Sean Manning

Pharmacotherapy for obesity: novel agents and paradigms.

Public health initiatives focused on obesity prevention and lifestyle intervention programmes for patients with obesity have struggled to contain the obesity epidemic to date. In recent years, antiobesity drug therapies have had a limited role in clinical treatment algorithms for patients with obesity. Indeed, a number of high-profile antiobesity drug suspensions have markedly impacted upon the landscape of obesity pharmacotherapy. In this review, we discuss the advent of an increasing array of pharmacotherapeutic agents, which are effective both in inducing weight loss and in maintaining weight loss achieved by lifestyle measures. The development of these drugs as antiobesity agents has followed varying paths, ranging from lorcaserin, a selective serotonin agent, exploiting the beneficial central actions of fenfluramine but without the associated systemic side effects, to liraglutide, a gut hormone already used as a glucose-lowering drug but with appetite-suppressant properties, or the novel drug combination of phentermine/topiramate, two ‘old’ drugs used in lower doses than with previous therapeutic uses, resulting in an additive effect on weight loss and fewer side effects. We summarize the key findings from recent randomized controlled trials of these three drugs. Although these agents lead to clinically important weight loss when used as monotherapy, the use of antiobesity drugs as adjunctive therapy post intensive lifestyle intervention could prove to be the most successful strategy. Moreover, a progressive approach to obesity pharmacotherapy perhaps offers the best opportunity to finally address the obesity crisis on a mass scale.

The Role of Gut Hormone Peptide YY in Energy and Glucose Homeostasis: Twelve Years On

Although the role of peptide YY (PYY) as a regulator of energy homeostasis was first highlighted only in 2002, our understanding of the physiological role of PYY has since rapidly advanced. In recent years, insights from mechanistic studies in patients undergoing bariatric surgery, from pancreatic islet research, from functional neuroimaging studies, and from exercise research have greatly added to the field, and these areas provide the focus of discussion for this narrative review. We critically discuss recent findings relating to the role of PYY in mediating the beneficial effects of bariatric surgery, the role of PYY in glucose homeostasis, the role of hepatoportal PYY in mediating its central physiological effects, the specific modulation of brain regions by PYY, and the exercise-induced PYY response.

Roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanisms

Bariatric surgery is the most effective treatment for severe obesity, producing marked sustained weight loss with associated reduced morbidity and mortality. Roux-en-Y gastric bypass surgery (RYGBP), the most commonly performed procedure, was initially viewed as a hybrid restrictive-malabsorptive procedure. However, over the last decade, it has become apparent that alternative physiologic mechanisms underlie its beneficial effects. RYGBP-induced altered feeding behavior, including reduced appetite and changes in taste/food preferences, is now recognized as a key driver of the sustained postoperative weight loss. The brain ultimately determines feeding behavior, and here we review the mechanisms by which RYGBP may affect central appetite-regulating pathways.

GLP-1: A Mediator of the Beneficial Metabolic Effects of Bariatric Surgery?

There has been increasing interest in the role that gut hormones may play in contributing to the physiological changes produced by certain bariatric procedures, such as Roux-en-Y gastric bypass and sleeve gastrectomy. Here, we review the evidence implicating one such gut hormone, glucagon-like peptide-1, as a mediator of the metabolic benefits of these two procedures.

Contribution of 32 GWAS-Identified Common Variants to Severe Obesity in European Adults Referred for Bariatric Surgery

The prevalence of severe obesity, defined as body mass index (BMI) ≥35.0 kg/m2, is rising rapidly. Given the disproportionately high health burden and healthcare costs associated with this condition, understanding the underlying aetiology, including predisposing genetic factors, is a biomedical research priority. Previous studies have suggested that severe obesity represents an extreme tail of the population BMI variation, reflecting shared genetic factors operating across the spectrum. Here, we sought to determine whether a panel of 32 known common obesity-susceptibility variants contribute to severe obesity in patients (n = 1,003, mean BMI 48.4±8.1 kg/m2) attending bariatric surgery clinics in two European centres. We examined the effects of these 32 common variants on obesity risk and BMI, both as individual markers and in combination as a genetic risk score, in a comparison with normal-weight controls (n = 1,809, BMI 18.0–24.9 kg/m2); an approach which, to our knowledge, has not been previously undertaken in the setting of a bariatric clinic. We found strong associations with severe obesity for SNP rs9939609 within the FTO gene (P = 9.3×10−8) and SNP rs2815752 near the NEGR1 gene (P = 3.6×10−4), and directionally consistent nominal associations (P<0.05) for 12 other SNPs. The genetic risk score associated with severe obesity (P = 8.3×10−11) but, within the bariatric cohort, this score did not associate with BMI itself (P = 0.264). Our results show significant effects of individual BMI-associated common variants within a relatively small sample size of bariatric patients. Furthermore, the burden of such low-penetrant risk alleles contributes to severe obesity in this population. Our findings support that severe obesity observed in bariatric patients represents an extreme tail of the population BMI variation. Moreover, future genetic studies focused on bariatric patients may provide valuable insights into the pathogenesis of obesity at a population level.

Feasibility and Impact of a Combined Supervised Exercise and Nutritional-Behavioral Intervention following Bariatric Surgery: A Pilot Study

Background. Lifestyle intervention programs after bariatric surgery have been suggested to maximise health outcomes. This pilot study aimed to investigate the feasibility and impact of an 8-week combined supervised exercise with nutritional-behavioral intervention following Roux-en-Y gastric bypass and sleeve gastrectomy. Methods. Eight female patients (44 ± 8 years old, BMI = 38.5 ± 7.2 kgm−2) completed the program. Before and after intervention, anthropometric measures, six-minute walk test (6MWT), physical activity level, eating behavior, and quality of life (QoL) were assessed. Percentage weight loss (%WL) outcomes were compared with a historical matched control group. Results. The program significantly improved functional capacity (mean increment in 6MWT was 127 ± 107 meters, p = 0.043), increased strenuous intensity exercise (44 ± 49 min/week, p = 0.043), increased consumption of fruits and vegetables (p = 0.034), reduced consumption of ready meals (p = 0.034), and improved “Change in Health” in QoL domain (p = 0.039). The intervention group exhibited greater %WL in the 3–12-month postsurgery period compared to historical controls, 12.2 ± 7.5% versus 5.1 ± 5.4%, respectively (p = 0.027). Conclusions. Lifestyle intervention program following bariatric surgery is feasible and resulted in several beneficial outcomes. A large randomised control trial is now warranted.

A case of severe anorexia, excessive weight loss and high peptide YY levels after sleeve gastrectomy

Summary Sleeve gastrectomy (SG) is the second most commonly performed bariatric procedure worldwide. Altered circulating gut hormones have been suggested to contribute post-operatively to appetite suppression, decreased caloric intake and weight reduction. In the present study, we report a 22-year-old woman who underwent laparoscopic SG for obesity (BMI 46 kg/m2). Post-operatively, she reported marked appetite reduction, which resulted in excessive weight loss (1-year post-SG: BMI 22 kg/m2, weight loss 52%, >99th centile of 1-year percentage of weight loss from 453 SG patients). Gastrointestinal (GI) imaging, GI physiology/motility studies and endoscopy revealed no anatomical cause for her symptoms, and psychological assessments excluded an eating disorder. Despite nutritional supplements and anti-emetics, her weight loss continued (BMI 19 kg/m2), and she required nasogastric feeding. A random gut hormone assessment revealed high plasma peptide YY (PYY) levels. She underwent a 3 h meal study following an overnight fast to assess her subjective appetite and circulating gut hormone levels. Her fasted nausea scores were high, with low hunger, and these worsened with nutrient ingestion. Compared to ten other post-SG female patients, her fasted circulating PYY and nutrient-stimulated PYY and active glucagon-like peptide 1 (GLP1) levels were markedly elevated. Octreotide treatment was associated with suppressed circulating PYY and GLP1 levels, increased appetite, increased caloric intake and weight gain (BMI 22 kg/m2 after 6 months). The present case highlights the value of measuring gut hormones in patients following bariatric surgery who present with anorexia and excessive weight loss and suggests that octreotide treatment can produce symptomatic relief and weight regain in this setting. Learning points Roux-en-Y gastric bypass and SG produce marked sustained weight reduction. However, there is a marked individual variability in this reduction, and post-operative weight loss follows a normal distribution with extremes of ‘good’ and ‘poor’ response. Profound anorexia and excessive weight loss post-SG may be associated with markedly elevated circulating fasted PYY and post-meal PYY and GLP1 levels. Octreotide treatment can produce symptomatic relief and weight regain for post-SG patients that have an extreme anorectic and weight loss response. The present case highlights the value of measuring circulating gut hormone levels in patients with post-operative anorexia and extreme weight loss.

Latent autoimmune diabetes in adults presenting as diabetes "recurrence" after bariatric surgery: a case report.

Here, we describe a novel presentation of latent autoimmune diabetes in adults (LADA) involving a deterioration of glycemic control in a patient after bariatric surgery. A 43-year-old woman with a 7-year diagnosis of type 2 diabetes (T2D), treated initially with metformin and then also insulin glargine 2 years later, and a background of hypothyroidism and vitiligo was referred for bariatric surgery. Her weight was 106 kg (maximum lifetime weight 114 kg), and BMI was 35 kg/m2. HBA1c 97 mmol/mol (11%) improved to 57 mmol/mol (7.4%) with no change in weight with addition of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide preoperatively. After laparoscopic proximal gastric bypass (LPGB), insulin and liraglutide were discontinued. Weight loss was 29% after 6 months and 38% after 1 year; however, glycemic improvement was less than expected: HbA …

Metabolic phenotype of skeletal muscle in early critical illness

Objectives To characterise the sketetal muscle metabolic phenotype during early critical illness. Methods Vastus lateralis muscle biopsies and serum samples (days 1 and 7) were obtained from 63 intensive care patients (59% male, 54.7±18.0 years, Acute Physiology and Chronic Health Evaluation II score 23.5±6.5). Measurements and main results From day 1 to 7, there was a reduction in mitochondrial beta-oxidation enzyme concentrations, mitochondrial biogenesis markers (PGC1α messenger mRNA expression (−27.4CN (95% CI −123.9 to 14.3); n=23; p=0.025) and mitochondrial DNA copy number (−1859CN (IQR −5557–1325); n=35; p=0.032). Intramuscular ATP content was reduced compared tocompared with controls on day 1 (17.7mmol/kg /dry weight (dw) (95% CI 15.3 to 20.0) vs. 21.7 mmol/kg /dw (95% CI 20.4 to 22.9); p<0.001) and decreased over 7 days (−4.8 mmol/kg dw (IQR −8.0–1.2); n=33; p=0.001). In addition, the ratio of phosphorylated:total AMP-K (the bioenergetic sensor) increased (0.52 (IQR −0.09–2.6); n=31; p<0.001). There was an increase in intramuscular phosphocholine (847.2AU (IQR 232.5–1672); n=15; p=0.022), intramuscular tumour necrosis factor receptor 1 (0.66 µg (IQR −0.44–3.33); n=29; p=0.041) and IL-10 (13.6 ng (IQR 3.4–39.0); n=29; p=0.004). Serum adiponectin (10.3 µg (95% CI 6.8 to 13.7); p<0.001) and ghrelin (16.0 ng/mL (IQR −7–100); p=0.028) increased. Network analysis revealed a close and direct relationship between bioenergetic impairment and reduction in muscle mass and between intramuscular inflammation and impaired anabolic signaling. ATP content and muscle mass were unrelated to lipids delivered. Conclusions Decreased mitochondrial biogenesis and dysregulated lipid oxidation contribute to compromised skeletal muscle bioenergetic status. In addition, intramuscular inflammation was associated with impaired anabolic recovery with lipid delivery observed as bioenergetically inert. Future clinical work will focus on these key areas to ameliorate acute skeletal muscle wasting. Trial registration number NCT01106300.

Timing of pregnancy in obese women after bariatric surgery.

AIMS There is an increased risk of preterm and small-for-gestational-age births associated with bariatric surgery, especially if maternal early pregnancy body mass index (BMI) is <30.0kg/m(2). However, the relationship between timing of pregnancy post-bariatric surgery and effects on pregnancy outcome are unknown. The aim of this study was to investigate the timing of pregnancy post-bariatric surgery and compare early pregnancy BMI between women who became pregnant before or after the recommended 12month postoperative window. METHODS/RESULTS Women who underwent either sleeve gastrectomy or gastric bypass and subsequently became pregnant were offered antenatal care in a multidisciplinary high-risk clinic. There were 50 such pregnancies in women who attended our high-risk clinic (n=26 <12months and n=24 >12months postoperatively, mean estimated times to conception 31.9±12.6weeks and 102.8±37.7weeks respectively). There was no significant difference in early pregnancy BMI between groups (33.2±6.8kg/m(2) and 32.5+2.1kg/m(2) respectively, p=0.78). There were 6 miscarriages in each group, however more women in the <12month (n=8) than in the >12months group (n=2) were lost-to-follow-up (likelihood ratio 4.2, p=0.04). CONCLUSIONS Women who became pregnant <12months post-bariatric surgery were, for unknown reasons, less likely to attend follow-up in a specialist antenatal clinic than those who became pregnant >12months postoperatively. Further research is required to explore the relationship between timing of pregnancy post-bariatric surgery and pregnancy outcome and to identify predictors more clinically useful than early pregnancy BMI, in this high-risk pregnancy group.