Javier Gómez-Ambrosi

Body mass index classification misses subjects with increased cardiometabolic risk factors related to elevated adiposity

Context:Body mass index (BMI) is widely used as a measure of overweight and obesity, but underestimates the prevalence of both conditions, defined as an excess of body fat.Objective:We assessed the degree of misclassification on the diagnosis of obesity using BMI as compared with direct body fat percentage (BF%) determination and compared the cardiovascular and metabolic risk of non-obese and obese BMI-classified subjects with similar BF%.Design:We performed a cross-sectional study.Subjects:A total of 6123 (924 lean, 1637 overweight and 3562 obese classified according to BMI) Caucasian subjects (69% females), aged 18–80 years.Methods:BMI, BF% determined by air displacement plethysmography and well-established blood markers of insulin sensitivity, lipid profile and cardiovascular risk were measured.Results:We found that 29% of subjects classified as lean and 80% of individuals classified as overweight according to BMI had a BF% within the obesity range. Importantly, the levels of cardiometabolic risk factors, such as C-reactive protein, were higher in lean and overweight BMI-classified subjects with BF% within the obesity range (men 4.3±9.2, women 4.9±19.5 mg l−1) as well as in obese BMI-classified individuals (men 4.2±5.5, women 5.1±13.2 mg l−1) compared with lean volunteers with normal body fat amounts (men 0.9±0.5, women 2.1±2.6 mg l−1; P<0.001 for both genders).Conclusion:Given the elevated concentrations of cardiometabolic risk factors reported herein in non-obese individuals according to BMI but obese based on body fat, the inclusion of body composition measurements together with morbidity evaluation in the routine medical practice both for the diagnosis and the decision-making for instauration of the most appropriate treatment of obesity is desirable.

The relationship of serum osteocalcin concentration to insulin secretion, sensitivity and disposal with hypocaloric diet and resistance training

CONTEXT Bone has recently been described as exhibiting properties of an endocrine organ by producing osteocalcin that increases insulin sensitivity and secretion in animal models. OBJECTIVE AND DESIGN We aimed to evaluate circulating osteocalcin in association with insulin sensitivity and insulin secretion in three different studies in nondiabetic subjects: one cross-sectional study in 149 men (using minimal model), and two longitudinal studies in two independent groups (one formed by 26 women, and the other by 9 men and 11 women), after a mean of 7.3 and 16.8% weight loss, and after a mean of 8.7% weight loss plus regular exercise. RESULTS In the cross-sectional study, circulating osteocalcin was associated with insulin sensitivity, mainly in lean subjects, and with insulin secretion (only in lean subjects). A mean of 16.8%, but not 7.3% weight loss, led to significant increases in circulating osteocalcin. However, a mean of 8.7% weight loss plus regular exercise led to the more pronounced effects on the serum osteocalcin concentration, which increased in parallel to reduced visceral fat mass, unchanged thigh muscle mass, and increased leg strength and force. The postintervention serum levels of osteocalcin were associated with both insulin sensitivity (r = 0.49; P = 0.03) and fasting triglycerides (r = -0.54; P = 0.01). The change in visceral fat was the parameter that best predicted the change in serum osteocalcin, once age, body mass index, and insulin sensitivity changes were controlled for (P = 0.002). CONCLUSION Circulating osteocalcin could mediate the role of bone as an endocrine organ in humans.

Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes

Objectives:The orexigenic hormone ghrelin circulates mainly in two forms, acylated and desacyl ghrelin. We evaluated the impact of obesity and obesity-associated type 2 diabetes (T2D) on ghrelin forms and the potential role of acylated and desacyl ghrelin in the control of adipogenesis in humans.Methods:Plasma concentrations of the different ghrelin forms were measured in 80 subjects. The expression of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) was analyzed in omental adipose tissue using western blot and immunohistochemistry, and the effect of acylated ghrelin and desacyl ghrelin (0.1–1000 pmol l−1) on adipogenesis was determined in vitro in omental adipocytes.Results:Circulating concentrations of acylated ghrelin were increased, whereas desacyl ghrelin levels were decreased, in obesity and obesity-associated T2D. Body mass index, waist circumference, insulin and HOMA (homeostasis model assessment) index were positively correlated with acylated ghrelin levels. Obese individuals showed a lower protein expression of GHS-R in omental adipose tissue. In differentiating omental adipocytes, incubation with both acylated and desacyl ghrelin significantly increased PPARγ (peroxisome proliferator-activated receptor γ) and SREBP1 (sterol-regulatory element binding protein-1) mRNA levels, as well as several fat storage-related proteins, including acetyl-CoA carboxylase, fatty acid synthase, lipoprotein lipase and perilipin. Consequently, both the ghrelin forms stimulated intracytoplasmatic lipid accumulation.Conclusions:Both acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes. Given the lipogenic effect of acylated ghrelin on visceral adipocytes, the herein-reported elevation of its circulating concentrations in obese individuals may play a role in excessive fat accumulation in obesity.

Targeting the Circulating MicroRNA Signature of Obesity

BACKGROUND Genomic studies have yielded important insights into the pathogenesis of obesity. Circulating microRNAs (miRNAs) are valuable biomarkers of systemic diseases and potential therapeutic targets. We sought to define the circulating pattern of miRNAs in obesity and examine changes after weight loss. METHODS We assessed the genomewide circulating miRNA profile cross-sectionally in 32 men and after surgery-induced weight loss in 6 morbidly obese patients. The most relevant miRNAs were cross-sectionally validated in 80 men and longitudinally in 22 patients (after surgery-induced weight loss). We evaluated the effects of diet-induced weight loss in 9 obese patients. Thirty-six circulating miRNAs were associated with anthropometric variables in the initial sample. RESULTS In the validation study, morbidly obese patients showed a marked increase of miR-140-5p, miR-142-3p (both P < 0.0001), and miR-222 (P = 0.0002) and decreased levels of miR-532-5p, miR-125b, miR-130b, miR-221, miR-15a, miR-423-5p, and miR-520c-3p (P < 0.0001 for all). Interestingly, in silico targets leukemia inhibitory factor receptor (LIFR) and transforming growth factor receptor (TGFR) of miR-140-5p, miR-142-3p, miR-15a, and miR-520c-3p circulated in association with their corresponding miRNAs. Moreover, a discriminant function of 3 miRNAs (miR-15a, miR-520c-3p, and miR-423-5p) was specific for morbid obesity, with an accuracy of 93.5%. Surgery-induced (but not diet-induced) weight loss led to a marked decrease of miR-140-5p, miR-122, miR-193a-5p, and miR-16-1 and upregulation of miR-221 and miR-199a-3p (P < 0.0001 for all). CONCLUSIONS Circulating miRNAs are deregulated in severe obesity. Weight loss-induced changes in this profile and the study of in silico targets support this observation and suggest a potential mechanistic relevance.

The Decrease in Plasma Ghrelin Concentrations following Bariatric Surgery Depends on the Functional Integrity of the Fundus

Background: Gastric bypass surgery, which involves the production of a reduced stomach pouch,has been shown to markedly suppress circulating ghrelin concentrations. Since bypassing the ghrelin-producing cell population may be relevant to the disruption of fundic-derived factors participating in food intake signaling, the effect of weight loss induced by either adjustable gastric banding (AGB), Roux-en-Y gastric bypass (RYGBP) or biliopancreatic diversion (BPD) was studied. Methods: 16 matched obese patients [35.0 + 2.4 years; initial body weight 124.8 ± 5.7 kg; body mass index (BMI) 47.1 ± 2.2 kg/m2] in whom similar weight loss had been achieved by either AGB (n=7), RYGBP (n=6) or BPD (n=3) were studied. Blood was obtained for biochemical and hormonal analyses. Body composition was assessed by air-displacement-plethysmography. Results: Comparable weight loss (AGB: 26.1 ± 5.1 kg; RYGBP: 32.1 ± 5.0; BPD: 31.7 ± 6.1; P=NS) and decrease in percentage body fat (AGB: 10.0 ± 1.5%; RYGBP: 14.2 ± 2.8; BPD: 10.3 ± 1.0; P=NS) induced by bariatric surgery exerted significantly different (P=0.004) effects on plasma ghrelin concentrations, depending on the surgical procedure applied (AGB: 480 ± 78 pg/ml; RYGBP: 117 ± 34; BPD: 406 ± 86). Without significant differences in BMI, body fat, glucose, triglycerides, cholesterol, insulin and leptin levels, patients who had undergone the RYGBP exhibited statistically significant diminished circulating fasting plasma ghrelin concentrations compared with the other two bariatric techniques which conserve direct contact of the fundus with ingested food (P=0.003 vs AGB and P=0.020 vs BPD). Conclusion: Fasting circulating ghrelin concentrations in patients undergoing diverse bariatric operations depend on the degree of dysfunctionality of the fundus.

Gene expression profile of omental adipose tissue in human obesity

The aim of the present study was to gain insight into the pathophysiology of obesity by comparing the pattern of gene expression of omental adipose tissue of obese and lean volunteers using DNA microarrays. Omental adipose tissue biopsies were obtained by laparoscopic surgery from six male patients (44.2±6.3 yr). RNA was extracted and pooled for the obese (BMI: 37.3±2.5 kg/m2) and lean (BMI: 23.4±0.8 kg/m2) groups. From the total number of genes analyzed (1,152 well‐characterized human genes), 41% were expressed at sufficient levels in human adipose tissue for detection in the microarray experiments, finding that 89 genes were up‐ regulated while 64 were down‐regulated at least twofold in the omental adipose tissue obtained from obese patients. We found a general tendency to blunt lipolysis inducer genes and a global down‐regulation of genes encoding growth factors. Moreover, an up‐regulation in the expression of several mitogen‐activated protein kinases (MAPKs) was observed. The down‐regulation of genes involved in lipolysis activation may be involved in the etiopathogenesis of obesity. In addition, down‐regulation of growth factors and the up‐regulation of MAPKs may indicate an attempt to restrain adipocyte proliferation and differentiation. Furthermore, obesity is accompanied by an altered expression in omental adipose tissue of genes involved not only in energy homeostasis but also in quite diverse biological functions, such as immune response. The genomic approach underlines the importance of adipose tissue beyond energy metabolism.

Circulating omentin concentration increases after weight loss

BackgroundOmentin-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.MethodsCirculating 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.ResultsBaseline 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 and fasting insulin, r = -0.42, p = 0.02 and r = -0.45, p = 0.01, respectively) and decreased BMI (r = -0.54, p = 0.001).ConclusionAs previously described with adiponectin, circulating omentin-1 concentrations increase after weight loss-induced improvement of insulin sensitivity.

Increased adipose tissue expression of lipocalin-2 in obesity is related to inflammation and matrix metalloproteinase-2 and metalloproteinase-9 activities in humans

Lipocalin-2 (LCN2) is a novel adipokine with potential roles in obesity, insulin resistance, and inflammation. The aim of the present work was to evaluate the effect of obesity on circulating concentrations and gene and protein expression levels of LCN2 in human visceral adipose tissue (VAT) as well as its involvement in inflammation. VAT biopsies from 47 subjects were used in the study. Real-time PCR and Western-blot analyses were performed to quantify levels of LCN2 in VAT as well as the association with other genes implicated in inflammatory pathways. Forty-four serum samples were used to analyze the circulating concentrations of LCN2. Zymography analysis was used to determine the activity of matrix metalloproteinase (MMP) in VAT. Obese patients exhibited increased mRNA (p < 0.0001) and protein (p = 0.017) expression levels of LCN2 compared to lean subjects. Although no differences in plasma LCN2 concentrations were observed, increased circulating LCN2/MMP-9 complex levels were found (p = 0.038) in the obese group. Moreover, obese individuals showed increased (p < 0.01) activity of MMP-2 and MMP-9/LCN2 complex, while a positive correlation (p < 0.01) between MMP-2 and MMP-9 activities and BMI was observed. Gene and protein expression levels of LCN2 in VAT were positively associated with inflammatory markers (p < 0.01). These findings represent the first observation that mRNA and protein levels of LCN2 are increased in human VAT of obese subjects. Furthermore, LCN2 is associated with MMP-2 and MMP-9 activities as well as with pro-inflammatory markers suggesting its potential involvement in the low-grade chronic inflammation accompanying obesity.

Fasting plasma Ghrelin concentrations 6 months after gastric bypass are not determined by weight loss or changes in insulinemia

Background: Ghrelin is a gastric peptide with potent orexigenic effects. Circulating ghrelin concentrations are increased in obese subjects, but increase after weight loss. However, in patients undergoing Roux-en-Y gastric bypass (RYGBP), a decrease in ghrelin levels has been reported. The effect of comparable weight loss induced by either adjustable gastric banding (AGB), RYGBP or conventional dietary treatment (Conv) on ghrelinemia was studied. Methods: 24 matched obese male patients in whom similar weight loss had been achieved by either AGB (n=8), RYGBP (n=8) or Conv (n=8) were studied before and 6 months after treatment start. The independence of ghrelin concentrations from body mass index (BMI) and weight loss was further analyzed in a group of patients with total gastrectomy (TtGx, n=6). Results: Comparable weight loss after 6 months exerted significantly different effects on plasma ghrelin concentrations, depending on the procedure applied (AGB: 424.6 ± 32.8 pg/ml; RYGBP: 131.4 ± 13.5; Conv: 457.3 ± 18.7; P<0.001). Without significant differences in body weight and BMI, patients who had undergone the RYGBP exhibited a statistically significant decrease in fasting ghrelin concentrations, while the other two procedures (AGB and Conv) showed a weight loss-induced increase in ghrelin levels. Despite significant differences in BMI between RYGBP and TtGx patients after 6 months (31.9 ± 2.2 vs 22.0 ± 0.7 kg/m2, respectively; P<0.05), both groups showed similar ghrelin concentrations. Conclusion: The reduction in circulating ghrelin concentrations in RYGBP patients after 6 months of surgery are not determined by an active weight loss or an improved insulin-sensitivity but rather depend on the surgically-induced bypass of the ghrelin-producing cell population of the fundus.

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.