Sleep apnea modifies the long‐term impact of surgically induced weight loss on cardiac function and inflammation

Objective:

Obesity is frequently associated with obstructive sleep apnea (OSA). Both conditions are proinflammatory and proposed to deteriorate cardiac function. We used a nested cohort study design to evaluate the long‐term impact of bariatric surgery on OSA and how weight loss and OSA relate to inflammation and cardiac performance.

Design and Methods:

At 10‐year follow‐up in the Swedish Obese Subjects (SOS) study, we identified 19 obese subjects (BMI 31.2 ± 5.3 kg m^?2), who following bariatric surgery at SOS‐baseline had displayed sustained weight losses (surgery group), and 20 obese controls (BMI 42.0 ± 6.2 kg m^?2), who during the same time‐period had maintained stable weight (control group). All study participants underwent overnight polysomnography examination, echocardiography and analysis of inflammatory markers.

Results:

The surgery group displayed a lower apnea hypopnea index (AHI) (19.9 ± 21.5 vs. 37.8 ± 27.7 n/h, P = 0.013), lower inflammatory activity (hsCRP 2.3 ± 3.0 vs. 7.2 ± 5.0 mg L^?1, P < 0.001), reduced left ventricular mass (165 ± 22 vs. 207 ± 22 g, P < 0.001) and superior left ventricular diastolic function (E/A ratio 1.24 ± 1.10 vs. 1.05 ± 0.20, P = 0.006) as compared with weight stable obese controls. In multiple regression analyses including all subjects (n = 39) and controlling for BMI, the AHI remained independently associated with hsCRP (β = 0.09, P < 0.001), TNF‐α (β = 0.03, P = 0.031), IL‐6 (β = 0.01, P = 0.007), IL 10 (β = ?0.06; P = 0.018), left ventricular mass (β = 0.64, P < 0.001), left atrial area (β = 0.08, P = 0.002), pulmonary artery pressure (β = 0.08, P = 0.011) and E/E_a ratio (β = 0.04, P = 0.021).

Conclusions:

Patients with sustained weight loss after bariatric surgery display less severe sleep apnea, reduced inflammatory activity, and enhanced cardiac function. Persisting sleep apnea appears to limit the beneficial effect of weight loss on inflammation and cardiac performance.

     

Retinol‐binding Protein 4 (RBP4) Protein Expression Is Increased in Omental Adipose Tissue of Severely Obese Patients

Visceral fat has been linked to insulin resistance and type 2 diabetes mellitus (T2DM); and emerging data links RBP4 gene expression in adipose tissue with insulin resistance. In this study, we examined RBP4 protein expression in omental adipose tissue obtained from 24 severely obese patients undergoing bariatric surgery, and 10 lean controls (4 males/6 females, BMI = 23.2 ± 1.5 kg/m²) undergoing elective abdominal surgeries. Twelve of the obese patients had T2DM (2 males/10 females, BMI: 44.7 ± 1.5 kg/m²) and 12 had normal glucose tolerance (NGT: 4 males/8 females, BMI: 47.6 ± 1.9 kg/m²). Adipose RBP4, glucose transport protein‐4 (GLUT4), and p85 protein expression were determined by western blot. Blood samples from the bariatric patients were analyzed for serum RBP4, total cholesterol, triglycerides, and glucose. Adipose RBP4 protein expression (NGT: 11.0 ± 0.6; T2DM: 11.8 ± 0.7; lean: 8.7 ± 0.8 arbitrary units) was significantly increased in both NGT (P = 0.03) and T2DM (P = 0.005), compared to lean controls. GLUT4 protein was decreased in both NGT (P = 0.02) and T2DM (P = 0.03), and p85 expression was increased in T2DM subjects, compared to NGT (P = 0.03) and lean controls (P = 0.003). Regression analysis showed a strong correlation between adipose RBP4 protein and BMI for all subjects, as well as between adipose RBP4 and fasting glucose levels in T2DM subjects (r = 0.76, P = 0.004). Further, in T2DM, serum RBP4 was correlated with p85 expression (r = 0.68, P = 0.01), and adipose RBP4 protein trended toward an association with p85 protein (r = 0.55, P = 0.06). These data suggest that RBP4 may regulate adiposity, and p85 expression in obese‐T2DM, thus providing a link to impaired insulin signaling and diabetes in severely obese patients.     

Severe Obesity Is Associated With Impaired Arterial Smooth Muscle Function in Young Adults

The degree of arterial dilatation induced by exogenous nitrates (nitrate‐mediated dilatation, NMD) has been similar in obese and normal‐weight adults after single high‐dose glyceryl trinitrate (GTN). We examined whether NMD is impaired in obesity by performing a GTN dose‐response study, as this is a potentially more sensitive measure of arterial smooth muscle function. In this cross‐sectional study, subjects were 19 obese (age 31.0 ± 1.2 years, 10 male, BMI 44.1 ± 2.1) and 19 age‐ and sex‐matched normal‐weight (BMI 22.4 ± 0.4) young adults. Blood pressure (BP), triglycerides, high‐density lipoprotein (HDL), and low‐density lipoprotein (LDL)‐cholesterol, glucose, insulin, high‐sensitivity C‐reactive protein (hs‐CRP), carotid intima‐media thickness (CIMT), and flow‐mediated dilatation (FMD) were measured. After incremental doses of GTN, brachial artery maximal percent dilatation (maximal NMD) and the area under the dose‐response curve (NMD AUC) were calculated. Maximal NMD (13.4 ± 0.9% vs. 18.3 ± 1.1%, P = 0.002) and NMD AUC (54,316 ± 362 vs. 55,613 ± 375, P = 0.018) were lower in obese subjects. The obese had significantly higher hs‐CRP, insulin, and CIMT and lower HDL‐cholesterol. Significant bivariate associations existed between maximal NMD or NMD AUC and BMI‐group (r = ?0.492, P = 0.001 or r = ?0.383, P = 0.009), hs‐CRP (r = ?0.419, P = 0.004 or r = ?0.351, P = 0.015), and HDL‐cholesterol (r = 0.374, P = 0.01 or r = 0.270, P = 0.05). On multivariate analysis, higher BMI‐group remained as the only significant determinant of maximal NMD (r² = 0.242, β = ?0.492, P = 0.002) and NMD AUC (r² = 0.147, β = ?0.383, P = 0.023). In conclusion, arterial smooth muscle function is significantly impaired in the obese. This may be important in their increased cardiovascular risk.     

Long‐term Successful Weight Loss Improves Vascular Endothelial Function in Severely Obese Individuals

Obesity is associated with increased cardiovascular risk. Although short‐term weight loss improves vascular endothelial function, longer term outcomes have not been widely investigated. We examined brachial artery endothelium‐dependent vasodilation and metabolic parameters in 29 severely obese subjects who lost ≥10% body weight (age 45 ± 13 years; BMI 48 ± 9 kg/m²) at baseline and after 12 months of dietary and/or surgical intervention. We compared these parameters to 14 obese individuals (age 49 ± 11 years; BMI 39 ± 7 kg/m²) who failed to lose weight. For the entire group, mean brachial artery flow‐mediated dilation (FMD) was impaired at 6.7 ± 4.1%. Following sustained weight loss, FMD increased significantly from 6.8 ± 4.2 to 10.0 ± 4.7%, but remained blunted in patients without weight decline from 6.5 ± 4.0 to 5.7 ± 4.1%, P = 0.013 by ANOVA. Endothelium‐independent, nitroglycerin‐mediated dilation (NMD) was unaltered. BMI fell by 13 ± 7 kg/m² following successful weight intervention and was associated with reduced total and low‐density lipoprotein cholesterol, glucose, hemoglobin A_1c, and high‐sensitivity C‐reactive protein (CRP). Vascular improvement correlated most strongly with glucose levels (r = ?0.51, P = 0.002) and was independent of weight change. In this cohort of severely obese subjects, sustained weight loss at 1 year improved vascular function and metabolic parameters. The findings suggest that reversal of endothelial dysfunction and restoration of arterial homeostasis could potentially reduce cardiovascular risk. The results also demonstrate that metabolic changes in association with weight loss are stronger determinants of vascular phenotype than degree of weight reduction.     

Pigment Epithelium‐Derived Factor,Insulin Sensitivity,and Adiposity in Polycystic Ovary Syndrome: Impact of Exercise Training

Pigment epithelium‐derived factor (PEDF) is upregulated in obese rodents and is involved in the development of insulin resistance (IR). We aim to explore the relationships between PEDF, adiposity, insulin sensitivity, and cardiovascular risk factors in obese women with polycystic ovary syndrome (PCOS) and weight‐matched controls and to examine the impact of endurance exercise training on PEDF. This prospective cohort intervention study was based at a tertiary medical center. Twenty obese PCOS women and 14 non‐PCOS weight‐matched women were studied at baseline. PEDF, cardiometabolic markers, detailed body composition, and euglycemic—hyperinsulinemic clamps were performed and measures were repeated in 10 PCOS and 8 non‐PCOS women following 12 weeks of intensified aerobic exercise. Mean glucose infusion rate (GIR) was 31.7% lower (P = 0.02) in PCOS compared to controls (175.6 ± 96.3 and 257.2 ± 64.3 mg.m^?2.min^?1) at baseline, yet both PEDF and BMI were similar between groups. PEDF negatively correlated to GIR (r = ?0.41, P = 0.03) and high‐density lipoprotein (HDL) (r = ?0.46, P = 0.01), and positively to cardiovascular risk factors, systolic (r = 0.41, P = 0.02) and diastolic blood pressure (r = 0.47, P = 0.01) and triglycerides (r = 0.49, P = 0.004). The correlation with GIR was not significant after adjusting for fat mass (P = 0.07). Exercise training maintained BMI and increased GIR in both groups; however, plasma PEDF was unchanged. In summary, PEDF is not elevated in PCOS, is not associated with IR when adjusted for fat mass, and is not reduced by endurance exercise training despite improved insulin sensitivity. PEDF was associated with cardiovascular risk factors, suggesting PEDF may be a marker of cardiovascular risk status.     

TNF‐α Promoter Methylation as a Predictive Biomarker for Weight‐loss Response

Tumor necrosis factor‐α (TNF‐α) is a proinflammatory cytokine which is commonly elevated in obese subjects and whose promoter is susceptible to be regulated by cytosine methylation. The aim of this research was to analyze whether epigenetic regulation of human TNF‐α promoter by cytosine methylation could be involved in the predisposition to lose body weight after following a balanced hypocaloric diet. Twenty‐four patients (12 women/12 men) with excessive body weight‐for‐height (BMI: 30.5 ± 0.32 kg/m²; age: 34 ± 4 years old) followed an 8‐week energy‐restricted diet. Blood mononuclear cell DNA, isolated before the nutritional intervention, was treated with bisulfite and a region of TNF‐α gene promoter (from ?360 to +50 bp) was sequenced. Obese men with successful weight loss (≥5% of initial body weight) showed lower levels of total TNF‐α promoter methylation (r = 0.74; P = 0.021), especially in the positions ?170 bp (r = 0.75, P = 0.005) and ?120 bp (r = 0.70, P = 0.011). Baseline TNF‐α circulating levels were positively associated with total promoter methylation (r = 0.84, P = 0.005) and methylation at position ?245 bp (r = 0.75, P = 0.020). TNF‐α promoter methylation could be a good inflammation marker predicting the hypocaloric diet‐induced weight‐loss, and constitutes a first step toward personalized nutrition based on epigenetic criteria.     

The influence of body composition, fat distribution, and sustained weight loss on left ventricular mass and geometry in obesity

Alterations in left ventricular mass and geometry vary along with the degree of obesity, but mechanisms underlying such covariation are not clear. In a case–control study, we examined how body composition and fat distribution relate to left ventricular structure and examine how sustained weight loss affects left ventricular mass and geometry. At the 10‐year follow‐up of the Swedish obese subjects (SOS) study cohort, we identified 44 patients with sustained weight losses after bariatric surgery (surgery group) and 44 matched obese control patients who remained weight stable (obese group). We also recruited 44 matched normal weight subjects (lean group). Dual‐energy X‐ray absorptiometry, computed tomography, and echocardiography were performed to evaluate body composition, fat distribution, and left ventricular structure. BMI was 42.5 kg/m², 31.5 kg/m², and 24.4 kg/m² for the obese, surgery, and lean groups, respectively. Corresponding values for left ventricular mass were 201.4 g, 157.7 g, and 133.9 g (P < 0.001). In multivariate analyses, left ventricular diastolic dimension was predicted by lean body mass (β = 0.03, P < 0.001); left ventricular wall thickness by visceral adipose tissue (β = 0.11, P < 0.001) and systolic blood pressure (β = 0.02, P = 0.019); left ventricular mass by lean body mass (β = 1.23, P < 0.001), total body fat (β = 1.15, P < 0.001) and systolic blood pressure (β = 2.72, P = 0.047); and relative wall thickness by visceral adipose tissue (β = 0.02, P < 0.001). Left ventricular adjustment to body size is dependent on body composition and fat distribution, regardless of blood pressure levels. Obesity is associated with concentric left ventricular remodeling and sustained 10‐year weight loss results in lower cavity size, wall thickness and mass.     

Plasma MR‐proADM Correlates to BMI and Decreases in Relation to Leptin After Gastric Bypass Surgery

Adrenomedullin (ADM) is a vasoactive peptide found to be related to obesity and its comorbidities: type 2 diabetes, hypertension, atherosclerosis, and coronary heart disease. ADM is increased both in plasma and in adipose tissue of obese individuals when compared to lean subjects and is considered as a member of the adipokine family. We determined plasma midregional proadrenomedullin (MR‐proADM) concentrations in a cohort of 357 subjects with BMI ranging from 17.5 to 42.3 kg/m² and no additional medical history. In parallel, 28 severely obese patients scheduled to undergo laparoscopic Roux‐en‐Y gastric bypass (RYGB) surgery were studied at two time points: before and 1 year after surgery. Outcome measurements were: MR‐proADM, cortisol, leptin, C‐reactive protein (CRP) thyroid‐stimulating hormone (TSH), creatinine and metabolic parameters. BMI correlated significantly to plasma MR‐proADM levels (r = 0.714, P < 0.001), also after adjustment for age and gender (r = 0.767, P < 0.001). In obese subjects, there was a positive relationship between MR‐proADM and leptin (r = 0.511, P = 0.006). Following RYGB, plasma MR‐proADM decreased from 0.76 ± 0.03 to 0.62 ± 0.02 pg/ml (P < 0.0001). RYGB‐induced changes in MR‐proADM correlated significantly to changes in leptin (r = 0.533, P = 0.004) and in CRP (r = 0.429, P = 0.023). We conclude that BMI is an independent predictor of circulating MR‐proADM levels. Weight loss after RYGB is associated with a significant decrease in plasma MR‐proADM, which is related to surgery‐induced changes in both circulating leptin and systemic inflammation.     

Fat Depot‐specific Impact of Visceral Obesity on Adipocyte Adiponectin Release in Women

Our objective was to examine omental and subcutaneous adipocyte adiponectin release in women. We tested the hypothesis that adiponectin release would be reduced to a greater extent in omental than in subcutaneous adipocytes of women with visceral obesity. Omental and subcutaneous adipose tissue samples were obtained from 52 women undergoing abdominal hysterectomies (age: 47.1 ± 4.8 years; BMI: 26.7 ± 4.7 kg/m²). Adipocytes were isolated and their adiponectin release in the medium was measured over 2 h. Measures of body fat accumulation and distribution were obtained using dual‐energy X‐ray absorptiometry and computed tomography, respectively. Adiponectin release by omental and subcutaneous adipocytes was similar in lean individuals; however, in subsamples of obese or visceral obese women, adiponectin release by omental adipocytes was significantly reduced while that of subcutaneous adipocytes was not affected. Omental adipocyte adiponectin release was significantly and negatively correlated with total body fat mass (r = ?0.47, P < 0.01), visceral adipose tissue area (r = ?0.50, P < 0.01), omental adipocyte diameter (r = ?0.43, P < 0.01), triglyceride levels (r = ?0.32, P ≤ 0.05), cholesterol/high‐density lipoprotein (HDL)‐cholesterol (r = ?0.31, P ≤ 0.05), fasting glucose (r = ?0.39, P ≤ 0.01), fasting insulin (r = ?0.36, P ≤ 0.05), homeostasis model assessment index (r = ?0.39, P ≤ 0.01), and positively associated with HDL‐cholesterol concentrations (r = 0.33, P ≤ 0.05). Adiponectin release from subcutaneous cells was not associated with any measure of adiposity, lipid profile, or glucose homeostasis. In conclusion, compared to subcutaneous adipocyte adiponectin release, omental adipocyte adiponectin release is reduced to a greater extent in visceral obese women and better predicts obesity‐associated metabolic abnormalities.     

Health Outcomes of Gastric Bypass Patients Compared to Nonsurgical,Nonintervened Severely Obese

Favorable health outcomes at 2 years postbariatric surgery have been reported. With exception of the Swedish Obesity Subjects (SOS) study, these studies have been surgical case series, comparison of surgery types, or surgery patients compared to subjects enrolled in planned nonsurgical intervention. This study measured gastric bypass effectiveness when compared to two separate severely obese groups not participating in designed weight‐loss intervention. Three groups of severely obese subjects (N = 1,156, BMI ≥ 35 kg/m²) were studied: gastric bypass subjects (n = 420), subjects seeking gastric bypass but did not have surgery (n = 415), and population‐based subjects not seeking surgery (n = 321). Participants were studied at baseline and 2 years. Quantitative outcome measures as well as prevalence, incidence, and resolution rates of categorical health outcome variables were determined. All quantitative variables (BMI, blood pressure, lipids, diabetes‐related variables, resting metabolic rate (RMR), sleep apnea, and health‐related quality of life) improved significantly in the gastric bypass group compared with each comparative group (all P < 0.0001, except for diastolic blood pressure and the short form (SF‐36) health survey mental component score at P < 0.01). Diabetes, dyslipidemia, and hypertension resolved much more frequently in the gastric bypass group than in the comparative groups (all P < 0.001). In the surgical group, beneficial changes of almost all quantitative variables correlated significantly with the decrease in BMI. We conclude that Roux‐en‐Y gastric bypass surgery when compared to severely obese groups not enrolled in planned weight‐loss intervention was highly effective for weight loss, improved health‐related quality of life, and resolution of major obesity‐associated complications measured at 2 years.     

Decreased Liver Fatty Acid Δ‐6 and Δ‐5 Desaturase Activity in Obese Patients

Steatosis in obese nonalcoholic fatty liver disease (NAFLD) patients is a clinicopathological condition associated with depletion of n‐3 polyunsaturated fatty acids (PUFA), a feature that may be related to PUFA desaturation. Liver Δ‐6 and Δ‐5 desaturase (Δ‐6D and Δ‐5D) activities, homeostasis model assessment of insulin resistance (HOMA_IR), and ferric reducing ability of plasma (FRAP) were evaluated in 13 obese patients who underwent subtotal gastrectomy with gastro‐jejunal anastomosis in Roux‐en‐Y and 15 nonobese patients who underwent laparoscopic cholecystectomy (controls). Liver Δ‐6D and Δ‐5D activities in obese patients were 87% and 66% lower than controls (P < 0.001), respectively, with a 62% diminution in the Δ‐6D/Δ‐5D activity ratio (P < 0.02). Δ‐6D inversely correlated with both HOMA_IR (r = ?0.70, P < 0.0001) and oxidative stress assessed as the reciprocal value of FRAP (r = ?0.40, P < 0.05). Δ‐5D negatively correlated with HOMA_IR (r = ?0.48, P < 0.01) but not with FRAP^?1 (r = ?0.13, not significant). In conclusion, liver PUFA desaturation is diminished in obese NAFLD patients, in association with underlying insulin resistance and oxidative stress, which may play a role in altering lipid metabolism favoring fatty infiltration.     

The Macrophage‐Specific Serum Marker,Soluble CD163, Is Increased in Obesity and Reduced After Dietary‐Induced Weight Loss

Objective: Soluble CD163 (sCD163) is a new macrophage‐specific serum marker elevated in inflammatory conditions. sCD163 is elevated in obesity and found to be a strong predictor of the development of type 2 diabetes. We investigated whether dietary intervention and moderate exercise was related to changes in sCD163 and how sCD163 is associated to insulin resistance in obesity. Design and Methods: Ninety‐six obese subjects were enrolled: 62 followed a very low energy diet (VLED) program for 8 weeks followed by 3‐4 weeks of weight stabilization, 20 followed a moderate exercise program for 12 weeks, and 14 were included without any intervention. Fasting blood samples and anthropometric measures were taken at baseline and after intervention. Thirty‐six lean subjects were included in a control group. Results: sCD163 was significantly higher in obese subjects (2.3 ± 1.0 mg/l) compared with lean (1.6 ± 0.4 mg/l, P < 0.001). Weight loss (11%) induced by VLED resulted in a reduction and partial normalization of sCD163 to 2.0 ± 0.9 mg/l (P < 0.001). Exercise for 12 weeks had no effect on sCD163. At baseline, sCD163 was significantly correlated with BMI (r = 0.46), waist circumference (r = 0.40), insulin resistance measured by the homeostasis model assessment (HOMA‐IR; r = 0.41; all P < 0.001), and the leptin‐to‐adiponectin ratio (r = 0.28, P < 0.05). In a multivariate linear regression analysis with various inflammatory markers, sCD163 (β = 0.25), adiponectin (β = ?0.24), and high sensitivity C‐reactive protein (hs‐CRP; β = 0.20) remained independently and significantly associated to HOMA‐IR (all P < 0.05). After further adjustment for waist circumference, only sCD163 was associated with HOMA‐IR (P < 0.05). Conclusion: The macrophage‐specific serum marker sCD163 is increased in obesity and partially normalized by dietary‐induced weight loss but not by moderate exercise. Furthermore, we confirm that sCD163 is a good marker for obesity‐related insulin resistance.     

The Gene Expression of the Main Lipogenic Enzymes is Downregulated in Visceral Adipose Tissue of Obese Subjects

Contradictory findings regarding the gene expression of the main lipogenic enzymes in human adipose tissue depots have been reported. In this cross‐sectional study, we aimed to evaluate the mRNA expression of fatty acid synthase (FAS) and acetyl‐CoA carboxilase (ACC) in omental and subcutaneous (SC) fat depots from subjects who varied widely in terms of body fat mass. FAS and ACC gene expression were evaluated by real time‐PCR in 188 samples of visceral adipose tissue which were obtained during elective surgical procedures in 119 women and 69 men. Decreased sex‐adjusted FAS (?59%) and ACC (?49%) mRNA were found in visceral adipose tissue from obese subjects, with and without diabetes mellitus type 2 (DM‐2), compared with lean subjects (both P < 0.0001). FAS mRNA was also decreased (?40%) in fat depots from overweight subjects (P < 0.05). Indeed, FAS mRNA was significantly and positively associated with ACC gene expression (r = 0.316, P < 0.0001) and negatively with BMI (r = ?0.274), waist circumference (r = ?0.437), systolic blood pressure (r = ?0.310), serum glucose (r = ?0.277), and fasting triglycerides (r = ?0.226), among others (all P < 0.0001). Similar associations were observed for ACC gene expression levels. In a representative subgroup of nonobese (n = 4) and obese women (n = 6), relative FAS gene expression levels significantly correlated (r = 0.657, P = 0.034; n = 10) with FAS protein values. FAS protein levels were also inversely correlated with blood glucose (r = ?0.640, P = 0.046) and fasting triglycerides (r = ?0.832, P = 0.010). In conclusion, the gene expression of the main lipogenic enzymes is downregulated in visceral adipose tissue from obese subjects.     

25‐Hydroxyvitamin D Concentration Correlates With Insulin‐Sensitivity and BMI in Obesity

The prevalence of hypovitaminosis D is high among obese subjects. Further, low 25‐hydroxyvitamin D (25(OH)D) concentration has been postulated to be a risk factor for type 2 diabetes, although its relation with insulin‐sensitivity is not well investigated. Thus, we aimed to investigate the relationship between 25(OH)D concentration and insulin‐sensitivity, using the glucose clamp technique. In total, 39 subjects with no known history of diabetes mellitus were recruited. The association of 25(OH)D concentration with insulin‐sensitivity was evaluated by hyperinsulinemic euglycemic clamp. Subjects with low 25(OH)D (<50 nmol/l) had higher BMI (P = 0.048), parathyroid hormone (PTH) (P = 0.040), total cholesterol (P = 0.012), low‐density lipoprotein (LDL) cholesterol (P = 0.044), triglycerides (P = 0.048), and lower insulin‐sensitivity as evaluated by clamp study (P = 0.047). There was significant correlation between 25(OH)D and BMI (r = ?0.58; P = 0.01), PTH (r = ?0.44; P < 0.01), insulin‐sensitivity (r = 0.43; P < 0.01), total (r = ?0.34; P = 0.030) and LDL (r = ?0.40; P = 0.023) (but not high‐density lipoprotein (HDL)) cholesterol, and triglycerides (r = 0.45; P = 0.01). Multivariate analysis using 25(OH)D concentration, BMI, insulin‐sensitivity, HDL cholesterol, LDL cholesterol, total cholesterol, and triglycerides, as the cofactors was performed. BMI was found to be the most powerful predictor of 25(OH)D concentration (r = ?0.52; P < 0.01), whereas insulin‐sensitivity was not significant. Our study suggested that there is no cause–effect relationship between vitamin D and insulin‐sensitivity. In obesity, both low 25(OH)D concentration and insulin‐resistance appear to be dependent on the increased body size.     

Leptin Responses to Weight Loss in Postmenopausal Women: Relationship to Sex‐Hormone Binding Globulin and Visceral Obesity

Objective: Leptin concentrations increase with obesity and tend to decrease with weight loss. However, there is large variation in the response of serum leptin levels to decreases in body weight. This study examines which endocrine and body composition factors are related to changes in leptin concentrations following weight loss in obese, postmenopausal women. Research Methods and Procedures: Body composition (DXA), visceral obesity (computed tomography), leptin, cortisol, insulin, and sex hormone‐binding globulin (SHBG) concentrations were measured in 54 obese (body mass index [BMI] = 32.0 ± 4.5 kg/m²; mean ± SD), women (60 ± 6 years) before and after a 6‐month hypocaloric diet (250 to 350 kcal/day deficit). Results: Body weight decreased by 5.8 ± 3.4 kg (7.1%) and leptin levels decreased by 6.6 ± 11.9 ng/mL (14.5%) after the 6‐month treatment. Insulin levels decreased 10% (p < 0.05), but mean SHBG and cortisol levels did not change significantly. Relative changes in leptin with weight loss correlated positively with relative changes in body weight (r = 0.50, p < 0.0001), fat mass (r = 0.38, p < 0.01), subcutaneous fat area (r = 0.52, p < 0.0001), and with baseline values of SHBG (r = 0.38, p < 0.01) and baseline intra‐abdominal fat area (r = ?0.27, p < 0.06). Stepwise multiple regression analysis showed that baseline SHBG levels (r² = 0.24, p < 0.01), relative changes in body weight (cumulative r² = 0.40, p < 0.05), and baseline intra‐abdominal fat area (cumulative r² = 0.48, p < 0.05) were the only independent predictors of the relative change in leptin, accounting for 48% of the variance. Discussion: These results suggest that obese, postmenopausal women with a lower initial SHBG and more visceral obesity have a greater decrease in leptin with weight loss, independent of the amount of weight lost.     

Cold‐Induced Adaptive Thermogenesis in Lean and Obese

On entering a cold environment, people react by increasing insulation and energy expenditure (EE). However, large interindividual differences exist in the relative contribution of each mechanism. Short‐term studies revealed that obese subjects increase EE (i.e., adaptive thermogenesis) less than lean subjects, which might have implications for the predisposition to obesity. In this study, we validate the differences in adaptive thermogenesis between lean and obese upon midterm mild cold exposure. Therefore, 10 lean and 10 obese subjects were exposed for 48 h to mild cold (16 °C) in a respiration chamber. The preceding 36 h they stayed in the same chamber at a neutral temperature (22 °C) for the baseline measurements. EE, physical activity, skin temperature, and core temperature have been measured for the last 24 h of both parts. Mean daytime EE increased significantly in the lean subjects (P < 0.01), but not in the obese. Physical activity decreased significantly in the lean (P < 0.01) and the obese (P < 0.001) subjects. The change in EE was related to the change in physical activity in both groups (respectively R² = 0.673, P < 0.01 and R² = 0.454, P < 0.05). Upon mild cold exposure, lean subjects decreased proximal skin temperature less, but distal skin temperature more than obese. In conclusion, the interindividual differences in cold‐induced thermogenesis were related to changes in physical activity in both lean and obese, pointing at the existence of individual variation in physical activity to compensate for cold‐induced thermogenesis. Furthermore, although a large part of the lean subjects counteracted the cold by increasing EE, most obese subjects changed temperature distribution, and therefore, increased insulation.     

Influence of Visceral Obesity and Liver Fat on Vascular Structure and Function in Obese Subjects

Endothelial dysfunction and increased intima–media thickness (IMT) have been found in obese patients. Both regional fat distribution and liver steatosis may influence these markers of subclinical atherosclerosis. We sought to determine the interrelationships of endothelial function, carotid IMT, visceral and subcutaneous adipose tissue accumulation, and liver steatosis in severely obese subjects. In 64 severely obese patients (BMI 42.3 ± 4.3 kg/m²), we determined (i) endothelial function as flow‐mediated dilation (FMD) of the brachial artery, (ii) carotid IMT, (iii) visceral fat diameter, and (iv) degree of liver steatosis using ultrasound. FMD was associated inversely with visceral fat diameter and degree of steatosis (r = ?0.577, P < 0.0001 and r = ?0.523, P < 0.0001, respectively). Carotid IMT correlated with visceral fat mass (r = 0.343, P = 0.007) but not with liver steatosis. After adjustment for conventional cardiovascular risk factors, FMD was predicted independently by the visceral fat diameter, age, and sex (r² = 0.48, P < 0.0001), but not by the degree of liver steatosis or plasma adiponectin levels. In contrast, age and sex were the only predictors of IMT (r² = 0.33, P < 0.001). In obese patients, visceral fat diameter is a major determinant of endothelial dysfunction, independent of traditional risk factors or the degree of liver steatosis and plasma adiponectin. Measurement of visceral fat diameter by ultrasound is a novel and simple method to identify subjects with an increased risk for atherosclerosis within an obese population.     

Improvements in Coronary Heart Disease Risk Indicators by Alternate‐Day Fasting Involve Adipose Tissue Modulations

The ability of alternate‐day fasting (ADF) to modulate adipocyte parameters in a way that is protective against coronary heart disease (CHD) has yet to be tested. Accordingly, we examined the effects of ADF on adipokine profile, body composition, and CHD risk indicators in obese adults. Sixteen obese subjects (12 women/4 men) participated in a 10‐week trial with three consecutive dietary intervention phases: (i) 2‐week baseline control phase, (ii) 4‐week ADF controlled feeding phase, and (iii) 4‐week ADF self‐selected feeding phase. After 8 weeks of treatment, body weight and waist circumference were reduced (P < 0.05) by 5.7 ± 0.9 kg, and 4.0 ± 0.9 cm, respectively. Fat mass decreased (P < 0.05) by 5.4 ± 0.8 kg, whereas fat‐free mass did not change. Plasma adiponectin was augmented (P < 0.05) by 30% from baseline. Leptin and resistin concentrations were reduced (P < 0.05) by 21 and 23%, respectively, post treatment. Low‐density lipoprotein cholesterol (LDL‐C) and triacylglycerol concentrations were 25% and 32% lower (P < 0.05), respectively, after 8 weeks of ADF. High‐density lipoprotein cholesterol (HDL‐C), C‐reactive protein, and homocysteine concentrations did not change. Decreases in LDL‐C were related to increased adiponectin (r = ?0.61, P = 0.01) and reduced waist circumference (r = 0.39, P = 0.04). Lower triacylglycerol concentrations were associated with augmented adiponectin (r = ?0.39, P = 0.04) and reduced leptin concentrations (r = 0.45, P = 0.03) post‐treatment. These findings suggest that adipose tissue parameters may play an important role in mediating the cardioprotective effects of ADF in obese humans.     

A 12‐Week Aerobic Exercise Program Reduces Hepatic Fat Accumulation and Insulin Resistance in Obese,Hispanic Adolescents

The rise in obesity‐related morbidity in children and adolescents requires urgent prevention and treatment strategies. Currently, only limited data are available on the effects of exercise programs on insulin resistance, and visceral, hepatic, and intramyocellular fat accumulation. We hypothesized that a 12‐week controlled aerobic exercise program without weight loss reduces visceral, hepatic, and intramyocellular fat content and decreases insulin resistance in sedentary Hispanic adolescents. Twenty‐nine postpubertal (Tanner stage IV and V), Hispanic adolescents, 15 obese (7 boys, 8 girls; 15.6 ± 0.4 years; 33.7 ± 1.1 kg/m²; 38.3 ± 1.5% body fat) and 14 lean (10 boys, 4 girls; 15.1 ± 0.3 years; 20.6 ± 0.8 kg/m²; 18.9 ± 1.5% body fat), completed a 12‐week aerobic exercise program (4 × 30 min/week at ≥70% of peak oxygen consumption (VO₂peak)). Measurements of cardiovascular fitness, visceral, hepatic, and intramyocellular fat content (magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS)), and insulin resistance were obtained at baseline and postexercise. In both groups, fitness increased (obese: 13 ± 2%, lean: 16 ± 4%; both P < 0.01). In obese participants, intramyocellular fat remained unchanged, whereas hepatic fat content decreased from 8.9 ± 3.2 to 5.6 ± 1.8%; P < 0.05 and visceral fat content from 54.7 ± 6.0 to 49.6 ± 5.5 cm²; P < 0.05. Insulin resistance decreased indicated by decreased fasting insulin (21.8 ± 2.7 to 18.2 ± 2.4 µU/ml; P < 0.01) and homeostasis model assessment of insulin resistance (HOMA_IR) (4.9 ± 0.7 to 4.1 ± 0.6; P < 0.01). The decrease in visceral fat correlated with the decrease in fasting insulin (R² = 0.40; P < 0.05). No significant changes were observed in any parameter in lean participants except a small increase in lean body mass (LBM). Thus, a controlled aerobic exercise program, without weight loss, reduced hepatic and visceral fat accumulation, and decreased insulin resistance in obese adolescents.