Christina Gabriele Prechtl

Background: Overweight and obesity affect over 60% of the United Kingdom population and constitute a major risk factor for the development of comorbidities. Preventing weight gain in periods of life where there is an elevated risk of adipose tissue expansion could be beneficial in preventing associated diseases in later life. This study investigated the impact of inulin-propionate ester on the prevention of weight gain in young people who were at risk of gaining weight. Objectives: To investigate the impact of increasing colonic production of the short-chain fatty acid propionate on preventing body weight gain, in younger adults, over 12 months. Several underpinning mechanisms were investigated in a substudy. Design: iPREVENT was a randomised, parallel-group, placebo-controlled, double-blind trial, designed with 90% power to detect a 2 kg between-arm difference in weight gain at 12 months. Setting: This trial was performed at the Imperial Clinical Research Facility in London and the University of Glasgow Clinical Research Facility. Participants: Participants were 20–40 years old, with a body mass index of 24.0–27.0 kg/m² if of South Asian ethnicity or 25.0–30.0 kg/m² if non-South Asian. Participants were also required to have at least one of the following risk factors: weight gain in the past year, low physical activity, low intake of fruit and vegetables or high intake of sugar-sweetened beverages. A total of 270 participants (135 per arm) were randomised. Intervention: Participants were randomised to either 10 g/day inulin-propionate ester or 10 g/day inulin control (fermentable oligosaccharide) consumed daily for 12 months. Main outcome measure: The primary outcome was weight gain from baseline to 12 months. Results: The mean (± standard deviation) body weight at baseline for inulin was 79.1 kg ± 10.6 (n = 135) and inulin-propionate ester 79.6 kg ± 10.9 (n = 135). At 12 months body weight was 78.9 kg ± 11.8 (n = 114) and 81.4 kg ± 11.9 (n = 112) for inulin and inulin-propionate ester, respectively. The baseline-adjusted mean difference in weight gain was 1.02 (95% confidence intervals −0.37 to 2.41) kg for inulin-propionate ester versus inulin control. Of the secondary outcomes, the confidence interval cautiously supports differences in fat-free mass; 1.07 kg (0.21 to 1.93) (N = 226), body water; 0.72 kg (0.1 to 1.33) (N = 226) and fasting glucose; 0.11 mmol/l (0.01 to 0.21) (N = 191). Compliance with inulin-propionate ester treatment of ≥ 50% over 12 months was 63% (n = 135). There were no unexpected adverse or serious adverse events. Limitations: This study aimed to explore the efficacy of enhanced propionate production above background fermentation. It could be argued a negative control (a non-fermentable substrate e.g. cellulose) would have been more suitable. Metabolomic analysis of compliance could only be conducted on a subsection of the study population. There was no intention to conduct follow-up assessments on participants beyond their 12-month visit. Conclusions: In adults below the age of 40 years, inulin-propionate ester did not affect weight gain compared with the control. Future work: Previously we observed that inulin-propionate ester prevented weight gain in older adults, but not in this younger cohort. We aim to investigate the variation in responses between these age groups. Trial registration: This trial is registered as ISRCTN16299902. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 15/185/16) and is published in full in Efficacy and Mechanism Evaluation; Vol. 12, No. 8. See the NIHR Funding and Awards website for further award information.

Context: The liver/foregut satiety hormone liver-expressed antimicrobial peptide 2 (LEAP2) is an inverse agonist at the acyl ghrelin receptor (GHSR), increasing after food intake and decreasing after bariatric surgery and short-term nonsurgical weight loss, but effects of long-term dietary weight loss are unknown. Objective: The objective of this study was to examine and compare the effects of these interventions on fasting and postprandial plasma LEAP2 and investigate potential metabolic mediators of changes in plasma LEAP2. Methods: Plasma LEAP2 was measured in a previously published 2-year trial comparing standard medical management (SMM) (including 600-kcal/day deficit) with duodenal-jejunal bypass liner (DJBL, Endobarrier) insertion (explanted after 1 year) in adults with obesity and inadequately controlled type 2 diabetes mellitus. Results: In the SMM group (n = 25-37), weight decreased by 4.3%, 8.1%, 7.8%, and 6.4% at 2, 26, 50, and 104 weeks and fasting plasma LEAP2 decreased from baseline mean ± SD 15.3 ± 0.9 ng/mL by 1.7, 3.8, 2.1, and 2.0 ng/mL, respectively. Absolute/decreases in fasting plasma LEAP2 positively correlated with absolute/decreases in body mass index, glycated hemoglobin A1c, fasting plasma glucose, serum insulin, homeostatic model assessment for insulin resistance, and serum triglycerides. Despite greater weight loss in the DJBL group (n = 23-30) at 26 to 50 weeks (10.4%-11.4%), the decrease in fasting plasma LEAP2 was delayed and attenuated (vs SMM), which may contribute to greater weight loss by attenuating GHSR signaling. Plasma LEAP2 did not increase with weight regain from 50 to 104 weeks after DJBL explant, suggesting a new set point with weight loss maintenance. Increases in plasma LEAP2 after a 600-kcal meal (10.8%-16.1% at 1-2 hours) were unaffected by weight loss, improved glucose metabolism, or DJBL insertion (n = 9-25), suggesting liver rather than duodenum/jejunum may be the primary source of postprandial LEAP2 secretion. Conclusion: These findings add to our understanding of the regulation and potential physiological role of plasma LEAP2.

Introduction: Left gastric artery embolisation (LGAE) is a well-established treatment for major upper gastrointestinal (GI) bleeding when control is not established via upper GI endoscopy and recently has shown promising results for weight loss in small single arm studies. LGAE could be a treatment option in between our current tier-3 and tier-4 services for obesity. EMBIO is a National Institute for Health Research funded trial, a multicentre double-blinded randomised controlled trial between Imperial College National Health Service Trust and University College London Hospital, comparing LGAE versus Placebo procedure. The key aims of the trial is to evaluate LGAE efficacy on weight loss, its mechanism of action, safety profile and obesity-related comorbidities. Methods and analysis: 76 participants will be recruited from the existing tier-3 database after providing informed consent. Key inclusion criteria include adults aged 18–70 with a body mass index 35–50 kg/m ² and appropriate anatomy of the left gastric artery and coeliac plexus on CT Angiogram. Key exclusion criteria included previous major abdominal and bariatric surgery, weight >150 kg, type 2 diabetes on any medications other than metformin and the use of weight modifying medications. Participants will undergo mechanistic visits 1 week prior to the intervention and 3, 6 and 12 months postintervention. Informed consent will be received from each participant and they will be randomised in a 1:1 ratio to left gastric artery embolisation and placebo treatment. Blinding strategies include the use of moderate doses of sedation, visual and auditory isolation. All participants will enter a tier-3 weight management programme postintervention. The primary analysis will estimate the difference between the groups in the mean per cent weight loss at 12 months. Ethics and dissemination: This trial shall be conducted in full conformity with the 1964 Declaration of Helsinki and all subsequent revisions. Local research ethics approval was granted by London-Central Research Ethics Committee, (Reference 19/LO/0509) on 11 October 2019. The Medicines and Healthcare products Regulatory Agency (MHRA) issued the Letter of No Objection on 8 April 2022 (Reference CI/2022/0008/GB). The trial’s development and progress are monitored by an independent trial steering committee and data monitoring and ethics committee. The researchers plan to disseminate results at conferences, in peer- reviewed journals as well as lay media and to patient organisations. Trial registration number: ISRCTN16158402 .

Background: Anticholinergic medications (ACMs) are associated with poorer age‐related outcomes, including falls and frailty. We investigate associations between ACM use and recurrent falls and frailty among older (aged ≥50 years) people with HIV in the POPPY study.Methods: Anticholinergic potential of co‐medications at study entry was coded using the anticholinergic burden score, anticholinergic risk score, and Scottish Intercollegiate Guidelines Network score; drugs scoring ≥1 on any scale were defined as ACM. Associations with recurrent falls (two or more falls in the previous 28 days) and frailty (modified Fried's) were assessed using logistic regression adjusting for (1) possible demographic/lifestyle confounders and (2) clinical factors and depressive symptoms (Patient Health Questionnaire‐9).Results: ACM use was reported by 193 (28%) of 699 participants, with 64 (9%) receiving two or more ACM; commonly prescribed ACMs were codeine (12%), citalopram (12%), loperamide (9%), and amitriptyline (7%). Falls were reported in 63/673 (9%), and 126/609 (21%) met the frailty criteria. Both recurrent falls and frailty were more common in ACM users than in non‐users (recurrent falls: 17% in users vs. 6% in non‐users, p < 0.001; frailty: 32% vs. 17%, respectively, p < 0.001). Use of two or more ACMs was associated with increased odds of falls after adjustment for demographic/lifestyle factors (odds ratio [OR] 4.53; 95% confidence interval [CI] 2.06–9.98) and for clinical factors (OR 3.58; 95% CI 1.37–9.38). Similar albeit weaker associations were seen with frailty (OR 2.26; 95% CI 1.09–4.70 and OR 2.12; 95% CI 0.89–5.0, respectively).Conclusions: ACM are commonly prescribed for people living with HIV, and evidence exists for an association with recurrent falls and frailty. Clinicians should be alert to this and reduce ACM exposure where possible.

Background The novel liver-gut hormone liver-expressed antimicrobial peptide-2 (LEAP2) is a centrally acting inverse agonist, and competitive antagonist of orexigenic acyl ghrelin (AG), at the GH secretagogue receptor, reducing food intake in rodents. In humans, the effects of LEAP2 on eating behavior and mechanisms behind the postprandial increase in LEAP2 are unclear, though this is reciprocal to the postprandial decrease in plasma AG. Methods Plasma LEAP2 was measured in a secondary analysis of a previous study. Twenty-two adults without obesity attended after an overnight fast, consuming a 730-kcal meal without or with subcutaneous AG administration. Postprandial changes in plasma LEAP2 were correlated with postprandial changes in appetite, high-energy (HE) or low-energy (LE) food cue reactivity using functional magnetic resonance imaging, ad libitum food intake, and plasma/serum AG, glucose, insulin, and triglycerides. Results Postprandial plasma LEAP2 increased by 24.5% to 52.2% at 70 to 150 minutes, but was unchanged by exogenous AG administration. Postprandial increases in LEAP2 correlated positively with postprandial decreases in appetite, and cue reactivity to HE/LE and HE food in anteroposterior cingulate cortex, paracingulate cortex, frontal pole, and middle frontal gyrus, with similar trend for food intake. Postprandial increases in LEAP2 correlated negatively with body mass index, but did not correlate positively with increases in glucose, insulin, or triglycerides, nor decreases in AG. Conclusions These correlational findings are consistent with a role for postprandial increases in plasma LEAP2 in suppressing human eating behavior in adults without obesity. Postprandial increases in plasma LEAP2 are unrelated to changes in plasma AG and the mediator(s) remain uncertain.

Introduction: Overweight and obesity affects over 70% of the UK population and is a major risk factor for the development of co-morbidities, including type 2 diabetes and cardiovascular disease. There now exists a considerable evidence base for the management of obesity. However, this is not the case for the prevention of obesity. Preventing weight gain in periods of life where there is an elevated risk of fat mass expansion could be beneficial to preventing associated diseases in later life. This protocol investigates the impact of novel food ingredient inulin propionate ester (IPE) in the prevention of weight gain. This trial aims to investigate the primary hypothesis that IPE has a superior effect on preventing body weight gain, compared with inulin, in young (<40 years old) adults over 12 months, whilst also investigating several complementary mechanisms that may explain the prevention of weight gain and improved long-term energy balance from consuming IPE. Methods: In this multi-centre, double-blind, randomised, parallel-group study, eligible participants will be randomly assigned to consume 10g IPE or 10g inulin (control) daily for 12 months. Study visits will be conducted at baseline, two-month, six-month and 12-month time points. The primary outcome is weight gain from baseline to 12 months. Secondary outcomes will examine changes in metabolic and cardiovascular health biomarkers, body composition and appetite. A mechanistic sub-group will explore causal mechanisms around energy balance, body composition, appetite regulation and the gut microbiota. Based on the power calculation, the sample size required is 270 participants or 135 per study group. Ethics and dissemination: The trial protocol and participant-facing documents have been reviewed and approved, by the London Hampstead Ethics Committee (REC Reference 19/LO/0095, 29th January 2019). Upon completion, the trial results will be published in peer-reviewed journals and presented at scientific conferences. Trial registration number: ISRCTN16299902, 1st March 2018.

The duodenal-jejunal bypass liner (Endobarrier) is an endoscopic treatment for obesity and type 2 diabetes mellitus (T2DM). It creates exclusion of the proximal small intestine similar to that after Roux-en-Y Gastric Bypass (RYGB) surgery. The objective of this study was to employ a reductionist approach to determine whether bypass of the proximal intestine is the component conferring the effects of RYGB on food intake and sweet taste preference using the Endobarrier as a research tool. A nested mechanistic study within a large randomised controlled trial compared the impact of lifestyle modification with vs. without Endobarrier insertion in patients with obesity and T2DM. Forty-seven participants were randomised and assessed at several timepoints using direct and indirect assessments of food intake, food preference and taste function. Patients within the Endobarrier group lost numerically more weight compared to the control group. Using food diaries, our results demonstrated similar reductions of food intake in both groups. There were no significant differences in food preference and sensory, appetitive reward, or consummatory reward domain of sweet taste function between groups or changes within groups. In conclusion, the superior weight loss seen in patients with obesity and T2DM who underwent the Endobarrier insertion was not due to a reduction in energy intake or change in food preferences.

Efficacy and Mechanism Evaluation Volume: 7, Issue: 6, Published in November 2020