Conclusion: These findings suggest a long-term regulation of serum sTfR concentration by exercise-induced improvement of insulin sensitivity in obese individuals.

Research paper thumbnail of Coxsackie and Adenovirus Receptor is increased in adipose tissue of obese subjects: A role for adenovirus infection?

The Journal of clinical endocrinology and metabolism, Jan 2, 2014

Context: The Coxsackie and Adenovirus Receptor (CAR) was originally identified as a common recept... more Context: The Coxsackie and Adenovirus Receptor (CAR) was originally identified as a common receptor for coxsackie B viruses and type C adenoviruses Objective: To investigate CAR gene expression in human adipose tissue to explore its associations with adipocyte physiology. Design and Setting: This was an ex vivo study in 91 visceral (VAT) and 109 subcutaneous adipose tissue (SAT) human samples (61 paired) obtained during elective surgical procedures Patients: Patients were recruited at the Endocrinology Service of the Hospital Universitari Dr. Josep Trueta Main outcome measure: CAR mRNA was measured in human adipose tissue samples and confirmed at protein level and in adipose tissue fractions. The effects of inflammatory stimuli on CAR gene expression were also evaluated. Results: In paired samples, CAR was 46-fold higher in VAT vs. SAT (p<0.0001), being higher also at protein level (p = 0.04). CAR was predominantly found in stromal vascular cell fraction (SVF) in both fat depots....

Research paper thumbnail of The MRC1/CD68 Ratio Is Positively Associated with Adipose Tissue Lipogenesis and with Muscle Mitochondrial Gene Expression in Humans

PLoS ONE, 2013

Background: Alternative macrophages (M2) express the cluster differentiation (CD) 206 (MCR1) at h... more Background: Alternative macrophages (M2) express the cluster differentiation (CD) 206 (MCR1) at high levels. Decreased M2 in adipose tissue is known to be associated with obesity and inflammation-related metabolic disturbances. Here we aimed to investigate MCR1 relative to CD68 (total macrophages) gene expression in association with adipogenic and mitochondrial genes, which were measured in human visceral [VWAT, n = 147] and subcutaneous adipose tissue [SWAT, n = 76] and in rectus abdominis muscle (n = 23). The effects of surgery-induced weight loss were also longitudinally evaluated (n = 6). Results: MCR1 and CD68 gene expression levels were similar in VWAT and SWAT. A higher proportion of CD206 relative to total CD68 was present in subjects with less body fat and lower fasting glucose concentrations. The ratio MCR1/CD68was positively associated with IRS1gene expression and with the expression of lipogenic genes such as ACACA, FASN and THRSP, even after adjusting for BMI. The ratio MCR1/CD68 in SWAT increased significantly after the surgery-induced weight loss (+44.7%; p = 0.005) in parallel to the expression of adipogenic genes. In addition, SWAT MCR1/CD68ratio was significantly associated with muscle mitochondrial gene expression (PPARGC1A, TFAM and MT-CO3). AT CD206 was confirmed by immunohistochemistry to be specific of macrophages, especially abundant in crown-like structures. Conclusion: A decreased ratio MCR1/CD68 is linked to adipose tissue and muscle mitochondrial dysfunction at least at the level of expression of adipogenic and mitochondrial genes.

Research paper thumbnail of MiRNA Expression Profile of Human Subcutaneous Adipose and during Adipocyte Differentiation

Research paper thumbnail of Human omental and subcutaneous adipose tissue exhibit specific lipidomic signatures

The FASEB Journal, 2013

Despite their differential effects on human metabolic pathophysiology, the differences in omental... more Despite their differential effects on human metabolic pathophysiology, the differences in omental and subcutaneous lipidomes are largely unknown. To explore this field, liquid chromatography coupled with mass spectrometry was used for lipidome analyses of adipose tissue samples (visceral and subcutaneous) selected from a group of obese subjects (n‫.)83؍‬ Transcriptomics and in vitro studies in adipocytes were used to confirm the pathways affected by location. The analyses revealed the existence of obesityrelated specific lipidome signatures in each of these locations, attributed to selective enrichment of specific triglycerides, glycerophospholipids, and sphingolipids, because these were not observed in adipose tissues from nonobese individuals. The changes were compatible with subcutaneous enrichment in pathways involved in adipogenesis, triacylglyceride synthesis, and lipid droplet formation, as well as increased ␣-oxidation. Marked differences between omental and subcutaneous depots in obese individuals were seen in the association of lipid species with metabolic traits (body mass index and insulin sensitivity). Targeted studies also revealed increased cholesterol (⌬56%) and cholesterol epoxide (⌬34%) concentrations in omental adi-pose tissue. In view of the effects of cholesterol epoxide, which induced enhanced expression of adipocyte differentiation and ␣-oxidation genes in human omental adipocytes, a novel role for cholesterol epoxide as a signaling molecule for differentiation is proposed. In summary, in obesity, adipose tissue exhibits a locationspecific differential lipid profile that may contribute to explaining part of its distinct pathogenic role.

Research paper thumbnail of Characterization of Herpes Virus Entry Mediator as a Factor Linked to Obesity

Research paper thumbnail of Subcutaneous Fat Shows Higher Thyroid Hormone Receptor-α1 Gene Expression Than Omental Fat

Research paper thumbnail of Circulating omentin concentration increases after weight loss

Nutrition & Metabolism, 2010

Background Omentin-1 is a novel adipokine expressed in visceral adipose tissue and negatively ass... more Background Omentin-1 is a novel adipokine expressed in visceral adipose tissue and negatively associated with insulin resistance and obesity. We aimed to study the effects of weight loss-induced improved insulin sensitivity on circulating omentin concentrations. Methods Circulating omentin-1 (ELISA) concentration in association with metabolic variables was measured in 35 obese subjects (18 men, 17 women) before and after hypocaloric weight loss. Results Baseline circulating omentin-1 concentrations correlated negatively with BMI (r = -0.58, p < 0.001), body weight (r = -0.35, p = 0.045), fat mass (r = -0.67, p < 0.001), circulating leptin (r = -0.7, p < 0.001) and fasting insulin (r = -0.37, p = 0.03). Circulating omentin-1 concentration increased significantly after weight loss (from 44.9 ± 9.02 to 53.41 ± 8.8 ng/ml, p < 0.001). This increase in circulating omentin after weight loss was associated with improved insulin sensitivity (negatively associated with HOMA value ...

Research paper thumbnail of Study of caveolin-1 gene expression in whole adipose tissue and its subfractions and during differentiation of human adipocytes

Nutrition & Metabolism, 2010

Context: Caveolins are 21-24 kDa integral membrane proteins that serve as scaffolds to recruit nu... more Context: Caveolins are 21-24 kDa integral membrane proteins that serve as scaffolds to recruit numerous signaling molecules. Specific subclasses of caveolae carry out specific functions in cell metabolism. In particular, triglycerides are synthesized at the site of fatty acid entry in one of these caveolae classes. Objective and Methods: We studied the expression of caveolin-1 (CAV-1) gene in association with metabolic variables in 90 visceral and 55 subcutaneous adipose tissue samples from subjects with a wide range of fat mass, in the stromovascular fraction (SVC) and isolated adipocytes, and during differentiation of human adipocytes. Results: CAV-1 gene expression was significantly decreased in visceral adipose tissue (v-CAV-1) of obese subjects. v-CAV-1 was positively associated with several lipogenic genes such as acetyl-coA carboxylase (ACACA, r = 0.34, p = 0.004) and spot-14 (r = 0.33, p = 0.004). In non-obese subjects v-CAV-1 also correlated with fatty acid synthase (FAS, r = 0.60, p < 0.0001). Subcutaneous (sc) adipose tissue (sc-CAV-1) gene expression was not associated with these lipogenic factors when obese and non-obese subjects were studied together. In obese subjects, however, sc-CAV-1 was associated with fatty acid synthase (FAS, r = 0.36, p = 0.02), sterol regulatory element binding protein-1c (SREBP-1c (r = 0.58, p < 0.0001), ACACA (r = 0.33, p = 0.03), spot-14 (r = 0.36, p = 0.02), PPAR-γ co-activator-1 (PGC-1, r = 0.88, n = 19). In these obese subjects, sc-CAV-1 was also associated with fasting triglycerides (r =-0.50, p < 0.0001). CAV-1 expression in mature adipocytes was significantly higher than in stromal vascular cells. CAV-1 gene expression in adipocytes from subcutaneous adipose tissue (but not in adipocytes from visceral adipose tissue) was significatively associated with fasting triglycerides. CAV-1 gene expression did not change significantly during differentiation of human preadipocytes from lean or obese subjects despite significant increase of FAS gene expression. Conclusion: Decreased CAV-1 gene expression was simultaneously linked to increased triglycerides and decreased lipogenic gene expression among obese subjects, paralleling the observations of hypertriglyceridemia in CAV-1 knockout mice. However, the regulation of CAV-1 gene expression seems independent of the adipogenic program.

Research paper thumbnail of Effect of Massive Weight Loss on Inflammatory Adipocytokines and the Innate Immune System in Morbidly Obese Women

The Journal of Clinical Endocrinology & Metabolism, 2007

Context: Obesity may be regarded as a low-grade inflammatory state.Objective: The aim of this stu... more Context: Obesity may be regarded as a low-grade inflammatory state.Objective: The aim of this study was to evaluate changes in pro-inflammatory adipocytokines and the innate immune system, cardiovascular risk, and insulin sensitivity after massive weight loss.Design: This was a longitudinal study.Setting: The study was conducted at Catholic University, Rome.Subjects and Methods: There were 10 normoglucose-tolerant obese women evaluated before and 36 months after bilio-pancreatic diversion (BPD). Glucose sensitivity (M value) was estimated using the euglycemic-hyperinsulinemic clamp. Mannan-binding lectin (MBL), bactericidal/permeability increasing protein (BPI), α-defensins, soluble CD14 receptor (sCD14), C-reactive protein, adiponectin, leptin, visfatin, IL-6, and TNF-α were assayed.Results: After massive weight loss (53% of excess body weight), leptin (P ≤ 0.0001), IL-6 (P ≤ 0.0001), α-defensins (P ≤ 0.001), and C-reactive protein (P ≤ 0.0001) decreased significantly. Adiponectin ...

Research paper thumbnail of Circulating Pigment Epithelium-Derived Factor Levels Are Associated with Insulin Resistance and Decrease after Weight Loss

The Journal of Clinical Endocrinology & Metabolism, 2010

Objective: We aimed to study circulating pigment epithelium-derived factor (PEDF) in vivo in asso... more Objective: We aimed to study circulating pigment epithelium-derived factor (PEDF) in vivo in association with insulin resistance and in vitro in human adipocytes. Methods: Circulating PEDF (ELISA) and metabolic profile were assessed in 125 Caucasian men. PEDF levels were also assessed in an independent cohort of subjects (n = 33) to study the effects of changing insulin action. PEDF gene expression and secretion were measured during differentiation of human preadipocytes. Results: In all subjects, PEDF was positively associated with body mass index (r = 0.326; P < 0.0001), waist-to-hip ratio (r = 0.380; P < 0.0001), HbA1c, and fasting triglycerides and negatively with insulin sensitivity (r = −0.320; P < 0.0001). PEDF levels were significantly increased in subjects with altered glucose tolerance and type 2 diabetes. Of the inflammatory markers measured, PEDF levels were positively associated with serum soluble TNF-α receptor 1 and IL-10 in obese subjects. Interestingly, wei...

Research paper thumbnail of Adiponectin is independently associated with insulin sensitivity in women with polycystic ovary syndrome

Clinical Endocrinology, 2004

In humans, adiponectin has been demonstrated to circulate in inverse proportion to the degree of ... more In humans, adiponectin has been demonstrated to circulate in inverse proportion to the degree of insulin resistance. To investigate the association between adiponectin and glycosylated haemoglobin (HbA1c) in a population-based study. Two hundred and ninety-seven individuals aged 30-75 years were enrolled in a cross-sectional study. They included patients with type 2 (non-insulin-dependent) diabetes mellitus and stable, good metabolic control (n=32) and individuals with glucose intolerance (n=54). Adiponectin was measured using a sandwich enzyme-linked immunosorbent assay (intra-assay and interassay coefficients of variation 3.3 and 7.4% respectively). Adiponectin correlated with age (r=0.161; P=0.006), body mass index (r=-0.197; P=0.001), diastolic blood pressure (r=-0.181; P=0.005), fasting glucose and HbA1c (r=-0.251 and r=-0.22 respectively; P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001), high-density lipoprotein cholesterol (r=0.442; P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) and serum triglycerides (r=-362; P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). In multiple regression analysis, sex, age, fasting and post-load glucose, and adiponectin independently contributed to 40% of the variance in HbA1c. Among individuals with normal glucose tolerance, fasting glucose (P=0.0033), post-load glucose (P=0.0015), age (P=0.001) and adiponectin (P=0.0083) independently contributed to 21% of the variance in HbA1c. Adiponectin is significantly associated with altered glucose metabolism and independently contributes to the variance of HbA1c in a population-based manner.

Research paper thumbnail of The relevance of EGFR, ErbB receptors and neuregulins in human adipocytes and adipose tissue in obesity

Biomedicine & Pharmacotherapy

To investigate the potential role of EGFR, ErbBs receptors and neuregulins in human adipose tissu... more To investigate the potential role of EGFR, ErbBs receptors and neuregulins in human adipose tissue physiology in obesity. Methods: Gene expression analysis in human subcutaneous (SAT) and visceral (VAT) adipose tissue in three independent cohorts [two cross-sectional (N = 150, N = 87) and one longitudinal (n = 25)], and in vitro gene knockdown and overexpression experiments were performed. Results: While both SAT and VAT ERBB2 and ERBB4 mRNA increased in obesity, SAT EGFR mRNA was negatively correlated with insulin resistance, but did not change in obesity. Of note, both SAT and VAT EGFR mRNA were significantly associated with adipogenesis and increased during human adipocyte differentiation. In vitro experiments revealed that EGFR, but not ERBB2 and ERBB4, gene knockdown in preadipocytes and in fully differentiated human adipocytes resulted in decreased expression of adipogenic-related genes. ERBB2 gene knockdown also reduced gene expression of fatty acid synthase in fully differentiated adipocytes. In addition, neuregulin 2 (NRG2) mRNA was associated with expression of adipogenic genes in human adipose tissue and adipocytes, and its overexpression increased expression of EGFR and relevant adipogenic genes. Conclusions: This study demonstrates the association between adipose tissue ERBB2 and obesity, confirms the relevance of EGFR on human adipogenesis, and suggests a possible adipogenic role of NRG2.

Research paper thumbnail of Serum neuregulin 4 is negatively correlated with insulin sensitivity in humans and impairs mitochondrial respiration in HepG2 cells

Frontiers in Physiology

Neuregulin 4 (NRG4) has been described to improve metabolic disturbances linked to obesity status... more Neuregulin 4 (NRG4) has been described to improve metabolic disturbances linked to obesity status in rodent models. The findings in humans are controversial. We aimed to investigate circulating NRG4 in association with insulin action in humans and the possible mechanisms involved. Insulin sensitivity (euglycemic hyperinsulinemic clamp) and serum NRG4 concentration (ELISA) were analysed in subjects with a wide range of adiposity (n = 89). In vitro experiments with human HepG2 cell line were also performed. Serum NRG4 was negatively correlated with insulin sensitivity (r = −0.25, p = 0.02) and positively with the inflammatory marker high-sensitivity C reative protein (hsCRP). In fact, multivariant linear regression analyses showed that insulin sensitivity contributed to BMI-, age-, sex-, and hsCRP-adjusted 7.2% of the variance in serum NRG4 (p = 0.01). No significant associations were found with adiposity measures (BMI, waist circumference or fat mass), plasma lipids (HDL-, LDL-choles...

Research paper thumbnail of A microRNA Cluster Controls Fat Cell Differentiation and Adipose Tissue Expansion By Regulating SNCG

Advanced Science, 2021

The H19X‐encoded miR‐424(322)/503 cluster regulates multiple cellular functions. Here, it is repo... more The H19X‐encoded miR‐424(322)/503 cluster regulates multiple cellular functions. Here, it is reported for the first time that it is also a critical linchpin of fat mass expansion. Deletion of this miRNA cluster in mice results in obesity, while increasing the pool of early adipocyte progenitors and hypertrophied adipocytes. Complementary loss and gain of function experiments and RNA sequencing demonstrate that miR‐424(322)/503 regulates a conserved genetic program involved in the differentiation and commitment of white adipocytes. Mechanistically, it is demonstrated that miR‐424(322)/503 targets γ‐Synuclein (SNCG), a factor that mediates this program rearrangement by controlling metabolic functions in fat cells, allowing adipocyte differentiation and adipose tissue enlargement. Accordingly, diminished miR‐424(322) in mice and obese humans co‐segregate with increased SNCG in fat and peripheral blood as mutually exclusive features of obesity, being normalized upon weight loss. The dat...

Research paper thumbnail of Inflammation triggers specific microRNA profiles in human adipocytes and macrophages and in their supernatants

Clinical Epigenetics, 2015

Research paper thumbnail of Inflammation and insulin resistance exert dual effects on adipose tissue tumor protein 53 expression

International journal of obesity (2005), 2014

The purpose of this study was to investigate the expression of human adipose tissue protein 53 (p... more The purpose of this study was to investigate the expression of human adipose tissue protein 53 (p53) in subjects who varied widely in terms of obesity and insulin resistance. We also analyzed different in vivo and in vitro models to try to comprehend the associations found in humans. p53 was analyzed in human adipose and isolated adipocytes, in high fat-fed and GLP-1R KO mice, during in vitro adipogenesis, and in adipocytes after high glucose, rosiglitazone and inflammatory conditions. The effects of surgery-induced weight loss and ex vivo metformin were also evaluated. Omental (OM) p53 gene expression (+27%, P=0.001) and protein (+11%, P=0.04) were increased in obese subjects and high fat diet-induced obese mice (+86%, P=0.018). Although the obesity-associated inflammatory milieu was associated with increased OM p53, this was negatively related to insulin resistance and glycated hemoglobin, and positively with biomarkers for insulin sensitivity. Multiple linear regression analyses ...

Research paper thumbnail of LIGHT is associated with hypertriglyceridemia in obese subjects and increased cytokine secretion from cultured human adipocytes

International journal of obesity (2005), 2010

LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry... more LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells) is a member of the tumor necrosis factor (TNF) family, primarily expressed in lymphocytes, which was associated with the induction of pro-inflammatory cytokines and alterations of lipid homeostasis in animal models. We aimed to analyze whether LIGHT has a role in the human obesity-associated inflammatory status. The association between circulating LIGHT concentrations and clinical variables was studied in 190 subjects with different degrees of obesity and glucose tolerance. The expression and release of 21 different cytokines, and the expression of genes involved in lipid metabolism were also evaluated after stimulation with LIGHT in cultured human differentiated adipocytes. Serum LIGHT concentrations positively associated with body mass index (BMI), fat mass, glycated hemoglobin and fasting triglycerides, and negatively with high-density lipoprotein cholesterol. Circulating...

Research paper thumbnail of Thyroid hormone responsive Spot 14 increases during differentiation of human adipocytes and its expression is down-regulated in obese subjects

International Journal of Obesity, 2009

Context: Very limited information is available regarding the function of human thyroid hormone re... more Context: Very limited information is available regarding the function of human thyroid hormone responsive Spot 14 (human S14, hS14) in adipogenesis and human adiposity. Objective: To evaluate hS14 levels during differentiation of human pre-adipocytes, in human fat depots and isolated fat cells. Design: This was a cross-sectional study. Subjects: A total of 161 omental (OM) and 87 subcutaneous (SC) adipose tissue samples obtained during elective surgical procedures from a population who varied widely in terms of obesity. Measurements: hS14 gene expression and protein levels during adipogenesis were assessed by RT-PCR, western blot, and using an automated confocal imaging approach. Results: hS14 gene expression levels were decreased in OM adipose tissue from overweight (À42.0%) and obese subjects (À56.5%) compared with lean subjects (Po0.05 and Po0.0001, respectively). hS14 mRNA (but not hS14-related) was inversely associated with obesity measures such as body mass index (P ¼ 0.001), percent fat mass (P ¼ 0.001), waist-to-hip ratio (P ¼ 0.020), and systolic blood pressure (P ¼ 0.031). hS14 gene expression and protein levels were up-regulated at the early stages of differentiation of human pre-adipocytes as well as for 3T3-L1 cells. That observation was most prominent in those individual cells exhibiting the more marked differentiation features. hS14 gene expression levels increased by B45 000-fold in mature adipocytes. Increased hS14 levels were also found in stromal-vascular cells/pre-adipocytes (3.8-fold, Po0.05) and in adipose tissue samples (1.9-fold, Po0.0001) from SC compared with OM fat depots. Conclusions: These results suggest that hS14 is involved in human adipogenesis, but inversely related to obesity and OM fat accumulation.

Research paper thumbnail of The lung innate immune gene surfactant protein-D is expressed in adipose tissue and linked to obesity status

International Journal of Obesity, 2013

BACKGROUND: Surfactant protein-D (SFTPD) is a component of the lung innate immunity that enhances... more BACKGROUND: Surfactant protein-D (SFTPD) is a component of the lung innate immunity that enhances clearance of pathogens and modulates inflammatory responses. An inverse association of putative, lung-derived circulating SFTPD with obesity has been reported but no information is available concerning possible SFTPD gene expression in human adipose tissue. METHODS: SFTPD gene expression was analyzed in human omental (OM; n ¼ 156) and subcutaneous (SC; n ¼ 106) adipose tissue, and in isolated fat cells (n ¼ 12) in association with measures of obesity and glucose tolerance. RESULTS: SFTPD gene was expressed in human adipose tissue and adipocytes. This expression was decreased in OM and SC adipose tissue from obese subjects with (À 47%, Po0.0001; and À 37%, P ¼ 0.048) and without (À 34%, P ¼ 0.001; and À 22%, P ¼ 0.08; respectively) type 2 diabetes when compared with the control group. Indeed, OM SFTPD was inversely associated with body mass index (r ¼ À 0.33, Po0.0001), percent fat mass (r ¼ À 0.36, Po0.0001), waist perimeter (r ¼ À 0.26, P ¼ 0.002), diastolic blood pressure (r ¼ À 0.21, P ¼ 0.018) and fasting glucose (r ¼ À 0.21, P ¼ 0.012); and positively linked to the expression of insulin receptor substrate 1 (IRS1; r ¼ 0.25, P ¼ 0.004), perilipin A (PLIN; r ¼ 0.38, P ¼ 0.007) and fatty acid synthase (FASN; r ¼ 0.36, Po0.0001). Accordingly, increased SFTPD (4.5-fold, P ¼ 0.02) was detected in isolated adipocytes when compared with the stromalvascular cell fraction, in parallel to IRS1, FASN and PLIN. CONCLUSIONS: Both OM and SC adipose tissue (mainly mature adipocytes) express SFTPD. This expression decreases with obesity and impaired glucose tolerance.

Research paper thumbnail of Circulating soluble transferrin receptor concentration decreases after exercise-induced improvement of insulin sensitivity in obese individuals

Int J Obes (Lond), 2009

Background: Circulating soluble transferrin receptor (sTfR) has been recently found to be associa... more Background: Circulating soluble transferrin receptor (sTfR) has been recently found to be associated negatively with insulin sensitivity. Objective: To evaluate circulating sTfR concentration after changing insulin sensitivity in obese individuals. Design: Circulating sTfR concentration was evaluated after diet-induced weight loss in obese women (diet (D) group, n=8); after diet-induced weight loss plus resistance training (D+RT group, n=11); and after follow-up without weight loss (control (C) group, n=7). Results: After 16 weeks, insulin sensitivity (HOMA (Homeostasis Model Assessment) value) significantly improved in parallel to weight loss (-7.3%) and reduced total fat mass (evaluated using magnetic resonance imaging) in the D group. Thigh muscle mass decreased significantly (P=0.03). Serum sTfR concentration did not change significantly. In the D+RT group, weight loss (-8.7%) and improvement of insulin sensitivity were of similar magnitude. Thigh muscle mass was preserved (P=0.8). Serum sTfR concentration decreased significantly (P=0.001). Interestingly, higher the thigh muscle volume after weight loss, higher the decrease in circulating sTfR concentration. We also found that higher the increases in leg force at week 16, higher the decrease in circulating sTfR concentration in all individuals as a whole. No significant changes were observed in insulin sensitivity, sTfR concentration or thigh muscle mass in the C group. Conclusion: These findings suggest a long-term regulation of serum sTfR concentration by exercise-induced improvement of insulin sensitivity in obese individuals.

Research paper thumbnail of Coxsackie and Adenovirus Receptor is increased in adipose tissue of obese subjects: A role for adenovirus infection?

The Journal of clinical endocrinology and metabolism, Jan 2, 2014

Context: The Coxsackie and Adenovirus Receptor (CAR) was originally identified as a common recept... more Context: The Coxsackie and Adenovirus Receptor (CAR) was originally identified as a common receptor for coxsackie B viruses and type C adenoviruses Objective: To investigate CAR gene expression in human adipose tissue to explore its associations with adipocyte physiology. Design and Setting: This was an ex vivo study in 91 visceral (VAT) and 109 subcutaneous adipose tissue (SAT) human samples (61 paired) obtained during elective surgical procedures Patients: Patients were recruited at the Endocrinology Service of the Hospital Universitari Dr. Josep Trueta Main outcome measure: CAR mRNA was measured in human adipose tissue samples and confirmed at protein level and in adipose tissue fractions. The effects of inflammatory stimuli on CAR gene expression were also evaluated. Results: In paired samples, CAR was 46-fold higher in VAT vs. SAT (p<0.0001), being higher also at protein level (p = 0.04). CAR was predominantly found in stromal vascular cell fraction (SVF) in both fat depots....

Research paper thumbnail of The MRC1/CD68 Ratio Is Positively Associated with Adipose Tissue Lipogenesis and with Muscle Mitochondrial Gene Expression in Humans

PLoS ONE, 2013

Background: Alternative macrophages (M2) express the cluster differentiation (CD) 206 (MCR1) at h... more Background: Alternative macrophages (M2) express the cluster differentiation (CD) 206 (MCR1) at high levels. Decreased M2 in adipose tissue is known to be associated with obesity and inflammation-related metabolic disturbances. Here we aimed to investigate MCR1 relative to CD68 (total macrophages) gene expression in association with adipogenic and mitochondrial genes, which were measured in human visceral [VWAT, n = 147] and subcutaneous adipose tissue [SWAT, n = 76] and in rectus abdominis muscle (n = 23). The effects of surgery-induced weight loss were also longitudinally evaluated (n = 6). Results: MCR1 and CD68 gene expression levels were similar in VWAT and SWAT. A higher proportion of CD206 relative to total CD68 was present in subjects with less body fat and lower fasting glucose concentrations. The ratio MCR1/CD68was positively associated with IRS1gene expression and with the expression of lipogenic genes such as ACACA, FASN and THRSP, even after adjusting for BMI. The ratio MCR1/CD68 in SWAT increased significantly after the surgery-induced weight loss (+44.7%; p = 0.005) in parallel to the expression of adipogenic genes. In addition, SWAT MCR1/CD68ratio was significantly associated with muscle mitochondrial gene expression (PPARGC1A, TFAM and MT-CO3). AT CD206 was confirmed by immunohistochemistry to be specific of macrophages, especially abundant in crown-like structures. Conclusion: A decreased ratio MCR1/CD68 is linked to adipose tissue and muscle mitochondrial dysfunction at least at the level of expression of adipogenic and mitochondrial genes.

Research paper thumbnail of MiRNA Expression Profile of Human Subcutaneous Adipose and during Adipocyte Differentiation

Research paper thumbnail of Human omental and subcutaneous adipose tissue exhibit specific lipidomic signatures

The FASEB Journal, 2013

Despite their differential effects on human metabolic pathophysiology, the differences in omental... more Despite their differential effects on human metabolic pathophysiology, the differences in omental and subcutaneous lipidomes are largely unknown. To explore this field, liquid chromatography coupled with mass spectrometry was used for lipidome analyses of adipose tissue samples (visceral and subcutaneous) selected from a group of obese subjects (n‫.)83؍‬ Transcriptomics and in vitro studies in adipocytes were used to confirm the pathways affected by location. The analyses revealed the existence of obesityrelated specific lipidome signatures in each of these locations, attributed to selective enrichment of specific triglycerides, glycerophospholipids, and sphingolipids, because these were not observed in adipose tissues from nonobese individuals. The changes were compatible with subcutaneous enrichment in pathways involved in adipogenesis, triacylglyceride synthesis, and lipid droplet formation, as well as increased ␣-oxidation. Marked differences between omental and subcutaneous depots in obese individuals were seen in the association of lipid species with metabolic traits (body mass index and insulin sensitivity). Targeted studies also revealed increased cholesterol (⌬56%) and cholesterol epoxide (⌬34%) concentrations in omental adi-pose tissue. In view of the effects of cholesterol epoxide, which induced enhanced expression of adipocyte differentiation and ␣-oxidation genes in human omental adipocytes, a novel role for cholesterol epoxide as a signaling molecule for differentiation is proposed. In summary, in obesity, adipose tissue exhibits a locationspecific differential lipid profile that may contribute to explaining part of its distinct pathogenic role.

Research paper thumbnail of Characterization of Herpes Virus Entry Mediator as a Factor Linked to Obesity

Research paper thumbnail of Subcutaneous Fat Shows Higher Thyroid Hormone Receptor-α1 Gene Expression Than Omental Fat

Research paper thumbnail of Circulating omentin concentration increases after weight loss

Nutrition & Metabolism, 2010

Background Omentin-1 is a novel adipokine expressed in visceral adipose tissue and negatively ass... more Background Omentin-1 is a novel adipokine expressed in visceral adipose tissue and negatively associated with insulin resistance and obesity. We aimed to study the effects of weight loss-induced improved insulin sensitivity on circulating omentin concentrations. Methods Circulating omentin-1 (ELISA) concentration in association with metabolic variables was measured in 35 obese subjects (18 men, 17 women) before and after hypocaloric weight loss. Results Baseline circulating omentin-1 concentrations correlated negatively with BMI (r = -0.58, p < 0.001), body weight (r = -0.35, p = 0.045), fat mass (r = -0.67, p < 0.001), circulating leptin (r = -0.7, p < 0.001) and fasting insulin (r = -0.37, p = 0.03). Circulating omentin-1 concentration increased significantly after weight loss (from 44.9 ± 9.02 to 53.41 ± 8.8 ng/ml, p < 0.001). This increase in circulating omentin after weight loss was associated with improved insulin sensitivity (negatively associated with HOMA value ...

Research paper thumbnail of Study of caveolin-1 gene expression in whole adipose tissue and its subfractions and during differentiation of human adipocytes

Nutrition & Metabolism, 2010

Context: Caveolins are 21-24 kDa integral membrane proteins that serve as scaffolds to recruit nu... more Context: Caveolins are 21-24 kDa integral membrane proteins that serve as scaffolds to recruit numerous signaling molecules. Specific subclasses of caveolae carry out specific functions in cell metabolism. In particular, triglycerides are synthesized at the site of fatty acid entry in one of these caveolae classes. Objective and Methods: We studied the expression of caveolin-1 (CAV-1) gene in association with metabolic variables in 90 visceral and 55 subcutaneous adipose tissue samples from subjects with a wide range of fat mass, in the stromovascular fraction (SVC) and isolated adipocytes, and during differentiation of human adipocytes. Results: CAV-1 gene expression was significantly decreased in visceral adipose tissue (v-CAV-1) of obese subjects. v-CAV-1 was positively associated with several lipogenic genes such as acetyl-coA carboxylase (ACACA, r = 0.34, p = 0.004) and spot-14 (r = 0.33, p = 0.004). In non-obese subjects v-CAV-1 also correlated with fatty acid synthase (FAS, r = 0.60, p < 0.0001). Subcutaneous (sc) adipose tissue (sc-CAV-1) gene expression was not associated with these lipogenic factors when obese and non-obese subjects were studied together. In obese subjects, however, sc-CAV-1 was associated with fatty acid synthase (FAS, r = 0.36, p = 0.02), sterol regulatory element binding protein-1c (SREBP-1c (r = 0.58, p < 0.0001), ACACA (r = 0.33, p = 0.03), spot-14 (r = 0.36, p = 0.02), PPAR-γ co-activator-1 (PGC-1, r = 0.88, n = 19). In these obese subjects, sc-CAV-1 was also associated with fasting triglycerides (r =-0.50, p < 0.0001). CAV-1 expression in mature adipocytes was significantly higher than in stromal vascular cells. CAV-1 gene expression in adipocytes from subcutaneous adipose tissue (but not in adipocytes from visceral adipose tissue) was significatively associated with fasting triglycerides. CAV-1 gene expression did not change significantly during differentiation of human preadipocytes from lean or obese subjects despite significant increase of FAS gene expression. Conclusion: Decreased CAV-1 gene expression was simultaneously linked to increased triglycerides and decreased lipogenic gene expression among obese subjects, paralleling the observations of hypertriglyceridemia in CAV-1 knockout mice. However, the regulation of CAV-1 gene expression seems independent of the adipogenic program.

Research paper thumbnail of Effect of Massive Weight Loss on Inflammatory Adipocytokines and the Innate Immune System in Morbidly Obese Women

The Journal of Clinical Endocrinology & Metabolism, 2007

Context: Obesity may be regarded as a low-grade inflammatory state.Objective: The aim of this stu... more Context: Obesity may be regarded as a low-grade inflammatory state.Objective: The aim of this study was to evaluate changes in pro-inflammatory adipocytokines and the innate immune system, cardiovascular risk, and insulin sensitivity after massive weight loss.Design: This was a longitudinal study.Setting: The study was conducted at Catholic University, Rome.Subjects and Methods: There were 10 normoglucose-tolerant obese women evaluated before and 36 months after bilio-pancreatic diversion (BPD). Glucose sensitivity (M value) was estimated using the euglycemic-hyperinsulinemic clamp. Mannan-binding lectin (MBL), bactericidal/permeability increasing protein (BPI), α-defensins, soluble CD14 receptor (sCD14), C-reactive protein, adiponectin, leptin, visfatin, IL-6, and TNF-α were assayed.Results: After massive weight loss (53% of excess body weight), leptin (P ≤ 0.0001), IL-6 (P ≤ 0.0001), α-defensins (P ≤ 0.001), and C-reactive protein (P ≤ 0.0001) decreased significantly. Adiponectin ...

Research paper thumbnail of Circulating Pigment Epithelium-Derived Factor Levels Are Associated with Insulin Resistance and Decrease after Weight Loss

The Journal of Clinical Endocrinology & Metabolism, 2010

Objective: We aimed to study circulating pigment epithelium-derived factor (PEDF) in vivo in asso... more Objective: We aimed to study circulating pigment epithelium-derived factor (PEDF) in vivo in association with insulin resistance and in vitro in human adipocytes. Methods: Circulating PEDF (ELISA) and metabolic profile were assessed in 125 Caucasian men. PEDF levels were also assessed in an independent cohort of subjects (n = 33) to study the effects of changing insulin action. PEDF gene expression and secretion were measured during differentiation of human preadipocytes. Results: In all subjects, PEDF was positively associated with body mass index (r = 0.326; P < 0.0001), waist-to-hip ratio (r = 0.380; P < 0.0001), HbA1c, and fasting triglycerides and negatively with insulin sensitivity (r = −0.320; P < 0.0001). PEDF levels were significantly increased in subjects with altered glucose tolerance and type 2 diabetes. Of the inflammatory markers measured, PEDF levels were positively associated with serum soluble TNF-α receptor 1 and IL-10 in obese subjects. Interestingly, wei...