Effects of bariatric surgery and dietary interventions for obesity on brain neurotransmitter systems and metabolism: A systematic review of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies

This systematic review collates studies of dietary or bariatric surgery interventions for obesity using positron emission tomography and single-photon emission computed tomography. Of 604 publications identified, 22 met inclusion criteria. Twelve studies assessed bariatric surgery (seven gastric bypass, five gastric bypass/sleeve gastrectomy), and ten dietary interventions (six low-calorie diet, three very low-calorie diet, one prolonged fasting). Thirteen studies examined neurotransmitter systems (six used tracers for dopamine DRD2/3 receptors: two each for 11C-raclopride, 18F-fallypride, 123I-IBZM; one for dopamine transporter, 123I-FP-CIT; one used tracer for serotonin 5-HT2A receptor, 18F-altanserin; two used tracers for serotonin transporter, 11C-DASB or 123I-FP-CIT; two used tracer for μ-opioid receptor, 11C-carfentanil; one used tracer for noradrenaline transporter, 11C-MRB); seven studies assessed glucose uptake using 18F-fluorodeoxyglucose; four studies assessed regional cerebral blood flow using 15O-H2O (one study also used arterial spin labeling); and two studies measured fatty acid uptake using 18F-FTHA and one using 11C-palmitate. The review summarizes findings and correlations with clinical outcomes, eating behavior, and mechanistic mediators. The small number of studies using each tracer and intervention, lack of dietary intervention control groups in any surgical studies, heterogeneity in time since intervention and degree of weight loss, and small sample sizes hindered the drawing of robust conclusions across studies

Effect of obesity surgery on taste

Obesity surgery is a highly efficacious treatment for obesity and its comorbidities. The underlying mechanisms of weight loss after obesity surgery are not yet fully understood. Changes to taste function could be a contributing factor. However, the pattern of change in different taste domains and among obesity surgery operations is not consistent in the literature. A systematic search was performed to identify all articles investigating gustation in human studies following bariatric procedures. A total of 3323 articles were identified after database searches, searching references and deduplication, and 17 articles were included. These articles provided evidence of changes in the sensory and reward domains of taste following obesity procedures. No study investigated the effect of obesity surgery on the physiological domain of taste. Taste detection sensitivity for sweetness increases shortly after Roux-en-Y gastric bypass. Additionally, patients have a reduced appetitive reward value to sweet stimuli. For the subgroup of patients who experience changes in their food preferences after Roux-en-Y gastric bypass or vertical sleeve gastrectomy, changes in taste function may be underlying mechanisms for changing food preferences which may lead to weight loss and its maintenance. However, data are heterogeneous; the potential effect dilutes over time and varies significantly between different procedures

Somatostatin infusion lowers plasma ghrelin withoug reducing appetite in adults with Pradi-Willi syndrome

Prader-Willi syndrome (PWS) is characterized by life-threatening childhood-onset hyperphagia, obesity and, uniquely, high plasma levels of ghrelin, the orexigenic gastric hormone. Somatostatin suppresses ghrelin secretion in normal subjects. We therefore examined the effect of somatostatin on plasma ghrelin and appetite in four male PWS adults fasted overnight in a double-blind, placebo-controlled, randomized cross-over study. Subjects received an intravenous infusion of somatostatin (250 mug/hr) or saline for 300min, and had blood samples taken every 30min for measurement of plasma ghrelin and PYY3-36 (anorexigenic intestinal hormone) by radio-immunoassay, and glucose. Appetite was measured by counting sandwiches eaten over a 60min free food access period from +120min. Despite somatostatin lowering fasting plasma ghrelin by 60 +/- 2% (P = 0.04) to levels seen in non-PWS men, there was no associated reduction in food intake (105 +/- 9% of food intake during saline infusion, P = 0.6). Somatostatin also lowered plasma PYY levels by 45 +/- 16% (P = 0.04), and produced post-prandial hyperglycemia (P = 0.04). We conclude that either hyperghrelinemia may not contribute to hyperphagia in PWS adults, or perhaps concomitant reductions in anorexigenic gastrointestinal hormones by somatostatin counteracted any anorexigenic effect of lowering orexigenic ghrelin. Somatostatin analogues may therefore not be an effective therapy for obesity in PWS. Larger chronic studies with long-acting somatostatin analogues will be needed to determine their benefits and risks in treating PWS obesity

Measurement of hepatic insulin sensitivity early after the bypass of the proximal small bowel in humans

Objective: Unlike gastric banding or sleeve gastrectomy procedures, intestinal bypass procedures, and the Roux-en-Y gastric bypass (RYGB) in particular, lead to rapid improvements in glycaemia early after surgery. The bypass of the proximal small bowel may have weight loss and even caloric restriction independent glucose-lowering properties on hepatic insulin sensitivity. In this first in humans mechanistic study, we examined this hypothesis by investigating the early effects of the duodeno-jejunal bypass liner (DJBL; GI Dynamics, USA) on the hepatic insulin sensitivity using the gold standard euglycaemic hyperinsulinaemic clamp methodology. Method: Seven patients with obesity underwent measurement of hepatic insulin sensitivity at baseline, one week after a low-calorie liquid diet and after a further one week following insertion of the DJBL whilst on the same diet. Results: DJBL did not improve the insulin sensitivity of hepatic glucose production (HGP) beyond the improvements achieved with caloric restriction. Conclusions: Caloric restriction may be the predominant driver of early increases in hepatic insulin sensitivity after the endoscopic bypass of the proximal small bowel. The same mechanism may be at play after RYGB and explain, at least in part, the rapid improvements in glycaemia

Neural substrates of cue reactivity and craving in Gambling Disorder

Cue reactivity is an established procedure in addictions research for examining the subjective experience and neural basis of craving. This experiment sought to quantify cue-related brain responses in Gambling Disorder using personally tailored cues in conjunction with subjective craving, as well as a comparison with appetitive non-gambling stimuli. Participants with Gambling Disorder (n=19) attending treatment and 19 controls viewed personally tailored blocks of gambling-related cues, as well as neutral cues and highly appetitive (food) images during a functional MRI scan performed ~2-3 hours after a usual meal. fMRI analysis examined cue-related brain activity, cue-related changes in connectivity, and associations with block-by-block craving ratings. Craving ratings in the participants with Gambling Disorder increased following gambling cues compared with non-gambling cues. fMRI analysis revealed group differences in left insula and anterior cingulate cortex, with the Gambling Disorder group showing greater reactivity to the gambling cues, but no differences to the food cues. In participants with Gambling Disorder, craving to gamble correlated positively with gambling cue-related activity in the bilateral insula and ventral striatum, and negatively with functional connectivity between the ventral striatum and the medial PFC. Gambling cues, but not food cues, elicit increased brain responses in reward-related circuitry in individuals with Gambling Disorder (compared to controls), providing support for the incentive sensitisation theory of addiction. Activity in the insula co-varied with craving intensity, and may be a target for interventions.This study was funded by the Medical Research Council—MRC G1002226 (Nutt) and G1100554 (Clark). We wish to thank the study participants and the clinical team at Imanova, Centre for Imaging Sciences. The research was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre. SPS was funded by the Cambridge Home Scholarship Scheme (CHSS)

Central adrenal insufficiency is rare in adults with Prader-Willi syndrome

CONTEXT: Prader-Willi syndrome (PWS) is associated with several hypothalamic-pituitary hormone deficiencies. There is no agreement on the prevalence of central adrenal insufficiency (CAI) in adults with PWS. In some countries, it is general practice to prescribe stress-dose hydrocortisone during physical or psychological stress in patients with PWS. Side effects of frequent hydrocortisone use are weight gain, osteoporosis, diabetes mellitus, and hypertension-already major problems in adults with PWS. However, undertreatment of CAI can cause significant morbidity-or even mortality. OBJECTIVE: To prevent both over- and undertreatment with hydrocortisone, we assessed the prevalence of CAI in a large international cohort of adults with PWS. As the synacthen test shows variable results in PWS, we only use the metyrapone test (MTP) and insulin tolerance test (ITT). DESIGN: Metyrapone test or ITT in adults with PWS (N = 82) and review of medical files for symptoms of hypocortisolism related to surgery (N = 645). SETTING: Outpatient clinic. PATIENTS OR OTHER PARTICIPANTS: Eighty-two adults with genetically confirmed PWS. MAIN OUTCOME MEASURE: For MTP, 11-deoxycortisol > 230 nmol/L was considered sufficient. For ITT, cortisol > 500 nmol/L (Dutch, French, and Swedish patients) or > 450 nmol/L (British patients) was considered sufficient. RESULTS: Central adrenal insufficiency was excluded in 81 of 82 patients. Among the 645 patients whose medical files were reviewed, 200 had undergone surgery without perioperative hydrocortisone treatment. None of them had displayed any features of hypocortisolism. CONCLUSIONS: Central adrenal insufficiency is rare (1.2%) in adults with PWS. Based on these results, we recommend against routinely prescribing hydrocortisone stress-doses in adults with PWS

Malignancies in Prader-Willi syndrome: results from a large international cohort and literature review

CONTEXT: Prader-Willi syndrome (PWS) is a complex disorder combining hypothalamic dysfunction, neurodevelopmental delay, hypotonia, and hyperphagia with risk of obesity and its complications. PWS is caused by the loss of expression of the PWS critical region, a cluster of paternally expressed genes on chromosome 15q11.2-q13. As life expectancy of patients with PWS increases, age-related diseases like malignancies might pose a new threat to health. OBJECTIVE: To investigate the prevalence and risk factors of malignancies in patients with PWS and to provide clinical recommendations for cancer screening. METHODS: We included 706 patients with PWS (160 children, 546 adults). We retrospectively collected data from medical records on past or current malignancies, the type of malignancy and risk factors for malignancy. Additionally, we searched the literature for information about the relationship between genes on chromosome 15q11.2-q13 and malignancies. RESULTS: Seven adults (age range 18-55 years old) had been diagnosed with a malignancy (acute lymphoblastic leukemia, intracranial hemangiopericytoma, melanoma, stomach adenocarcinoma, biliary cancer, parotid adenocarcinoma and colon cancer). All patients with a malignancy had a paternal 15q11-13 deletion. The literature review showed that several genes on chromosome 15q11.2-q13 are related to malignancies. CONCLUSION: Malignancies are rare in patients with PWS. Therefore, screening for malignancies is only indicated when clinically relevant symptoms are present such as unexplained weight loss, loss of appetite, symptoms suggestive of paraneoplastic syndrome, or localizing symptoms. Given the increased cancer risk associated with obesity, which is common in PWS, participation in national screening programs should be encouraged

Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study

OBJECTIVE: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). METHODS: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. RESULTS: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p  22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). CONCLUSIONS: DCCR administration to people with PWS was well-tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families

Periodontal disease in a patient with Prader-Willi syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>Prader-Willi syndrome is a complex genetic disease caused by lack of expression of paternally inherited genes on chromosome 15q11-q13. The prevalence of Prader-Willi syndrome is estimated to be one in 10,000 to 25,000. However, descriptions of the oral and dental phenotype are rare.</p> <p>Case presentation</p> <p>We describe the clinical presentation and periodontal findings in a 20-year-old Japanese man with previously diagnosed Prader-Willi syndrome. Clinical and radiographic findings confirmed the diagnosis of periodontitis. The most striking oral findings were anterior open bite, and crowding and attrition of the lower first molars. Periodontal treatment consisted of tooth-brushing instruction and scaling. Home care involved recommended use of adjunctive chlorhexidine gel for tooth brushing twice a week and chlorhexidine mouthwash twice daily. Gingival swelling improved, but further treatment will be required and our patient's oral hygiene remains poor. The present treatment of tooth-brushing instruction and scaling every three weeks therefore only represents a temporary solution.</p> <p>Conclusions</p> <p>Rather than being a direct result of genetic defects, periodontal diseases in Prader-Willi syndrome may largely result from a loss of cuspid guidance leading to traumatic occlusion, which in turn leads to the development of periodontal diseases and dental plaque because of poor oral hygiene. These could be avoided by early interventions to improve occlusion and regular follow-up to monitor oral hygiene. This report emphasizes the importance of long-term follow-up of oral health care by dental practitioners, especially pediatric dentists, to prevent periodontal disease and dental caries in patients with Prader-Willi syndrome, who appear to have problems maintaining their own oral health.</p