Lipid peroxides in obese patients and effects of weight loss with orlistat on lipid peroxides levels

OBJECTIVE: Obesity is a well-known risk factor of atherosclerosis. Recent studies showed that obesity is associated with enhanced lipid peroxidation. The aim of this study is to investigate the effect of weight reduction with orlistat treatment on lipid peroxidation levels. We assessed lipid peroxidation by measuring the concentration of plasma malondialdehyde (MDA). DESIGN: A randomized, controlled, open-label 6-month study. SUBJECTS: In total, 36 obese (body mass index (BMI) >30 kg/m2) and 11 healthy age-matched control subjects were enrolled in the study. MEASUREMENTS: Fasting glucose, triglyceride, total cholesterol, HDL cholesterol and LDL cholesterol and MDA levels were measured in both groups. Obese subjects received orlistat, 120 mg three times daily together with hypocaloric diet. After 6 months of treatment laboratory tests were repeated. RESULTS: MDA levels were significantly higher in obese patients than the control group (P<0.0001). After 6 months of treatment in obese subjects, the mean weight of the patients decreased by 6.8 kg, the BMI by 3.2 kg/m2. Plasma MDA levels were significantly reduced by weight loss from 2+/-0.77 to 0.89+/-0.41 nmol/ml (P<0.001). BMI correlated with MDA levels at baseline (r=0.6, P<0.0001). Changes in BMI was positively associated with plasma MDA level reduction (r=0.36, P<0.05). CONCLUSION: These results indicate that obesity is associated with increases in endogenous lipid peroxides. Our data show that the indicator of lipid peroxidation-MDA-falls markedly in association with weight loss with orlistat. The demonstration of decreased free radical generation has important implications for oxidative mechanism underlying obesity-associated disorders.     

Efficacy and safety of a short-time orlistat treatment in obese subjects

Obesity is frequently associated with a high cardiovascular risk. The aim of this study was to assess safety, tolerability and efficacy of orlistat treatment in comparison with placebo in the reduction of body weight in obese subjects and the related cardiovascular risk factors. For such a purpose, 146 obese patients were randomly assigned to two treatments over a period of 27 weeks: 1) hypocaloric diet, exercise and placebo (n = 72); 2) hypocaloric diet, exercise and orlistat 120 mg twice/day (n = 74). The side effects observed were similar for the two treatment groups, with exception of gastrointestinal symptoms, which were significantly more frequent in the orlistat group than in the placebo group. Nevertheless, the side effects were limited and resolved. In fact, none of the patients dropped-out. During the observation period a significantly higher reduction in body weight (-6.9 kg, p < 0.001), systolic blood pressure (-4.9 mmHg, p < 0.001), diastolic blood pressure (-2.9 mmHg, p < 0.001), LDL cholesterol (12.8%, p < 0.001) was observed in the orlistat group than in the placebo group (-4.1 kg, 3.2 mmHg, 1.8 mmHg and 5.1%, respectively). By using a validated questionnaire, in the orlistat group a significantly higher motivation (p < 0.01) to continue diet and exercise than in the placebo group was observed. In addition, at the end of the study, patients receiving orlistat treatment gave a better evaluation of their own image than patients receiving placebo (p < 0.01).     

Effect of five dopaminergic drugs on plasma growth hormone levels in acromegalic subjects.

The effect of 5 dopaminergic drugs, 2-Br-alpha-ergocryptine (CB 154), L-dopa, 1-(2-pyrimidyl)-4-piperonylpiperazine (Piribedil), amantadine and 1,3-dimethyl-5-amino-adamantan (d 145), on human growth hormone levels (hGH) was studied in 38 acromegalic subjects. Acute administration of CB 154 (2.5 mg p.o.) in 34 patients was followed by a significant and sustained fall in plasma hGH levels; in 19 cases (55.6%) the observed fall was clearly below the +/- 2SD of the mean GH changes present in the same subjects after placebo. In patients previously shown to be responsive to CB 154, Significant GH falls were also present following the single administration of L-dopa (500 mg p.o.) (9 patients) and Piribedil (100 mg p.o.) (5 patients), although CB 154 exhibited a more frequent, striking (reduction of up to 1-2 ng/ml) and long-lasting (4 h more) effect. In contrast, amantadine (200 mg p.o.) or D 145 (20 or 50 mg p.o.) did not induce significant changes in hGH levels (7 patients). These results broaden and corroborate previous findings on the hGH-lowering effect of dopaminergic stimulation in acromegaly. The possible reason(s) for the difference in hGH response with different dopaminergic compounds is discussed.     

Effect of subacute administration of human growth hormone on various serum lipid and hormone levels of hypercholesterolemic and normocholesterolemic subjects

Six hypercholesterolemic and five normocholesterolemic subjects were injected twice daily with human growth hormone for 7 days. During HGH administration, the average serum cholesterol of both types of subjects fell significantly, and their serum triglyceride levels increased. Peak insulin responses to glucose also increased. However, no change occurred in the serum phospholipid, FFA, cortisol, or thyroxine concentrations during HGH treatment.     

Effect of orlistat on cardiovascular disease risk in obese adults

AIM: The aim of this study is to compare the effect of orlistat vs. placebo on the predicted 10-year cardiovascular disease (CVD) risk in obese people with one or more cardiovascular risk factors treated for 12 months, in conjunction with a fat-reduced, but otherwise ad libitum, diet. METHODS: A double-blind, randomized, placebo-controlled, parallel study was performed in conjunction with a fat-reduced diet and physical activity advice for 1 year. Participants (n = 339) from eight centres in Australia and New Zealand were randomized to either orlistat (120 mg) three times daily (n = 104 women, 66 men; mean +/- s.d. age = 52.0 +/- 7.5 years, body mass index (BMI) = 37.6 +/- 5.1 kg/m(2)) or placebo three times daily (n = 89 women, 80 men; age = 52.5 +/- 7.4 years, BMI = 38.0 +/- 4.9 kg/m(2)). The primary efficacy criterion was the 10-year risk of developing CVD calculated from the Framingham equation. Secondary efficacy criteria were body weight, waist circumference, blood pressure and serum concentrations of triglycerides, cholesterol (total, LDL and HDL), glucose, insulin and glycated haemoglobin and quality of life. RESULTS: There was no difference in the change in 10-year CVD risk between orlistat and placebo groups over 1 year. The orlistat group, however, had significant favourable changes in many of the individual CVD risk factors (total cholesterol, LDL-cholesterol, glucose, glycated haemoglobin, insulin, body weight and waist circumference) and one of the domains of quality of life measured by means of the SF-36 questionnaire (vitality), compared to the placebo group. Significant reductions in medication use for hypertension and diabetes were observed in the orlistat group, compared to those in placebo, but there were no significant differences in medication use for blood lipids. CONCLUSIONS: Orlistat may have reduced CVD risk, as judged by the favourable changes in individual risk factors and reductions in medication use, but the method used in order to measure absolute CVD risk in this study (Framingham CVD equation) was not sensitive enough to detect the changes in this relatively low-risk group (approximately 10% of risk of a CVD event over 10 years).     

Effect of orlistat on plasma leptin levels and risk factors for the metabolic syndrome

Background: The aim of this research was to assess the impact of treatment with Orlistat 120 mg three times daily on serum leptin levels, weight loss, glycemic control, and cardiovascular risk factors involved in the metabolic syndrome. Methods: A 3-month open-labeled prospective study was conducted on 40 patients with the clinical features of the metabolic syndrome divided into two groups-with and without type 2 diabetes mellitus. Twenty type 2 diabetic obese patients (group A) were studied, with BMI of 35.4 +/- 0.9 kg/m(2), as were 20 obese patients without diabetes (group B), with BMI of 36.2 +/- 0.7 kg/m(2). Weight, serum leptin levels, insulin resistance, and cardiovascular risk factors were measured at baseline and at the end of each month. Results: Patients reduced weight at 8.5 +/- 2.3 kg for men and 5.7 +/- 2.6 kg for women in group A against 7.9 +/- 1.9 kg for men and 5.6 +/- 2.0 kg for women in group B. Plasma leptin levels decreased at 4.5 +/- 1.9 ng/mL for men and 1.9 +/- 0.9 ng/mL for women in group A against 3.8 +/- 2.0 ng/mL for men and 2.8 +/- 1.4 ng/mL for women in group B. The level of insulin resistance measured with HOMA-IR decreased from 4.54 +/- 2.35 to 2.69 +/- 0.86 in group A against 3.98 +/- 1.89 to 2.87 +/- 0.93 in group B. In the lipid parameters, the highest decrease was found in triglycerides levels: 6.1 +/- 2.3 mmol/L for men and 3.5 +/- 2.6 mmol/L for women in group A against 2.1 +/- 1.9 mmol/L for men and 1.8 +/- 0.7 mmol/L for women in group B (all p < 0.05). Conclusions: Orlistat beneficially enhances weight loss, contributing to a decrease of serum leptin, insulin resistance level, and cardiovascular risk factors in both groups. An additional beneficial pleotropic effect of Orlistat could be proposed through a reduction of plasma leptin and lipid levels.     

Study on the effect of insulin on carbohydrate and lipid metabolism in obese subjects with normal glucose tolerance]

In altogether 32 test persons with normal weight and obese test persons glucose-insulin-tolerance-tests were carried out. In obese persons with normal carbohydrate tolerance -- characterized by 50 g oral glucose tolerance test -- by the decreased glucose assimilation coefficients and the significantly increased level of glycaemia after intravenous application of glucose a disturbance of the glucose-insulin-homoeostasis is already implied. Basal and glucose-stimulated concentrations of IRI in the peripheral venous blood were significantly increased in obese persons. The parameters of lipolysis glycerol and free fatty acids show after a glucose-stimulated insulin excretion and after exogenic insulin application a somewhat retarded decrease in obese persons compared with the control group. In connection with the significantly increased insulin levels in obese persons these findings might refer to a decreased antilipolytic effect of insulin. The two fundamental physiological effects of insulin in the carbohydrate and fat metabolism -- glucose utilization and inhibition of lipolysis -- seem to be distrubed in the same way in obesity.     

Effect of small doses of dexamethasone on plasma leptin levels in normal and obese subjects: a dose-response study

To further elucidate the role of glucocorticoids in the regulation of leptin secretion, we studied the effects of overnight small doses of dexamethasone on plasma leptin levels in normal weight controls and in obese patients and correlated the results with indexes of insulin sensitivity and body fat distribution. In 114 subjects (81 obese patients, 49 women and 32 men, BMI 37.4 +/- 0.77 kg/m2 and 33 normal-weight subjects, 17 women and 16 men, BMI 22.1 +/- 0.41 kg/m2) plasma F and leptin levels were measured at 08:00 h basally and after the administration of different doses of dexamethasone (a fixed dose of 1-mg and 0.0035, 0.007, 0.015-mg/kg bw, given po at 23:00 h the night before). Tests were performed one week apart with bw remaining stable over the study period. Basal leptin levels were significantly higher in obese than in normal subjects (31.9 +/- 2.41 vs 7.7 +/- 0.93 ng/ml, p<0.0001). In obese patients, leptin levels increased significantly by 1-mg (from 31.9 +/- 2.41 to 35.0 +/- 2.59 ng/ml, p<0.005) and the 0.015-mg/kg bw dose (from 31.5 +/- 2.34 to 33.7 +/- 2.44 ng/ml, p<0.05), while they were unaffected by each dose of dexamethasone in normal subjects. However, after splitting subjects by gender, mean leptin levels rose from 39.3 +/- 2.97 to 43.3 +/- 3.12 ng/ml after the 1-mg dose, p<0.005, from 39.1 +/- 2.87 to 43.6 +/- 2.91 ng/ml after the 0.015-mg/kg bw dose, p<0.005, from 39.3 +/- 2.90 to 42.2 +/- 2.90 ng/ml after the 0.007-mg/kg bw dose, p<0.05 and from 38.8 +/- 2.66 to 41.1 +/- 2.87 ng/ml after the 0.0035-mg/kg bw dose, p=0.055, only in obese women. Conversely, no leptin changes were seen in the other groups and no differences were observed in the leptin response between groups. After the 1-mg dose, in the whole group, the absolute leptin variation was weakly but significantly related to BMI values (r=0.231, p<0.02) while in all sessions the percent leptin changes over baseline were not significantly correlated with age, BMI, waist, WHR, insulin, HOMA index, a marker of insulin sensitivity, plasma dexamethasone concentrations and to the percent cortisol variation following dexamethasone. In conclusion, in obese women but not in obese men and in normal weight subjects, small overnight increases in plasma glucocorticoid concentrations induced gender-related plasma leptin elevations that were unrelated to body fat distribution and insulin sensitivity. A greater sensitivity of female adipose tissue to glucocorticoids probably underlies this sexually dimorphic pattern of leptin response. These findings provide an additional piece of information on the regulation of leptin secretion exerted by glucocorticoids.     

Effects of sibutramine and orlistat on mood in obese and overweight subjects: a randomised study

Background and aimIntentional weight loss results in improvement in mood. Very few data exist regarding the effects of sibutramine on the mood of obese and overweight patients in general clinical samples. Moreover, no study has evaluated the effects of orlistat treatment on mood. The purpose of our study was to assess the effects of sibutramine and orlistat on mood in obese and overweight subjects.Methods and resultsSixty obese and overweight women were divided into three groups. The first group (n = 20) received a low-calorie diet and sibutramine 10 mg; the second group (n = 20) received a low-calorie diet and orlistat 120 mg three times a day, and the third group received only the low-calorie diet.ConclusionA psychiatric assessment was performed with the Hamilton Depression Rating Scale (HAMD) before and after 3 months of treatment. In all the groups a statistically significant decrease in HAMD scores was observed. However, the decrease in the sibutramine group was greater compared to that observed in the two other groups (P < 0.01). These results suggest that sibutramine treatment may improve mood more than diet alone or orlistat therapy in a general clinical sample of obese patients.     

Elevated plasma levels of oxytocin in obese subjects before and after gastric banding

Impaired glucose tolerance and hyperinsulinaemia are common features of obesity. Since oxytocin has been shown to influence glucose metabolism and insulin secretion, the objective of the present study was to investigate whether the plasma level of oxytocin is elevated in obese subjects and if so, whether it is affected by weight reduction following gastric banding. Repeated blood samples were collected in connection with ingestion of a liquid test meal from subjects weighing about 130 kg. Normal weight subjects were tested likewise. Further tests were performed on obese subjects 6 months after operation with gastric banding and a subsequent weight reduction of about 30 kg. Plasma levels of oxytocin were measured by radioimmunoassay. It was found that plasma levels of oxytocin were 4-fold higher in the obese subjects when compared to the control subjects. Analysis with high performance liquid chromatography demonstrated that the oxytocin-like material, as determined by radioimmunoassay, in extracted plasma from one obese subject coeluted with synthetic oxytocin standard. Ingestion of a test meal did not seem to influence oxytocin levels. The mean oxytocin level was equally elevated in male and female obese subjects. Following operation oxytocin levels decreased significantly, but were still significantly higher than in the control subjects. The mechanism behind the hyperoxytocinaemia and possible consequence of it remain obscure.     

The effects of glucose ingestion and fasting on plasma immunoreactive beta-endorphin, adrenocorticotropic hormone and cortisol in obese subjects.

It has been demonstrated that opioid peptides are involved in the stimulation of food intake in rats and that the circulating beta-endorphin levels are increased in genetically obese rodents. Therefore, to assess whether the changes in food intake may influence circulating beta-endorphin levels in obese subjects, plasma beta-endorphin, ACTH and cortisol concentrations were determined in obese patients after an oral glucose load and during a 7-day total starvation. Baseline plasma beta-endorphin concentrations were significantly higher in obese patients than in control normal-weight subjects, while ACTH and cortisol levels were similar in both groups. Plasma beta-endorphin, ACTH and cortisol concentrations were not affected by the ingestion of 75 g glucose, neither were plasma beta-endorphin concentrations modified during prolonged starvation. Moreover, the lack of nycthemeral variations in beta-endorphin levels, documented before and during starvation while plasma ACTH and cortisol were significantly reduced in the evening, suggests that some extra anterior pituitary sources or some obesity-related changes in beta-endorphin metabolism may contribute to the pool of circulating beta-endorphin in obese subjects. On the other hand, even the extreme changes in nutritional conditions, such as total food deprivation or glucose ingestion, are devoid of any detectable influence on circulating beta-endorphin levels.     

Gallbladder motility and gut hormone plasma levels in subjects with and without gallstones

Hormonal control of gallbladder motility is still unclear in patients with cholelithiasis. In a case-control study, we determined the characteristics of gallbladder emptying evaluated sonographically and the hormone levels of somatostatin, gastrin, and pancreatic polypeptide, before and after a fatty meal in 10 gallstone patients compared with 20 healthy subjects. Patients with lithiasis had a larger residual volume (median 12,0 ml vs 6,5 ml; P = 0.01) and a lower gallbladder ejection fraction (43% vs 70%, P = 0.02) than healthy subjects. During fasting, plasma pancreatic polypeptide concentrations were significantly higher in lithiasis patients (P < 0.03). In contrast, no differences between the two groups of patients were observed during the post prandial period. Somatostatin and gastrin plasma levels were similar in the two groups. Lastly, the serum bile salt levels were in the normal range and were not different between groups both during fasting and postprandial states. We conclude that large basal plasma concentrations of pancreatic polypeptide, a gut peptide inducing gallbladder relaxation, may constitute a factor facilitating lithogenesis.     

Failure of carbohydrate to spare leucine oxidation in obese subjects

Leucine kinetics were studied in six obese subjects (W/H2 = 39 +/- 4) and six normal subjects (W/H2 = 21 +/- 3) before and after an oral load of 150 g glucose. An intravenous infusion of 1(-13)C leucine was given to the fasting subjects for 450 min: a steady state of plasma leucine enrichment was established 90 min after the start of the infusion, and the glucose load was given 220 min after the start of the infusion. Compared with the lean controls the obese subjects showed a greater area under the curve of blood glucose after the glucose load (P less than 0.025) and higher insulin and glucagon levels both before and after the meal (P less than 0.05), thus indicating the well-known insulin insensitivity of obese (but not diabetic) subjects with respect to glucose metabolism. After the glucose load the lean subjects showed a significant and sustained decrease in leucine oxidation (from 20.0 +/- 2.2 to 13.3 +/- 1.5 mumol/kg LBM/h: P less than 0.01). This response is similar to that observed when insulin-dependent diabetic subjects are given insulin. However the obese subjects showed no decrease in leucine oxidation after the glucose meal (20.3 +/- 1.9 before, and 21.2 +/- 3.6 after). This indicates that obese subjects show insensitivity to the action of insulin with respect to protein metabolism as well as carbohydrate metabolism.     

Biological effects of growth hormone on carbohydrate and lipid metabolism

This review will summarize the metabolic effects of growth hormone (GH) on the adipose tissue, liver, and skeletal muscle with focus on lipid and carbohydrate metabolism. The metabolic effects of GH predominantly involve the stimulation of lipolysis in the adipose tissue resulting in an increased flux of free fatty acids (FFAs) into the circulation. In the muscle and liver, GH stimulates triglyceride (TG) uptake, by enhancing lipoprotein lipase (LPL) expression, and its subsequent storage. The effects of GH on carbohydrate metabolism are more complicated and may be mediated indirectly via the antagonism of insulin action. Furthermore, GH has a net anabolic effect on protein metabolism although the molecular mechanisms of its actions are not completely understood. The major questions that still remain to be answered are (i) What are the molecular mechanisms by which GH regulates substrate metabolism? (ii) Does GH affect substrate metabolism directly or indirectly via IGF-1 or antagonism of insulin action?