Camilo Silva

Body Adiposity and Type 2 Diabetes: Increased Risk With a High Body Fat Percentage Even Having a Normal BMI

Obesity is the major risk factor for the development of prediabetes and type 2 diabetes. BMI is widely used as a surrogate measure of obesity, but underestimates the prevalence of obesity, defined as an excess of body fat. We assessed the presence of impaired glucose tolerance or impaired fasting glucose (both considered together as prediabetes) or type 2 diabetes in relation to the criteria used for the diagnosis of obesity using BMI as compared to body fat percentage (BF%). We performed a cross‐sectional study including 4,828 (587 lean, 1,320 overweight, and 2,921 obese classified according to BMI) white subjects (66% females), aged 18–80 years. BMI, BF% determined by air‐displacement plethysmography (ADP) and conventional blood markers of glucose metabolism and lipid profile were measured. We found a higher than expected number of subjects with prediabetes or type 2 diabetes in the obese category according to BF% when the sample was globally analyzed (P < 0.0001) and in the lean BMI‐classified subjects (P < 0.0001), but not in the overweight or obese‐classified individuals. Importantly, BF% was significantly higher in lean (by BMI) women with prediabetes or type 2 diabetes as compared to those with normoglycemia (NG) (35.5 ± 7.0 vs. 30.3 ± 7.7%, P < 0.0001), whereas no differences were observed for BMI. Similarly, increased BF% was found in lean BMI‐classified men with prediabetes or type 2 diabetes (25.2 ± 9.0 vs. 19.9 ± 8.0%, P = 0.008), exhibiting no differences in BMI or waist circumference. In conclusion, assessing BF% may help to diagnose disturbed glucose tolerance beyond information provided by BMI and waist circumference in particular in male subjects with BMI <25 kg/m2 and over the age of 40.

Circulating betatrophin concentrations are decreased in human obesity and type 2 diabetes.

CONTEXT Betatrophin is a secreted protein recently involved in β-cell replication with a potential role in type 2 diabetes mellitus (T2D). OBJECTIVE The aim of the present study was to compare the circulating concentrations of betatrophin in human obesity and T2D. DESIGN, SETTING, AND PARTICIPANTS Serum concentrations of betatrophin were measured by ELISA in 153 subjects: 75 obese normoglycemic subjects (OB-NG), 30 obese subjects with impaired glucose tolerance (OB-IGT), and 15 obese subjects with T2D (OB-T2D) matched by sex, age, and body adiposity, in comparison with 33 lean normoglycemic individuals (LN-NG). RESULTS Circulating levels of betatrophin were significantly decreased in obese individuals and further diminished in IGT and T2D participants (LN-NG, 45.1 ± 24.4 ng/mL; OB-NG, 26.9 ± 15.4 ng/mL; OB-IGT, 18.3 ± 10.7 ng/mL; OB-T2D, 13.5 ± 8.8 ng/mL; P < .001). A marked sexual dimorphism was found, with betatrophin levels being significantly higher in women than in men (males, 21.1 ± 16.0 ng/mL; females, 34.1 ± 20.1 ng/mL; P < .001). Interestingly, betatrophin levels were positively correlated with the quantitative insulin sensitivity check index (r = 0.46; P < .001) and with high-density lipoprotein-cholesterol concentrations (r = 0.51; P < .001). CONCLUSIONS We conclude that serum betatrophin is decreased in human obesity, being further reduced in obesity-associated insulin resistance. Betatrophin levels are closely related to obesity-associated cardiometabolic risk factors, emerging as a potential biomarker of insulin resistance and T2D.

Clinical Usefulness of a New Equation for Estimating Body Fat

OBJECTIVE To assess the predictive capacity of a recently described equation that we have termed CUN-BAE (Clínica Universidad de Navarra-Body Adiposity Estimator) based on BMI, sex, and age for estimating body fat percentage (BF%) and to study its clinical usefulness. RESEARCH DESIGN AND METHODS We conducted a comparison study of the developed equation with many other anthropometric indices regarding its correlation with actual BF% in a large cohort of 6,510 white subjects from both sexes (67% female) representing a wide range of ages (18–80 years) and adiposity. Additionally, a validation study in a separate cohort (n = 1,149) and a further analysis of the clinical usefulness of this prediction equation regarding its association with cardiometabolic risk factors (n = 634) was carried out. RESULTS The mean BF% in the cohort of 6,510 subjects determined by air displacement plethysmography was 39.9 ± 10.1%, and the mean BF% estimated by the CUN-BAE was 39.3 ± 8.9% (SE of the estimate, 4.66%). In this group, BF% calculated with the CUN-BAE showed the highest correlation with actual BF% (r = 0.89, P < 0.000001) compared with other anthropometric measures or BF% estimators. Similar agreement was found in the validation sample. Moreover, BF% estimated by the CUN-BAE exhibits, in general, better correlations with cardiometabolic risk factors than BMI as well as waist circumference in the subset of 634 subjects. CONCLUSIONS CUN-BAE is an easy-to-apply predictive equation that may be used as a first screening tool in clinical practice. Furthermore, our equation may be a good tool for identifying patients at cardiovascular and type 2 diabetes risk.

Increased Serum Amyloid A Concentrations in Morbid Obesity Decrease after Gastric Bypass

Background: Obesity is considered a state of low-grade chronic inflammation, which may favor the development of cardiovascular diseases. Serum amyloid A (SAA) is an acute phase protein synthesized in response to infection, inflammation, injury, and stress. The aim of the present study was to compare the circulating concentrations of SAA and the mRNA expression in omental adipose tissue between lean and obese individuals and to analyze the effect of weight loss after gastric bypass. Methods: 16 lean volunteers (BMI 20.5 ± 0.6 kg/m2) and 24 obese patients (BMI 47.0 ± 1.2 kg/m2) were included in the study. Serum concentrations of SAA were measured by ELISA. In addition, the concentrations of SAA in 18 morbidly obese patients (7 male/11 female; BMI 44.6 ± 1.9 kg/m2) were measured before and after weight loss following Roux-en-Y gastric bypass (RYGBP). SAA expression in omental adipose tissue was quantified by RT-PCR in biopsies from obese patients undergoing RYGBP and from age-matched lean individuals subjected to Nissen fundoplication. Results: Obese patients exhibited significantly increased circulating SAA concentrations (6.6 ± 0.5 vs 39.3 ± 9.1 μg/ml; P<0.01) compared to lean subjects. A significant positive correlation was found between logSAA and body fat (r=0.631, P<0.0001). Obese patients showed significantly increased (P<0.05) mRNA expression of SAA in omental adipose tissue compared to lean subjects. Weight loss significantly decreased SAA concentrations after RYGBP (final BMI 28.5 ± 0.9 kg/m2, P<0.0001 vs initial) from 47.5 ± 14.5 to 15.7 ± 2.9 μg/ml (P<0.05). Conclusion: It can be concluded that serum SAA and mRNA expression of SAA in omental adipose tissue are increased in obese patients contributing to the obesity-associated cardiovascular disease risk. Moreover, weight loss reduces SAA concentrations, which may contribute to the beneficial effects accompanying weight reduction.

Expression of caveolin‐1 in human adipose tissue is upregulated in obesity and obesity‐associated type 2 diabetes mellitus and related to inflammation

Objective  Caveolin‐1 (CAV‐1) plays important roles in many aspects of cellular biology, including vesicular transport, cholesterol homeostasis and signal transduction. The aim of the present study was to explore gene expression levels of CAV‐1 in human adipose tissue in obesity and obesity‐associated type 2 diabetes mellitus (T2DM) and to analyse its potential implication in the inflammatory state associated with obesity.

Influence of Morbid Obesity and Insulin Resistance on Gene Expression Levels of AQP7 in Visceral Adipose Tissue and AQP9 in Liver

BackgroundGlycerol production and its efflux from adipocytes to the liver are key to modulate lipid and glucose homeostasis. Aquaporin 7 (AQP7) is an aquaglyceroporin that acts as the adipose glycerol channel, whereas aquaporin 9 (AQP9) is the specific channel operating in the liver. The aim of the present work was to evaluate the effect of obesity and type 2 diabetes mellitus (T2DM) on gene expression levels of AQP7 in visceral adipose tissue (VAT) and AQP9 in liver.MethodsVAT and liver biopsies obtained from 20 women were used in the study. Patients were classified as lean or obese with the last group being further subclassified as normoglycemic (NG), patients with impaired glucose tolerance (IGT), or with T2DM. Anthropometric measurements as well as circulating metabolites, hormones, and adipokines were determined. Real-time polymerase chain reaction analyses were performed to quantify transcript levels of AQP7 in VAT and AQP9 in the liver.ResultsGene expression levels of AQP7 in VAT showed a tendency toward an increase (P = 0.065) in obese patients (both NG and T2DM) compared to lean subjects. AQP9 showed a significant downregulation in the hepatic biopsies obtained from obese T2DM patients compared to obese NG and IGT patients (P = 0.028).ConclusionThe tendency toward an elevation of mRNA expression of VAT AQP7 in obesity together with the decreased hepatic AQP9 expression observed in obese T2DM subjects suggests a potential role in facilitating glycerol release from adipose tissue and reducing glycerol entry into hepatocytes in obesity and T2DM, respectively.

Increased Levels of Calprotectin in Obesity Are Related to Macrophage Content: Impact on Inflammation and Effect of Weight Loss

Calprotectin has been recently described as a novel marker of obesity. The aim of this study was to determine the circulating concentrations and expression levels of calprotectin subunits (S100A8 and S100A9) in visceral adipose tissue (VAT), exploring its impact on insulin resistance and inflammation and the effect of weight loss. We included 53 subjects in the study. Gene expression levels of the S100A8/A9 complex were analyzed in VAT as well as in both adipocytes and stromovascular fraction cells (SVFCs). In addition, circulating calprotectin and soluble receptor for the advanced glycation end product (sRAGE) concentrations were measured before and after weight loss achieved by Roux-en-Y gastric bypass (RYGB) (n = 26). Circulating concentrations and VAT expression of S100A8/A9 complex were increased in normoglycemic and type 2 diabetic obese patients (P < 0.01) and associated with markers of inflammation (P < 0.01). Oppositely, concentrations of sRAGE were significantly lower (P < 0.001) in both obese groups compared to lean volunteers. Elevated calprotectin levels in obese patients decreased (P < 0.00001) after RYGB, whereas sRAGE concentrations tended to increase. Calprotectin was mainly expressed by SVFCs, and its expression was significantly correlated (P < 0.01) with mRNA levels of the monocyte-macrophage-related molecules macrophage-specifc antigen CD68 (CD68), monocyte chemotactic protein 1 (MCP1), integrin α-M (CD11B), and NADPH oxidase 2 (NOX2). Tumor necrosis factor-α treatment significantly enhanced (P < 0.05) the mRNA levels of S100 calcium-binding protein A8 (S100A8) of human visceral adipocytes. The increased levels of calprotectin in obesity and obesity-associated type 2 diabetes, its positive association with inflammation as well as the higher expression levels in the SVFCs in VAT suggests a potential role of this protein as a chemotactic factor in the recruitment of macrophages to VAT, increasing inflammation and the development of obesity-associated comorbidities.

Association of increased Visfatin/PBEF/NAMPT circulating concentrations and gene expression levels in peripheral blood cells with lipid metabolism and fatty liver in human morbid obesity

BACKGROUND AND AIMS Nicotinamide phosphoribosyltransferase (NAMPT) is an adipokine with physiological effects on the control of glucose homeostasis as well as potentially involved in inflammation. The association of circulating NAMPT concentrations with obesity has not been clearly established. The aim of the present work was to evaluate the effect of obesity on circulating concentrations and gene expression levels of NAMPT in human peripheral blood cells (PBCs) as well as its involvement in inflammation, glucose and lipid metabolism. METHODS AND RESULTS Forty-four serum samples obtained from 14 lean and 30 obese volunteers were used to analyse the circulating concentrations of NAMPT. In addition, PBC, omental adipose tissue (OM) and liver biopsy samples obtained from a subgroup of subjects were used to determine transcript levels of NAMPT by Real-time PCR. Glucose and lipid profile as well as several inflammatory factors and hepatic enzymes were analysed. NAMPT circulating concentrations (P<0.01) and gene expression levels in PBC (P<0.05) were significantly increased in obese patients as compared to lean subjects. Total-cholesterol (P=0.016), HDL-cholesterol (P=0.036) and triglycerides (P=0.050) were significant and independent determinants of circulating concentrations of NAMPT (P<0.01). Moreover, a positive correlation (P<0.01) was found with the hepatic enzymes alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase after BMI adjustment. CONCLUSION Our work shows that NAMPT circulating concentrations and mRNA expression levels in PBC are increased in obese patients and that plasma NAMPT levels are related to inflammation, lipid metabolism and hepatic enzymes suggesting a potential involvement in fatty liver disease and in the obesity-associated inflammatory state.

Increased Cardiometabolic Risk Factors and Inflammation in Adipose Tissue in Obese Subjects ClassifiedasMetabolicallyHealthy

OBJECTIVE It has been suggested that individuals with the condition known as metabolically healthy obesity (MHO) may not have the same increased risk for the development of metabolic abnormalities as their non–metabolically healthy counterparts. However, the validity of this concept has recently been challenged, since it may not translate into lower morbidity and mortality. The aim of the current study was to compare the cardiometabolic/inflammatory profile and the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) in patients categorized as having MHO or metabolically abnormal obesity (MAO). RESEARCH DESIGN AND METHODS We performed a cross-sectional analysis to compare the cardiometabolic/inflammatory profile of 222 MHO and 222 MAO patients (62% women) matched by age, including 255 lean subjects as reference (cohort 1). In a second cohort, we analyzed the adipokine profile and the expression of genes involved in inflammation and extracellular matrix remodeling in visceral adipose tissue (VAT; n = 82) and liver (n = 55). RESULTS The cardiometabolic and inflammatory profiles (CRP, fibrinogen, uric acid, leukocyte count, and hepatic enzymes) were similarly increased in MHO and MAO in both cohorts. Moreover, above < 30% of patients classified as MHO according to fasting plasma glucose exhibited IGT or T2D. The profile of classic (leptin, adiponectin, resistin) as well as novel (serum amyloid A and matrix metallopeptidase 9) adipokines was almost identical in MHO and MAO groups in cohort 2. Expression of genes involved in inflammation and tissue remodeling in VAT and liver showed a similar alteration pattern in MHO and MAO individuals. CONCLUSIONS The current study provides evidence for the existence of a comparable adverse cardiometabolic profile in MHO and MAO patients; thus the MHO concept should be applied with caution. A better identification of the obesity phenotypes and a more precise diagnosis are needed for improving the management of obese individuals.

Increased levels of chemerin and its receptor, chemokine-like receptor-1, in obesity are related to inflammation: tumor necrosis factor-α stimulates mRNA levels of chemerin in visceral adipocytes from obese patients

BACKGROUND Chemerin is a novel adipokine that regulates adipocyte development and metabolic function and glucose metabolism. Our aim was to determine the effect of chemerin and its receptor, chemokine-like receptor-1, in obesity-associated low-grade chronic inflammation, exploring its circulating and gene expression levels in obesity and the effect of weight loss and to analyze the effect of the stimulation with tumor necrosis factor-α in human visceral adipocytes at a University hospital. METHODS We included 52 women (16 lean and 36 obese) in the present study. The plasma concentrations of chemerin and the expression levels of chemerin and its receptor in visceral adipose tissue were analyzed. The chemerin concentrations were also measured before and after weight loss achieved by Roux-en-Y gastric bypass (n = 26). RESULTS The circulating concentrations and visceral adipose tissue expression of chemerin were increased in obese patients (P < .01) and were associated with well-established markers of inflammation (P < .001). Gene expression levels of chemokine-like receptor-1 followed the same trend and were upregulated (P < .05) in human obesity. Elevated chemerin levels in obese patients did not change after Roux-en-Y gastric bypass weight loss. Tumor necrosis factor-α treatment significantly enhanced (P < .05) the mRNA levels of chemerin in human visceral adipocytes, but the gene expression levels of chemokine-like receptor-1 were not affected. CONCLUSION The increased levels of chemerin in obesity and its positive association with inflammation suggest a role for this chemoattractant protein in the changes that take place in visceral adipose tissue in the presence of energy surplus, establishing a link between inflammation and the greater risk of the development of metabolic disease.