Matthias Lannoo

Interleukin-1 Receptor-Associated Kinase-3 Is a Key Inhibitor of Inflammation in Obesity and Metabolic Syndrome

Background Visceral obesity is associated with the rising incidence of type 2 diabetes and metabolic syndrome. Low-grade chronic inflammation and oxidative stress synergize in obesity and obesity-induced disorders. Objective We searched a cluster of molecules that support interactions between these stress conditions in monocytes. Methods RNA expressions in blood monocytes of two independent cohorts comprising 21 and 102 obese persons and 46 age-matched controls were determined by microarray and independently validated by quantitative RT-PCR analysis. The effect of three-month weight loss after bariatric surgery was determined. The effect of RNA silencing on inflammation and oxidative stress was studied in human monocytic THP-1 cells. Results Interleukin-1 receptor-associated kinase-3 (IRAK3), key inhibitor of IRAK/NFκB-mediated chronic inflammation, is downregulated in monocytes of obese persons. Low IRAK3 was associated with high superoxide dismutase-2 (SOD2), a marker of mitochondrial oxidative stress. A comparable expression profile was also detected in visceral adipose tissue of the same obese subjects. Low IRAK3 and high SOD2 was associated with a high prevalence of metabolic syndrome (odds ratio: 9.3; sensitivity: 91%; specificity: 77%). By comparison, the odds ratio of high-sensitivity C-reactive protein, a widely used marker of systemic inflammation, was 4.3 (sensitivity: 69%; specificity: 66%). Weight loss was associated with an increase in IRAK3 and a decrease in SOD2, in association with a lowering of systemic inflammation and a decreasing number of metabolic syndrome components. We identified the increase in reactive oxygen species in combination with obesity-associated low adiponectin and high glucose and interleukin-6 as cause of the decrease in IRAK3 in THP-1 cells in vitro. Conclusion IRAK3 is a key inhibitor of inflammation in association with obesity and metabolic syndrome. Our data warrant further evaluation of IRAK3 as a diagnostic and prognostic marker, and as a target for intervention.

Maternal Micronutrient Deficiencies and Related Adverse Neonatal Outcomes after Bariatric Surgery: A Systematic Review

Pregnant and postpartum women with a history of bariatric surgery are at risk of micronutrient deficiencies as a result of the combination of physiologic changes related to pregnancy and iatrogenic postoperative alterations in the absorption and metabolism of crucial nutrients. This systematic review investigates micronutrient deficiencies and related adverse clinical outcomes in pregnant and postpartum women after bariatric surgery. A systematic approach involving critical appraisal was conducted independently by 2 researchers to examine deficiencies of phylloquinone, folate, iron, calcium, zinc, magnesium, iodide, copper, and vitamins A, D, and B-12 in pregnant and postpartum women after bariatric surgery, together with subsequent outcomes in the neonates. The search identified 29 relevant cases and 8 cohort studies. The quality of reporting among the case reports was weak according to the criteria based on the CARE (CAse REporting) guidelines as was that for the cohort studies based on the criteria from the Cohort Study Quality Assessment list of the Dutch Cochrane Center. The most common adverse neonatal outcomes related to maternal micronutrient deficiencies include visual complications (vitamin A), intracranial hemorrhage (phylloquinone), neurological and developmental impairment (vitamin B-12), and neural tube defects (folate). On the basis of the systematically collected information, we conclude that the evidence on micronutrient deficiencies in pregnant and postpartum women after bariatric surgery and subsequent adverse neonatal outcomes remains weak and inconclusive.

Roux-en-y gastric bypass attenuates hepatic mitochondrial dysfunction in mice with non-alcoholic steatohepatitis

Objective No therapy for non-alcoholic steatohepatitis (NASH) has been approved so far. Roux-en-y gastric bypass (RYGB) is emerging as a therapeutic option, although its effect on NASH and related hepatic molecular pathways is unclear from human studies. We studied the effect of RYGB on pre-existent NASH and hepatic mitochondrial dysfunction—a key player in NASH pathogenesis—in a novel diet-induced mouse model nicely mimicking human disease. Design C57BL/6J mice were fed a high-fat high-sucrose diet (HF-HSD). Results HF-HSD led to early obesity, insulin resistance and hypercholesterolaemia. HF-HSD consistently induced NASH (steatosis, hepatocyte ballooning and inflammation) with fibrosis already after 12-week feeding. NASH was accompanied by hepatic mitochondrial dysfunction, characterised by decreased mitochondrial respiratory chain (MRC) complex I and IV activity, ATP depletion, ultrastructural abnormalities, together with higher 4-hydroxynonenal (HNE) levels, increased uncoupling protein 2 (UCP2) and tumour necrosis factor-α (TNF-α) mRNA and free cholesterol accumulation. In our model of NASH and acquired mitochondrial dysfunction, RYGB induced sustained weight loss, improved insulin resistance and inhibited progression of NASH, with a marked reversal of fibrosis. In parallel, RYGB preserved hepatic MRC complex I activity, restored ATP levels, limited HNE production and decreased TNF-α mRNA. Conclusions Progression of NASH and NASH-related hepatic mitochondrial dysfunction can be prevented by RYGB. RYGB preserves respiratory chain complex activity, thereby restoring energy output, probably by limiting the amount of oxidative stress and TNF-α. These data suggest that modulation of hepatic mitochondrial function contributes to the favourable effect of RYBG on established NASH.

Health related quality of life, physical fitness and physical activity participation in treatment-seeking obese persons with and without binge eating disorder

This study compared the mental and physical health related quality of life (HRQL) of 40 obese persons with BED with 20 age, gender and body mass index (BMI) matched obese persons without BED and 40 age and gender matched non-obese volunteers. Variables contributing to the variability in HRQL were identified. Participants were asked to fill in the MOS 36-item Short Form Health Survey (SF-36), the Symptoms Checklist-90 (SCL-90), the Baecke questionnaire, the bulimia subscale of the Eating Disorder Inventory and the Body Attitude Test. All participants also performed a 6-minute walk test (6MWT). BED patients showed a significant impaired physical and mental HRQL compared with obese and non-obese control groups. In the BED-group female participants showed a significantly more impaired mental HRQL than male participants (40.0±21.2 versus 66.6±10.1). The distance achieved on the 6MWT (512.1±75.8m) explained 22.5% of the variability in physical HRQL in the obese BED-group while gender and the SCL-90 depression score (39.1±12.2) explained 47.1% of the variability in mental HRQL. The present findings suggest that the treatment of obese individuals with BED might benefit by giving more attention to HRQL, depressive symptoms and physical fitness.

Bariatric Surgery Induces Weight Loss but Does Not Improve Glycemic Control in Patients With Type 1 Diabetes

Brethauer et al. (1) report an improvement of glycemic control following bariatric surgery in patients with type 1 diabetes. However, the small sample size and limited time of follow-up of this latest and other previous reports preclude drawing firm conclusions (1–3). We collected data from 22 patients with confirmed type 1 diabetes and BMI ≥35 kg/m2 from three Belgian bariatric surgery centers. Six patients underwent sleeve gastrectomy and 16 had Roux-en-Y gastric bypass surgery. Overall, we compared BMI, glycemic control (as assessed by A1C), and daily insulin dose between pre- and postsurgery using a linear mixed model with a random patient and a fixed period effect. P values < 0.05 are considered significant. At each time point, mean ± SEM is given in Fig. 1. …

Laparoscopy for primary and secondary bariatric procedures.

Recently obesity has been defined as a disease and has turned bariatric surgery into a part of a chronic illness management. Obesity induces several comorbidities leading to cardiovascular disease and mortality. The effects of bariatric surgery on these comorbidities used to be classified as weight-loss induced. However bariatric surgery has recently been termed metabolic surgery because of the suspected direct, weight loss independent effect of bariatric procedures on the physiopathological mechanisms causing excess fat storage and insulin resistance. This review describes the standard procedures commonly performed and their specific outcomes on metabolic diseases in order to work towards more patient tailored treatment of obesity and to reduce side effects. Furthermore this review focuses on gaps in understanding the pathogenesis of obesity and its treatment with bariatric surgery. Surgery failures as well as new techniques are discussed and evaluated.

A pilot study of the effects of the somatostatin analog pasireotide in postoperative dumping syndrome

Dumping syndrome is characterized by distinct pathophysiological features such as postprandial increase in hematocrit (HT) and pulse rate (PR) and delayed hypoglycemia (HG). Treatment is based on dietary measures and somatostatin analogs (SA), but current SAs have incomplete efficacy, possibly through limited affinity for various somatostatin receptor subtypes. We evaluated the effect of pasireotide, a novel SA with high affinity for 4/5 human somatostatin receptors, on pathophysiological events and symptoms in dumping.

Urinary phenotyping indicates weight loss-independent metabolic effects of Roux-en-Y gastric bypass in mice.

Patients with a body mass index (BMI) above 35 kg/m(2) with metabolic diseases benefit from Roux-en-Y gastric bypass (RYGB) independently of their final BMI and the amount of body weight lost. However, the weight loss independent metabolic effects induced by RYGB remain less well understood. To elucidate metabolic changes after RYGB, (1)H NMR spectroscopy-based urine metabolic profiles from RYGB (n = 7), ad libitum-fed sham (AL, n = 5), and body-weight-matched sham (BWM, n = 5) operated mice were obtained. Gut morphometry and fecal energy content were analyzed. Food intake and body weight of RYGB mice were significantly reduced (p = 0.001) compared to sham-AL. There was a strong tendency that BWM-shams required less food to maintain the same body weight as RYGB mice (p = 0.05). No differences were found in fecal energy content between the groups, excluding malabsorption in RYGB animals. Unlike RYGB-operated rats, gut hypertrophy was not observed in RYGB-operated mice. Urinary tricarboxylic acid cycle intermediates were higher in the sham groups, suggesting altered mitochondrial metabolism after RYGB surgery. Higher urinary levels of trimethylamine, hippurate and trigonelline in RYGB mice indicate that the RYGB operation caused microbial disturbance. Taken together, we demonstrate for the first time that there are RYGB specific metabolic effects, which are independent of food intake and body weight loss. Increased utilization of TCA cycle intermediates and altered gut microbial-host co-metabolites might indicate increased energy expenditure and microbial changes in the gut, respectively.

Micronutrient intake, from diet and supplements, and association with status markers in pre- and post-RYGB patients

BACKGROUND & AIMS Roux-en-Y gastric bypass (RYGB) is associated with an increased risk for micronutrient deficiencies. This study aimed to assess total (dietary and supplement) intake and association with iron (including hepcidin), vitamin B12, vitamin C and zinc status markers before and after Roux-en-Y gastric bypass (RYGB). METHODS This prospective study included patients with a planned RYGB in University Hospitals Leuven, Belgium; who were followed until 12 months post-RYGB. Patients completed an estimated dietary record of two non-consecutive days before and 1, 3, 6 and 12 months post-RYGB and supplement/drug use was registered. Associations between total micronutrient intake and status markers were analyzed. RESULTS Fifty-four patients (21 males; mean age: 48.0 [95%CI 46.6; 49.3] years; mean preoperative BMI: 40.4 [95%CI 39.4; 41.4] kg/m2) were included. One month post-RYGB, usual dietary intake of the studied micronutrients was significantly decreased compared to pre-RYGB, but gradually increased until 12 months post-RYGB, remaining below baseline values. By including micronutrient supplement intake, 12 months post-RYGB values were higher than baseline, except for zinc. Hemoglobin, ferritin, vitamin B12 and C-reactive protein serum concentrations were significantly decreased and transferrin saturation and mean corpuscular volume were significantly increased 12 months post-RYGB. Serum hepcidin concentration was significantly decreased 6 months post-RYGB. CONCLUSIONS Medical nutritional therapy is essential following RYGB as dietary intake of iron, vitamin B12, vitamin C, copper and zinc was markedly decreased postoperatively and some patients still had an inadequate total intake one year post-RYGB.

Higher plasma motilin levels in obese patients decrease after Roux-en-Y gastric bypass surgery and regulate hunger

Objective Motilin-induced phase III contractions of the migrating motor complex (MMC) signal hunger in healthy volunteers. The current aim was to study the role of motilin as a hunger-inducing factor in obese patients and to evaluate the effect of Roux-en-Y gastric bypass (RYGB) surgery on plasma motilin levels and hunger scores. Design Motilin and ghrelin plasma levels were determined during a complete MMC cycle in controls and obese patients selected for RYGB before, 6 months and 1 year after surgery. 20 min after the end of the second phase III, obese patients received an intravenous infusion of 40 mg erythromycin. Hunger was scored every 5 min. Hedonic hunger was assessed in obese patients with the Power of Food Scale questionnaire. Results Obesity caused a switch in the origin of phase III from antrum to duodenum. Obese patients had significantly higher motilin levels compared with controls during the MMC but tended to lack the motilin peak prior to phase III necessary to trigger hunger. Hunger scores during phase III were significantly lower in obese patients, but could be restored to control levels through the administration of a low dose of the motilin agonist, erythromycin. After RYGB surgery motilin, but not ghrelin, levels decreased in parallel with hedonic hunger scores. Conclusions Motilin may be an important regulator involved in the pathogenesis of obesity.