Telomere length increase after weight loss induced by bariatric surgery: results from a 10 year prospective study.

BACKGROUND/OBJECTIVES: Obesity contributes to telomere attrition. Studies focusing on short-term effects of weight loss have been unable to identify protection of telomere length. This study investigates long-term effects of pronounced weight loss induced by bariatric surgery on telomere length. SUBJECTS/METHODS: One hundred forty-two patients were recruited in a prospective, controlled intervention study, follow-up investigations were done after 10.46±1.48 years. A control group of normal weight participants was recruited and followed from 1995 to 2005 in the Bruneck Study. A total of 110 participants from each study was matched by age and sex to compare changes in telomere length. Quantitative PCR was used to determine telomere length. RESULTS: Telomere length increased significantly by 0.024±0.14 (P=0.047) in 142 bariatric patients within 10 years after surgery. The increase was different from telomere attrition in an age- and sex-matched cohort population of the Bruneck Study (-0.057±0.18; ß=0.08; P=0.003). Significant changes in telomere length disappeared after adjusting for baseline body mass index (BMI) because of general differences in BMI and telomere length between the two study populations (ß=0.07; P=0.06). Age was proportional to telomere length in matched bariatric patients (r=0.188; P=0.049) but inversely correlated with telomere length in participants of the Bruneck Study (r=-0.197; P=0.039). There was no association between percent BMI/excess weight loss and telomere attrition in bariatric patients. Baseline telomere length in bariatric patients was inversely associated with baseline plasma cholesterol and triglyceride concentrations. Telomere shortening was associated with lower high-density lipoprotein cholesterol and higher fasting glucose concentration at baseline in bariatric patients. CONCLUSIONS: Increases in relative telomere length were found after bariatric surgery in the long term, presumably due to amelioration of metabolic traits. This may overrule the influence of age and baseline telomere length and facilitate telomere protection in patients experiencing pronounced weight loss.

Serum prolactin in advanced chronic liver disease.

Hyperprolactinemia is a frequent endocrine disorder with well known harmful effects on the reproductive system and bone metabolism. Besides prolactinomas several drugs and disorders such as renal failure and hypothyroidism have been shown to cause hyperprolactinemia. Based on former studies, liver cirrhosis has also been suggested to cause hyperprolactinemia, while mechanisms have not been identified yet. In this study, we set out to investigate the prevalence and predictors of hyperprolactinemia in 178 patients with liver cirrhosis of different etio-logies. Eighteen out of 178 patients - 7 females and 11 males - displayed elevated serum pro-lactin levels. When patients were excluded who suffered from co-morbidities or took medication that are discussed to potentially interfere with prolactin metabolism, only 3 males displayed increased serum prolactin levels. Prolactin levels were similar in patients with liver cirrhosis of different etiologies. Our data suggest that hyperprolactinemia is not commonly found in patients with liver cirrhosis, but is mostly associated with intake of drugs or presence of comorbidites which are known to potentially cause hyperprolactinemia. We thus hypothesize that in contrast to former studies liver cirrhosis is not a common cause of hyperprolactinemia and that in the absence of co-morbidities or drugs that are known to potentially increase prolactin levels, marked hyperprolactinemia needs further investigation in patients with liver cirrhosis.

Plasminogen activator inhibitor 1 and visceral obesity during pronounced weight loss after bariatric surgery.

BACKGROUND AND AIMS: Elevated plasminogen activator inhibitor 1 (PAI-1) concentrations are a hallmark of obesity and are considered to contribute to the development of cardiovascular disease. As adipose tissue constitutes a major source for PAI-1 in obesity, we investigated the individual contribution of subcutaneous and intra-abdominal fat on PAI-1 concentrations during pronounced weight loss after bariatric surgery. METHODS AND RESULTS: Thirty-seven obese adults were examined before and 18 months after surgery. Abdominal fat distribution was determined by ultrasound, metabolic parameters and plasma PAI-1 levels by standard methods. BMI was reduced by 9.2 ± 4.9 kg/m(2), while total fat mass and visceral fat diameter (VFD) decreased by 20.7 ± 11.9 kg and 4.2 ± 2.3 cm, respectively. Concomitantly, PAI-1 levels diminished by 3.2 ± 5.6 ng/ml (all p ≤ 0.015). Change in PAI-1 levels was correlated with change in VFD (r = 0.441, p = 0.008), but not with subcutaneous fat diameter. In stepwise multiple regression analysis change in VFD was an independent predictor of change in PAI-1 concentrations. When adjusted for age and sex or total fat mass associations between PAI-1 and VFD remained significant. CONCLUSION: We demonstrate that VFD is a major determinant for PAI-1 concentrations during pronounced weight loss after bariatric surgery. Thus, significant reduction of visceral fat mass may contribute to the reduced cardiovascular morbidity and mortality after bariatric surgery by a concomitant decrease in PAI-1 concentrations.

The role of apolipoprotein A5 in non-alcoholic fatty liver disease.

BACKGROUND: Apolipoprotein A5 (apoA5) is a recently described liver-specific protein that has been shown to influence triglyceride (TG) metabolism. ApoA5 transgenic mice display dramatically reduced TG levels, while in contrast apoA5 deficiency in humans was reported to result in marked hypertriglyceridemia. ApoA5 exerts its extracellular effects by increasing lipolysis of TG-rich lipoproteins, while in vitro data suggest additional intrahepatic effects. METHODS: In this study the authors set out to investigate a possible role of apoA5 in non-alcoholic fatty liver disease (NAFLD). We thus determined hepatic apoA5 expression in 15 obese subjects with histologically proven NAFLD undergoing bariatric surgery. In addition, the authors established a hepatic cell culture model of apoA5 knockdown by transfecting human hepatoma cells (HepG2) with apoA5 small interfering (si) RNA, and determined intracellular TG content and expression levels of key enzymes and transcription factors of intrahepatic lipid metabolism in these cells. RESULTS: Pronounced weight loss and associated histologically verified improvement of hepatic steatosis were accompanied by significant reductions of hepatic apoA5 mRNA expression levels. Significant apoA5 knockdown in HepG2 cells resulted in a marked decrease of intracellular TG content. When HepG2 cells were co-transfected with apoA5 and peroxisome proliferator-activated receptor gamma (PPARγ), reductions in hepatic TG accumulation were significantly less pronounced when compared to apoA5 siRNA transfected HepG2 cells. CONCLUSIONS: In obese subjects, hepatic apoA5 mRNA expression decreases after weight loss and improvements in hepatic steatosis. The authors' in vitro data demonstrate that apoA5 influences intrahepatic TG metabolism and that these intracellular effects of apoA5 are accompanied by changes in PPARγ mRNA expression. In summary, the data suggest that as well as several other factors, apoA5 might be involved in the pathogenesis of hepatic steatosis.

Effect of bariatric surgery on circulating chemerin levels.

BACKGROUND: Subclinical inflammation in obesity is critical for development of several obesity-associated disorders. We set out to investigate the effect of pronounced weight loss on circulating chemerin levels, a chemoattractant protein that also influences adipose cell function by paracrine and autocrine mechanisms. MATERIAL AND METHODS: Thirty-two obese patients undergoing bariatric surgery were tested before and on an average of 18 months after gastric banding or gastric bypass surgery. RESULTS: Pronounced weight loss after bariatric surgery was accompanied by improvements in parameters of lipid and glucose metabolism and increased adiponectin levels. Chemoattractant chemerin significantly decreased from 175.91 +/- 24.50 to 145.53 +/- 26.44 ng mL(-1) after bariatric surgery (P < or = 0.01). Concomitantly, hs-CRP as a marker of subclinical inflammation was significantly reduced after weight reduction (P < or = 0.01). CONCLUSIONS: We hypothesize that weight-loss induced reduction in circulating chemerin might in conjunction with other factors be associated with diminished recruitment of macrophages in adipose tissue and reduction of subclinical inflammation, which again could partly explain beneficial long-term effects of weight reduction in obese subjects.

Effect of postprandial lipemia on plasma concentrations of A-FABP, RBP-4 and visfatin.

BACKGROUND AND AIMS: Several studies indicate that changes in the plasma concentrations of adipocyte-fatty acid binding protein (A-FABP), retinol binding protein-4 (RBP-4) and visfatin are associated with chronic states of insulin resistance. Recent studies have shown that postprandial lipemia induces an acute state of insulin resistance. The aim of this study was to investigate the effect of postprandial lipemia on the plasma concentrations of A-FABP, RBP-4 and visfatin. METHODS AND RESULTS: In a within-subject crossover study, we administered a standardized high-fat meal to 24 healthy subjects (12 males and 12 females). Plasma concentrations of adipocytokines were measured in the morning after an overnight fast and during postprandial lipemia, i.e. 2, 4 and 6 hours after meal ingestion (postprandial experiment). To exclude potential confounding factors affecting the adipocytokine plasma concentrations, a control experiment without meal ingestion was performed over the same time period (postabsorptive control experiment). Comparing plasma concentrations of A-FABP, RBP-4 and visfatin between the postprandial and the postabsorptive control experiments, we found no significant differences. Within either of the two experiments, a decrease of A-FABP was noted reaching, however, statistical significance only in the postprandial experiment, i.e. 2 and 4 hours after meal ingestion. CONCLUSION: Postprandial lipemia has no significant effect on the plasma concentrations of visfatin, A-FABP or RBP-4 in relation to their postabsorptive plasma profiles. We conclude that prolonged states of insulin resistance are required to affect plasma concentrations of these adipocytokines.

Effect of pronounced weight loss on visceral fat, liver steatosis and adiponectin isoforms.

BACKGROUND: Weight loss induced by bariatric surgery is an effective method to reverse obesity and comorbidities. The aim of this prospective weight loss study was to investigate changes of body fat distribution in relation to adiponectin and its isoforms and further to investigate the influence of both body fat distribution and adiponectin on the degree of liver steatosis. DESIGN: Fifteen severely obese female patients (body mass index 43.1 +/- 4.1, mean age 34.5 +/- 8.6 years) were examined before and after surgical treatment. Grading of fatty liver disease and the subcutaneous and visceral fat diameters were determined by abdominal ultrasonography. Metabolic parameters were determined using standard methods; serum total adiponectin and its isoforms were detected by enzyme immuno assay (EIA). RESULTS: Mean weight loss was 28.3 kg, which was mostly due to a loss in fat mass, accompanied by an increase in total adiponectin and the high molecular weight (HMW) adiponectin isoform. Visceral adipose tissue (VAT) diameter was highly correlated with liver steatosis, even more strongly than the parameters of liver function. In addition, liver steatosis correlated negatively with HMW adiponectin and binary logistic regression revealed that changes in fat mass, HMW adiponectin and alanine aminotransferase (ALT) were the best predictors for changes in the degree of hepatic steatosis. CONCLUSIONS: Our results suggest that circulating HMW adiponectin is associated with both VAT and liver steatosis. In summary, the major findings were that the VAT diameter is highly correlated with liver steatosis, even stronger than the parameters of liver function and the association of HMW adiponectin with liver steatosis was better than with total adiponectin.

Effect of obesity and insulin sensitivity on adiponectin isoform distribution.

BACKGROUND: Adiponectin is an insulin-sensitizing, antiatherogenic and anti-inflammatory adipocytokine that circulates in three isoforms: a trimer [low-molecular weight (LMW)], a hexamer (trimer-dimer) of medium molecular weight (MMW) and a multimeric high molecular weight (HMW) isoform. Evidence is accumulating that HMW adiponectin is the active isoform of the adipocytokine. We investigated the impact of adipose tissue and insulin sensitivity on adiponectin isoform distribution. MATERIALS AND METHODS: One hundred and eighty-seven normolipidaemic, non-diabetic lean or obese subjects with or without insulin resistance participating in the Salzburg Atherosclerosis Prevention program in subjects at High Individual Risk (SAPHIR) were included in the study. Insulin sensitivity was determined by the short insulin tolerance test and the homeostasis model assessment (HOMA) index. Serum adiponectin isoform distribution was determined by an enzyme immunoassay. RESULTS: Total adiponectin as well as HMW/total adiponectin ratio was significantly increased in female subjects. Circulating total adiponectin levels were lowest in obese patients due to reduced concentrations of HMW adiponectin. As determined by stepwise regression analysis, besides age and high density lipoprotein (HDL) cholesterol, visceral fat area and waist-to-hip ratio predicted concentrations of HMW adiponectin, while insulin sensitivity had no influence on either total adiponectin or its isoforms. CONCLUSIONS: Our results underline that determination of adiponectin isoforms are more useful than measurement of total adiponectin in clinical settings. Our data suggest that adiponectin concentrations are strongly associated with visceral fat area but not with insulin sensitivity. Thus, we hypothesize that insulin resistance is a consequence rather than the cause of hypoadiponectinaemia in obese subjects.

The novel insulin resistance parameters RBP4 and GLP-1 in patients treated with valproic acid: just a sidestep?

Valproic acid (VPA), as one of the most widely prescribed antiepileptic drugs (AED) for many types of epilepsy in adults and children, is associated with weight gain, alteration of adipocytokine homeostasis, insulin resistance and Non-Alcoholic Fatty Liver Disease (NAFLD). Retinol-binding protein 4 (RBP4) and Glucagon-like peptide-1 (GLP-1) are considered as important new targets in modern type 2 diabetes mellitus therapy linked to insulin resistance, NAFLD and visceral obesity acting via peripheral or central mechanisms. We herein demonstrate the lack of an influence of VPA treatment on RBP4 and GLP-1 in otherwise healthy patients. In summary, the absence of any relationship with RBP4 and GLP-1 concentrations does not suggest a role of these novel insulin resistance parameters as potential regulators of glucose and fat metabolism during VPA-therapy.

Long-term effects of weight loss after bariatric surgery on functional and structural markers of atherosclerosis.

OBJECTIVE: Pronounced weight loss after bariatric surgery was demonstrated to have significant beneficial effects on surrogates of early atherosclerosis. The aim of this prospective examination was to investigate whether these improvements of endothelial function and vascular structure are persistent in the long-term. DESIGN AND METHODS: A total of 52 obese adults were examined before and 5 years after bariatric surgery. Carotid intima media thickness (IMT), brachial flow-mediated dilation (FMD), abdominal fat distribution, and metabolic parameters were determined. Additional 18 months data were available from 27 patients. RESULTS: After 5 years, mean weight loss ± SD of 25% ± 12 in all subjects was accompanied by known improvements in metabolism. Change in IMT was -0.02 mm ± 0.007, whereas FMD improved by +1.5% ± 0.5. In the subgroup IMT decreased by 0.04 mm ± 0.06 within the first 18 months, whereas no significant change was observed between 18 month and 5 years. FMD improved by 3.8% ± 0.6 after 18 months followed by a nonsignificant decrease of -1.4% ± 0.9. CONCLUSIONS: These long-term results demonstrate that bariatric surgery-induced weight loss improves both functional and structural markers of early atherosclerosis providing further evidence for the beneficial effects of weight loss on obesity-associated alterations of the vasculature.

Effects of six second generation antipsychotics on body weight and metabolism - risk assessment and results from a prospective study.

BACKGROUND: Due to the association of second generation antipsychotics (SGAs) with weight gain and alterations of glucose and lipid homeostasis, we aimed to group six commonly prescribed SGAs into classes of differing risks. METHODS: Twenty-eight patients meeting the criteria for a diagnosis of schizophrenic disorder according to ICD-10 were assigned to monotherapy with olanzapine, clozapine, quetiapine, amisulpride, ziprasidone or risperidone. The levels of glucose and lipid metabolism were assessed before and after 28 days of treatment. RESULTS: Based on cluster analysis, olanzapine and clozapine were found to constitute a high-risk group for metabolic dysregulation while amisulpride, quetiapine, risperidone and ziprasidone could be assigned to a non-high-risk group. Subjects from the high-risk group displayed significant weight gain with concomitant increases of HOMA-IR, levels of insulin, total cholesterol, TG, LDL-C and leptin. No significant changes were observed in the non-high-risk group. CONCLUSION: The results of this study support the conclusion of the Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes that certain SGAs are associated with a higher risk for weight gain, insulin resistance and dyslipidemia.

Metabolic side effects of antipsychotic medication.

The use of second-generation antipsychotics (SGAs) is associated with metabolic side effects including weight gain, diabetes mellitus and an atherogenic lipid profile. These adverse effects are not only the risk factors for cardiovascular disease, insulin resistance and diabetes mellitus leading to increased morbidity and mortality but may also impair the patient's adherence to treatment. SGAs in particular are associated with significant weight gain with clozapine and olanzapine carrying the highest risk, whereas newer agents, such as risperidone and aripiprazole, are considered to be less prone to cause weight gain. Consequently, a consensus development conference convened issuing recommendations on patient monitoring when treated with SGAs. The metabolic effects of antipsychotic drugs should be of concern when planning a patient's treatment strategy. Baseline screening and regular follow-up monitoring whose intervals should depend on the individual predisposition are advised. Possible therapeutical strategies for the management of drug-induced obesity include therapeutic approaches, such as life style change and pharmaceutical intervention. Drugs with a weight reducing effect become more important because of the lack of compliance with behavioural intervention. Topiramate, histamine-antagonists, dopaminergic- and serotoninergic agents have shown positive results in the management of psychotropic medication induced weight gain. However, further trials are required to support a specific therapeutical approach as well as studies to investigate the underlying mechanisms for future drug development.