Fat Overload Induces Changes in Circulating Lactoferrin That Are Associated With Postprandial Lipemia and Oxidative Stress in Severely Obese Subjects

Lactoferrin is an innate immune system protein with anti‐inflammatory and antioxidant activities. We aimed to evaluate circulating lactoferrin levels in association with lipid concentrations, and parameters of oxidative stress and inflammation in subjects with morbid obesity after an acute fat intake. The effects of a 60 g fat overload on circulating lactoferrin and antioxidant activities were evaluated in 45 severely obese patients (15 men and 30 women, BMI 53.4 ± 7.2 kg/m²). The change in circulating lactoferrin after fat overload was significantly and inversely associated with the free fatty acid (FFA) change. In those subjects with the highest increase in lactoferrin (in the highest quartile), high‐density lipoprotein (HDL)‐cholesterol decreased after fat overload to a lesser extent (P = 0.03). In parallel to lipid changes, circulating lactoferrin concentrations were inversely linked to the variations in catalase (CAT) and glutathione reductase (GSH‐Rd). Baseline circulating lactoferrin concentration was also inversely associated with the absolute change in antioxidant activity after fat overload, and with the change in C‐reactive protein (CRP). Furthermore, those subjects with higher than the median value of homeostasis model assessment of insulin secretion (HOMA_IS) had significantly increased lactoferrin concentration after fat load (885 ± 262 vs. 700 ± 286 ng/ml, P = 0.03). Finally, we further explored the action of lactoferrin in vitro. Lactoferrin (10 µmol/l) led to significantly lower triglyceride (TG) concentrations and lactate dehydrogenase activity (as expression of cell viability) in the media from adipose explants obtained from severely obese subjects. In conclusion, circulating lactoferrin concentrations, both at baseline and fat‐stimulated, were inversely associated with postprandial lipemia, and parameters of oxidative stress and fat‐induced inflammation in severely obese subjects.     

Restoration of acute insulin response in T2DM subjects 1 month after biliopancreatic diversion

Objective: Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes. Methods and Procedures: Twenty‐one consecutive morbid obese subjects, 9 with type 2 diabetes (T2DM) and 12 with normal fasting glucose (NFG) were evaluated, just before and 1 month after BPD, by measuring body weight (BW), glucose, adipocitokines, homeostasis model assessment of insulin resistance (HOMA‐IR), acute insulin response (AIR) to e.v. glucose and the insulinogenic index adjusted for insulin resistance ([ΔI5/ΔG5]/HOMA‐IR). Results: Preoperatively, those with T2DM differed from those with NFG in showing higher levels of fasting glucose, reduced AIR (57.9 ± 29.5 vs. 644.9 ± 143.1 pmol/l, P < 0.01) and reduced adjusted insulinogenic index (1.0 ± 0.5 vs. 17.6 ± 3.9 1/mmol², P < 0.001). One month following BPD, in both groups BW was reduced (by ～11%), but all subjects were still severely obese; HOMA‐IR and leptin decreased significanlty, while high‐molecular weight (HMW) adiponectin and adjusted insulinogenic index increased. In the T2DM group, fasting glucose returned to non‐diabetic values. AIR did not change in the NFG group, while in the T2DM group it showed a significant increase (from 58.0 ± 29.5 to 273.8 ± 47.2 pmol/l, P < 0.01). In the T2DM group, the AIR percentage variation from baseline was significantly related to changes in fasting glucose (r = 0.70, P = 0.02), suggesting an important relationship exists between impaired AIR and hyperglycaemia. Discussion: BPD is able to restore AIR in T2DM even just 1 month after surgery. AIR restoration is associated with normalization of fasting glucose concentrations.     

Association of Obesity and Hypertension With Left Ventricular Geometry and Function in Children and Adolescents

Obesity, especially when complicated with hypertension, is associated with structural and functional cardiac changes. Recent studies have focused on the prognostic impact of the type of left ventricular (LV) geometric remodeling. This study looked at the prevalence and clinical correlates of LV geometric patterns and their relation to cardiac function in a sample of predominantly African‐American (AA) youth. Echocardiographic data was collected on 213 obese (BMI of 36.53 ± 0.53 kg/m²) and 130 normal‐weight subjects (BMI of 19.73 ± 0.21 kg/m²). The obese subjects had significantly higher LV mass index (LVMI; 49.6 ± 0.9 vs. 46.0 ± 1.0 g/m^2.7, P = 0.01), relative wall thickness (RWT; 0.45 ± 0.00 vs. 0.40 ± 0.00, P < 0.001), left atrial (LA) index (33.2 ± 0.7 vs. 23.5 ± 0.6 ml/m, P < 0.001), more abnormal diastolic function by tissue Doppler E/Ea septal (7.5 ± 0.14 vs. 6.5 ± 0.12 ms, P < 0.001), E/Ea lateral (5.7 ± 0.12 vs. 4.8 ± 0.1 ms, P < 0.001), myocardial performance index (MPI; 0.43 ± 0.00 vs. 0.38 ± 0.00, P < 0.001), and Doppler mitral EA ratio (2.0 ± 0.04 vs. 2.4 ± 0.07, P < 0.001) but similar systolic function. Concentric remodeling (CR) was the most prevalent pattern noted in the obese group and concentric hypertrophy (CH) in the obese and hypertensive group. Obesity, hypertension, and CH were independent predictor of diastolic dysfunction. Systolic (SBP) and diastolic blood pressures (DBP) were the prime mediators for CH whereas obesity and diastolic blood pressure were predictors of CR. No significant association was observed between the geometric patterns and systolic function. Tracking LV hypertrophy (LVH) status and geometric adaptations in obesity may be prognostic tools for assessing cardiac risk and therapeutic end points with weight loss.     

Effect of Lifestyle Modification on Adipokine Levels in Obese Subjects with Insulin Resistance

Objective: To study the effect of weight loss in response to a lifestyle modification program on the circulating levels of adipose tissue derived cytokines (adipokines) in obese individuals with insulin resistance. Research Methods and Procedures: Twenty‐four insulin‐resistant obese subjects with varying degrees of glucose tolerance completed a 6‐month program consisting of combined hypocaloric diet and moderate physical activity. Adipokines [leptin, adiponectin, resistin, tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6)] and highly sensitive C‐reactive protein were measured before and after the intervention. Insulin sensitivity index was evaluated by the frequently sampled intravenous glucose tolerance test. Results: Participants had a 6.9 ± 0.1 kg average weight loss, with a significant improvement in sensitivity index and reduction in plasma leptin (27.8 ± 3 vs. 23.6 ± 3 ng/mL, p = 0.01) and IL‐6 (2.75 ± 1.51 vs. 2.3 ± 0.91 pg/mL, p = 0.012). TNF‐α levels tended to decrease (2.3 ± 0.2 vs. 1.9 ± 0.1 pg/mL, p = 0.059). Adiponectin increased significantly only among diabetic subjects. The reductions in leptin were correlated with the decreases in BMI (r = 0.464, p < 0.05) and with changes in highly sensitive C‐reactive protein (r = 0.466, p < 0.05). Discussion: Weight reduction in obese individuals with insulin resistance was associated with a significant decrease in leptin and IL‐6 and a tendency toward a decrease in circulating TNF‐α, whereas adiponectin was increased only in diabetic subjects. Further studies are needed to elucidate the relationship between changes of adipokines and the health benefits of weight loss.     

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.     

High Prevalence of Prolonged QT Interval in Obese Hypogonadal Males

Obese subjects show several electrocardiographic alterations, including prolonged QT interval, a marker for fatal cardiac arrhythmias. Prolonged QT interval has recently been linked to low testosterone levels, a frequent occurrence in male obese patients but no study has yet assessed whether hypoandrogenism contributes to QT interval prolongation in this population. Aim of this study was to evaluate whether prolonged QT interval is linked to hypogonadism in male obese subjects. QT interval corrected for heart rate (QTc) was measured from standard electrocardiogram recordings in 136 obese men (BMI 30 >kg/m², range 30.1–75.4 kg/m²). Obese men were classified as eugonadal or hypogonadal according to serum total testosterone levels (i.e., greater or less than 9.9 nmol/l). Our study showed that QTc measurements corrected by either Bazett (419 ± 3.2 vs. 408 ± 3.4 ms, P < 0.05), Fridericia (406.3 ± 3.39 vs. 396.4 ± 3.03 ms, P < 0.05) or Hodges (407.0 ± 3.12 vs. 397.3 ± 2.84 ms, P < 0.05) were longer in hypogonadal compared with eugonadal obese men; further, prolonged QTc interval (i.e., >440 ms) was more frequent among hypogonadal compared with eugonadal obese men (23% vs. 10%, P < 0.05). The degree of weight excess, diabetes, sleep apnoea and potassium levels were not associated with prolonged QTc. In conclusion, obese hypogonadal men show a greater prevalence of prolonged QT interval compared with their eugonadal counterparts. It appears therefore that low levels of testosterone in obese men may contribute to the arrhythmogenic profile of these patients, a heretofore unknown link which warrants further clinical attention.     

Lower than predicted resting metabolic rate is associated with severely impaired cardiorespiratory fitness in obese individuals

Obese individuals have reduced cardiorespiratory fitness as compared with leaner counterparts. Regular exercise maintains or increases fitness and lean body mass. Lean body mass, in turn, has a direct impact on resting metabolic rate (RMR). Given these relationships, we sought to evaluate the association between RMR and cardiorespiratory fitness in obese individuals. We evaluated 64 obese individuals (78% female) with direct assessment of RMR and cardiorespiratory fitness via breath‐by‐breath measurement of oxygen consumption and carbon dioxide production at rest and during exercise. The mean age and BMI were 47.4 ± 12.2 years and 47.2 ± 9.2 kg/m², respectively. The majority of subjects, 69%, had a measured RMR above that predicted by the Harris‐Benedict equation. Compared with the higher RMR group, those with a lower than predicted RMR had increased BMI, with values of 52.9 vs. 44.7 kg/m², P = 0.001, respectively. Analysis of those demonstrating significant effort during cardiopulmonary exercise testing (peak respiratory exchange ratio ≥1.10) revealed a significantly higher peak oxygen uptake (VO₂ peak) in the higher RMR group (17.3 ± 3.5 ml/min/kg) compared with the lower RMR group (13.6 ± 1.9 ml/min/kg), P = 0.003. In summary, a lower than predicted RMR was associated with a severely reduced VO₂ peak and a higher BMI in this cohort. These data suggest that morbid obesity may be a vicious cycle of increasing BMI, reduced cardiorespiratory fitness, muscle deconditioning, and lower RMR. Collectively, these responses may, over time, exacerbate the imbalance between energy intake and expenditure, resulting in progressive increases in body weight and fat stores.     

Oxidative Stress in Severely Obese Persons Is Greater in Those With Insulin Resistance

The postprandial state seems to have a direct influence on oxidative status and insulin resistance. We determined the effect of an increase in plasma triglycerides after a high‐fat meal on oxidative stress in severely obese patients with differing degrees of insulin resistance. The study was undertaken in 60 severely obese persons who received a 60‐g fat overload with a commercial preparation. Measurements were made of insulin resistance, the plasma activity of various antioxidant enzymes, the total antioxidant capacity (TAC) and the plasma concentration of thiobarbituric acid reactive substances (TBARS). The patients with greater insulin resistance had a lower plasma superoxide dismutase (SOD) activity (P < 0.05) and a greater glutathione peroxidase (GSH‐Px) activity (P < 0.05). The high‐fat meal caused a significant reduction in SOD activity and an increase in the plasma concentration of TBARS in all the patients. Only the patients with lower insulin resistance experienced a significant increase in plasma catalase activity (2.22 ± 1.02 vs. 2.93 ± 1.22 nmol/min/ml, P < 0.01), remaining stable in the patients with greater insulin resistance. These latter patients had a reduction in plasma TAC (6.92 ± 1.93 vs. 6.29 ± 1.80 mmol/l, P < 0.01). In conclusion, our results show a close association between the degree of insulin resistance and markers of oxidative stress, both before and after a high‐fat meal. The postprandial state causes an important increase in oxidative stress, especially in severely obese persons with greater insulin resistance. However, we are unable to determine from this study whether there is first an increase in oxidative stress or in insulin resistance.     

Fiber Intake of Normal Weight,Moderately Obese and Severely Obese Subjects

ALFEERI, MARGARET AH, JOCELINE POMERLEAU, D MICHAEL GRACE AND LORRAINE ANDERSON. Fiber intake of normal weight, moderately obese and severely obese subjects. Obes Res. The lack of dietary fiber may be a contributing factor in obesity. This study examined the fiber intake of three weight groups: normal (20.0≤BMI≤27.0), moderately obese (27.1≤BMI≤39.9) and severely obese (BMI≥40.0). Each group contained 50 subjects. Detailed 3-day food records were used to gather the nutritional data. Fiber intake in the normal weight group was 18.8 ± 9.3 grams, the moderately obese consumed 13.3 ± 5.8 grams of fiber and the severely obese 13.7 ± 5.7 grams. Total fiber intake in grams was found to be significantly higher in the lean group (p<0.05) and was positively associated with sex and education level with men and more highly educated individuals consuming more fiber. Using regression analysis total fiber in grams and fiber in g/1000 kcalories was inversely associated with BMI after adjusting for sex, age, education level and income (p<0.01). A high fiber diet may help to promote a negative energy balance by causing early satiety secondary to gastric distention. Dietitians and physicians need to emphasize the importance of a high fiber diet to their obese patients.     

Effect of Gastric Banding on Aminoterminal Pro‐brain Natriuretic Peptide in the Morbidly Obese

Objective: Aminoterminal pro‐brain natriuretic peptide (NT‐proBNP), like brain natriuretic peptide, might have diagnostic utility in detecting left ventricular hypertrophy and/or left ventricular dysfunction. The aim of the study was to investigate the relationship between morbid obesity and NT‐proBNP and the effect of weight reduction on this parameter. Research Methods and Procedures: A total of 34 morbidly obese patients underwent laparoscopic adjustable gastric banding (LAGB). NT‐proBNP levels were measured before and 12 months after the surgery. Results: Metabolic features and systolic and diastolic blood pressure were significantly decreased (p < 0.00001 for both) after a cumulative weight loss of 19.55 kg 1 year after LAGB. NT‐proBNP concentration was significantly higher in morbidly obese patients before LAGB than in normal‐weight control subjects (341.15 ± 127.78 fmol/mL vs. 161.68 ± 75.78 fmol/mL; p < 0.00001). After bariatric surgery, NT‐proBNP concentration decreased significantly from 341.15 ± 127.78 fmol/mL to 204.87 ± 59.84 fmol/mL (p < 0.00, 001) and remained statistically significantly elevated (204.88 ± 59.84 fmol/mL vs. 161.68 ± 75.78 fmol/mL; p = 0.04) compared with normal‐weight subjects. Discussion: This investigation demonstrates higher levels of NT‐proBNP in morbidly obese subjects and a significant decrease during weight loss after laparoscopic adjustable gastric banding. In obesity, NT‐proBNP might be useful as a routine screening method for identifying left ventricular hypertrophy and/or left ventricular dysfunction.     

Adipocyte Fatty Acid‐binding Protein as a Determinant of Insulin Sensitivity in Morbid‐obese Women

The aim of the study was to evaluate human plasma circulating levels of adipocyte fatty acid‐binding protein (A‐FABP) and its relationship with proinflammatory adipocytokines and insulin resistance in a severely obese cohort, before and 1 year after a surgical gastric bypass. Plasmatic levels of A‐FABP were measured in 77 morbid‐obese women before and 1 year after bariatric surgery. Anthropometrical parameters and body composition by bioelectrical impedance analysis were determined. Circulating levels of soluble tumor necrosis factor receptor 2 (sTNFR2), Interleukin 18 (IL‐18), adiponectin, and high‐sensitive C‐reactive protein (hsCRP) were also analyzed. Insulin resistance by homeostasis model assessment of insulin resistance (HOMA‐IR) index was calculated. After massive weight loss, A‐FABP plasmatic levels decreased significantly [7.6 (8.9) vs. 4.3 (5.1); P < 0,001] but no association with circulating adipokines or proinflammatory cytokines, both at the beginning and at the end of follow‐up, was observed. A decrease in sTNFR2, IL‐18, hsCRP, and an increase in adiponectin levels (P < 0.001 in all cases) were observed after the gastric bypass. HOMA‐IR index improved 1 year after surgery and after multiple regression analysis remained associated with A‐FABP after controlling for confounding variables (β = 0.322, P = 0.014; R² for the model 0.281). In morbid‐obese women, plasma A‐FABP concentrations were dramatically reduced after gastric bypass surgery. After weight loss this protein contributed to HOMA‐IR index independently of proinflammatory/antinflammatory cytokine profile. Further studies are warranted to elucidate the role of A‐FABP in the pathogenesis of insulin resistance in morbid obesity.     

Association Between the 4 bp Proinsulin Gene Insertion Polymorphism (IVS‐69) and Body Composition in Black South African Women

The objective of the study was to examine the association between a functional 4 bp proinsulin gene insertion polymorphism (IVS‐69), fasting insulin concentrations, and body composition in black South African women. Body composition, body fat distribution, fasting glucose and insulin concentrations, and IVS‐69 genotype were measured in 115 normal‐weight (BMI <25 kg/m²) and 138 obese (BMI ≥30 kg/m²) premenopausal women. The frequency of the insertion allele was significantly higher in the class 2 obese (BMI ≥35kg/m²) compared with the normal‐weight group (P = 0.029). Obese subjects with the insertion allele had greater fat mass (42.3 ± 0.9 vs. 38.9 ± 0.9 kg, P = 0.034) and fat‐free soft tissue mass (47.4 ± 0.6 vs. 45.1 ± 0.6 kg, P = 0.014), and more abdominal subcutaneous adipose tissue (SAT, 595 ± 17 vs. 531 ± 17 cm², P = 0.025) but not visceral fat (P = 0.739), than obese homozygotes for the wild‐type allele. Only SAT was greater in normal‐weight subjects with the insertion allele (P = 0.048). There were no differences in fasting insulin or glucose levels between subjects with the insertion allele or homozygotes for the wild‐type allele in the normal‐weight or obese groups. In conclusion, the 4 bp proinsulin gene insertion allele is associated with extreme obesity, reflected by greater fat‐free soft tissue mass and fat mass, particularly SAT, in obese black South African women.     

Activation profile of CXCL8-stimulated neutrophils and aging

Neutrophils are pivotal effector cells of innate immunity representing the first line of defense against aggression. They are the first cells to arrive at the site of the aggression, where they can directly eliminate the invading microorganisms. Their activation and recruitment into peripheral tissues is indispensable for host defense. With aging, there are alterations of the receptor by driven functions of human neutrophils as a decrease in the functional changes in signaling elicited by specific receptors, as CXCR1. We investigated the activation of neutrophils from elderly after the cells were cultivated with CXCL8. Although, CXCL8 induced elastase (ELA) secretion, data showed neither myeloperoxidase (MPO) activity nor production of IL-6, IL-10, GM-CSF by neutrophils from elderly compared with young individuals. On the other hand, in the presence of only LPS or LPS associated with CXCL8 neutrophils from elderly individuals, there were significant levels of IL-6, IL-10, GM-CSF but not MPO. These results indicate that neutrophils from elderly do not respond to CXCL8 stimulus, but they are activated by LPS to produce cytokines. However, MPO activity from elderly individuals was not different in the presence or absence of LPS and CXCL8.     

Ghrelin Does Not Influence Gastric Emptying in Obese Subjects

Objective: To evaluate the relationship between fasting plasma concentrations of ghrelin and gastric emptying in obese individuals compared with lean subjects. Research Methods and Procedures: We included 20 obese patients (9 men and 11 women, BMI > 30 kg/m²) and 16 nonobese control subjects (7 men and 9 women, BMI ≤ 25 kg/m²). Gastric emptying of solids (egg sandwich labeled with radionuclide) was measured at 120 minutes with (99m)Tc‐single photon emission computed tomography imaging. Ghrelin and leptin were analyzed by radioimmunoassay and ELISA methods, respectively. Results: The gastric half‐emptying time was similar in obese men and women (67.8 ± 14.79 vs. 66.6 ± 13.56 minutes) but significantly shorter (p < 0.001) than in the control population (men: 88.09 ± 11.72 minutes; women: 97.25 ± 10.31 minutes). Ghrelin levels were significantly lower in obese subjects (131.37 ± 47.67 vs. 306.3 ± 45.52 pg/mL; p < 0.0001 in men and 162.13 ± 32.95 vs. 272.8 ± 47.77 pg/mL; p < 0.0001 in women). A negative correlation between gastric emptying and fasting ghrelin levels was observed only in lean subjects (y = ?0.2391x + 157.9; R² = 0.95). Also, in the lean group, ghrelin was the only significant independent determinant of gastric emptying, explaining 98% of the variance (adjusted R²) in a multiple regression analysis. Discussion: This report shows that, in humans, gastric emptying is faster in obese subjects than in lean controls and that, whereas ghrelin is the best determinant of gastric kinetics in healthy controls, this action is lost in obesity.     

Involvement of serum vascular endothelial growth factor family members in the development of obesity in mice and humans

Adipose tissue is highly vascularized implying that angiogenesis takes place in its expansion. The aim of this study was to compare the concentrations of members of the vascular endothelial growth factor (VEGF) family in obesity. Serum concentrations of VEGFs were analyzed in 15 lean (BMI 20.3±2.5 kg/m²) and 24 obese (BMI 47.6±5.9 kg/m²) volunteers. Obese patients showed significantly increased circulating VEGF-A (150±104 vs. 296±160 pg/ml; P<.05), VEGF-B (2788±1038 vs. 4609±2202 arbitrary units; P<.05) and VEGF-C (13 453±5750 vs. 17 635±5117 pg/ml; P<.05) concentrations. Interestingly, levels of VEGF-D were reduced in obese individuals (538±301 vs. 270±122 pg/ml; P<.01). In addition, VEGF-A significantly decreased after weight loss following Roux-en-Y gastric bypass (BMI from 46.0±8.0 to 28.9±4.2 kg/m² P<.0001 vs. initial) from 345±229 to 290±216 pg/ml (P<.01). Moreover, in order to corroborate the human findings VEGF-A levels were analyzed during the expansion of adipose tissue in two dynamic models of murine obesity. Serum VEGF-A was significantly increased after 12 weeks on a high-fat diet (43.3±9.0 vs. 29.7±9.1 pg/ml; P<.01) or in ob/ob mice (52.2±18.0 vs. 29.2±7.7 pg/ml; P<.01) and was normalized after leptin replacement in the latter (32.4±14.0 pg/ml; P<.01 vs. untreated ob/ob). Our data indicates the involvement of these factors in the expansion of adipose tissue that takes place in obesity in relation to the need for increased vascularization, suggesting that manipulation of the VEGF system may represent a potential target for the pharmacological treatment of obesity.     

Low Plasma Leptin Concentration and Low Rates of Fat Oxidation in Weight‐Stable Post‐Obese Subjects

Objective: A low resting metabolic rate for a given body size and composition, a low rate of fat oxidation, low levels of physical activity, and low plasma leptin concentrations are all risk factors for body weight gain. The aim of the present investigation was to compare resting metabolic rate (RMR), respiratory quotient (RQ), levels of physical activity, and plasma leptin concentrations in eight post‐obese adults (2 males and 6 females; 48.9 ± 12.2 years; body mass index [BMI]: 24.5 ± 1.0 kg/m²; body fat 33 ± 5%; mean ± SD) who lost 27.1 ± 21.3 kg (16 to 79 kg) and had maintained this weight loss for ≥2 months (2 to 9 months) to eight age‐ and BMI‐matched control never‐obese subjects (1 male and 7 females; 49.1 ± 5.2 years; BMI 24.4 ± 1.0 kg/m²; body fat 33 ± 7%). Research Methods and Procedures: Following 3 days of weight maintenance diet (50% carbohydrate and 30% fat), RMR and RQ were measured after a 10‐hour fast using indirect calorimetry and plasma leptin concentrations were measured using radioimmunoassay. Levels of physical activity were estimated using an accelerometer over a 48‐hour period in free living conditions. Results: After adjustment for fat mass and fat‐free mass, post‐obese subjects had, compared with controls, similar levels of physical activity (4185 ± 205 vs. 4295 ± 204 counts) and similar RMR (1383 ± 268 vs. 1430 ± 104 kcal/day) but higher RQ (0.86 ± 0.04 vs. 0.81 ± 0.03, p < 0.05). Leptin concentration correlated positively with percent body fat (r = 0.57, p < 0.05) and, after adjusting for fat mass and fat‐free mass, was lower in post‐obese than in control subjects (4.5 ± 2.1 vs. 11.6 ± 7.9 ng/mL, p < 0.05). Discussion: The low fat oxidation and low plasma leptin concentrations observed in post‐obese individuals may, in part, explain their propensity to relapse.     

High Serum Leptin Is Associated with Attenuated Coronary Vasoreactivity

Objective: Hyperleptinemia, a hallmark of obesity, appears to be a risk factor for coronary artery disease. However, although leptin is a vasoactive hormone, no studies addressing leptin's effect on coronary perfusion have been performed. We examined the association between circulating leptin concentration and coronary vasoreactivity in young obese and nonobese males. Research Methods and Procedures: Myocardial blood flow was quantitated in 10 obese men (age 31 ± 7 years, BMI 34 ± 2 kg/m²) and 10 healthy matched nonobese men (age 33 ± 8 years, BMI 24 ± 2 kg/m²) using positron emission tomography and O‐15‐water. The measurements were performed basally and during adenosine infusion (140 μg/kg per minute). Results: Serum leptin was significantly higher in obese than nonobese subjects (10.3 ± 5.6 vs. 4.3 ± 2.5 ng/mL, p < 0.01). Basal myocardial blood flow was not significantly different between obese and nonobese subjects. Adenosine‐stimulated flow was blunted in obese (3.2 ± 0.6 mL/g per minute) when compared with nonobese subjects (4.0 ± 1.1 mL/g per minute, p < 0.05). Serum leptin concentration was inversely associated with adenosine‐stimulated flow in study subjects (r = ?0.50, p < 0.05). This association was no longer observed after adjustment for obesity and/or hyperinsulinemia. Discussion: Hyperleptinemia and reduced coronary vasoreactivity occur concomitantly in young obese but otherwise healthy men. Moreover, the adenosine‐stimulated myocardial flow is inversely related to prevailing concentration of serum leptin. Although this relationship appears to be explained by obesity and/or hyperinsulinemia, leptin might have a role in regulation of myocardial blood supply.     

Correlation of neutrophil and monocyte derived interleukin-1 receptor antagonist and interleukin-8 with colitis severity in the rabbit

Activated neutrophils and monocytes produce interleukin (IL)-8, a pro-inflammatory chemokine, but also IL-1 receptor antagonist (IL-1ra), which is an anti-inflammatory cytokine. We were interested to see the profiles of IL-8 and IL-1ra in the colonic tissue and in the peripheral blood leukocytes (PBL) during the development of immune complex induced colitis in rabbits. IL-1ra and IL-8 in PBL were measured in 26 rabbits at time 0 h, 24 h, and 48 h after induction of colitis. The colons were removed at 48 h for measuring myeloperoxidase (MPO), ulcer area, IL-1ra and IL-8. Epithelial damage, crypt abscess formation and leukocyte infiltration of the colonic tissue were major features of this colitis model. During the development of colitis, there was an increase in circulating neutrophils and monocytes (P < 0.0001), but not lymphocytes. Likewise, elevated amounts of IL-1ra (P = 0.0001) and IL-8 (P = 0.0219) production by PBL were observed following induction of colitis. Flow cytometry revealed major source of IL-1ra was monocytes, while the main sources of IL-8 were neutrophils and monocytes. There was correlation between MPO and ulcer area (R_s = 0.6327, P < 0.0001). At 24 h, PBL from MPO^High group (n = 11) showed increased IL-1ra (P = 0.027) and IL-8 (P = 0.0128) levels vs MPO^Low group (n = 15). IL-8 production by PBL showed correlation with tissue MPO (R_s = 0.4273, P = 0.0295). The colitis in this model was associated with an increase in circulating monocytes and neutrophils, which released increased amounts of IL-8 and IL-1ra. Further, IL-8 and IL-1ra showed correlation with the severity of colitis. These observations should significantly further understandings on the role of neutrophils and monocytes in the immunopathogenesis of ulcerative colitis.