Phenotype tailored lifestyle intervention on weight loss and cardiometabolic risk factors in adults with obesity: a single-centre, non-randomised, proof-of-concept study.

Background: Lifestyle interventions for weight loss are currently not individualised to underlying pathophysiology and behavioral traits in obesity. We aim to compare the outcome of a standard lifestyle intervention (SLI) to phenotype-tailored lifestyle interventions (PLI) on weight loss, cardiometabolic risk factors and physiologic variables contributing to obesity. Methods: This 12-week, single-centre non-randomised proof-of-concept clinical trial including men and women aged 18-65 years with a body mass index (BMI) greater than 30 without history of any bariatric procedure, and current use of any medication known to affect weight. Participants lived anywhere in the United States, and underwent in-person testing in Rochester, MN at a teaching hospital. All participants completed in-person phenotype testing at baseline and after 12 weeks. Participants were assigned to their intervention based on their period of enrollment. In the first phase, participants were assigned to SLI with a low-calorie diet (LCD), moderate physical activity, and weekly behavioral therapy sessions. In the second phase, other participants were assigned to PLI according to phenotype: abnormal satiation (time-restricted volumetric LCD); abnormal postprandial satiety (LCD with pre-meal protein supplementation); emotional eating (LCD with intensive behavioral therapy); and abnormal resting energy expenditure (LCD with post-workout protein supplementation and high-intensity interval training). The primary outcome was total body weight loss in kg at 12 weeks using multiple imputation for missing data. Linear models estimated the association of study group allocation and study endpoints adjusting for age, sex, and baseline weight. This study was registered with ClinicalTrials.gov, NCT04073394. Findings: Between July 2020 and August 2021, 211 participants were screened, and 165 were assigned to one of the two treatments in the two phases: 81 SLI (mean [SD] age 42.9 [12] years; 79% women; BMI 38.0 [6.0]) and 84 PLI (age 44.8 [12.2] years; 83% women; BMI 38.7 [6.9]); 146 completed the 12-week programs. The weight loss was -7.4 kg (95%CI, -8.8, -6.0) with PLI vs. -4.3 kg (95%CI, -5.8, -2.7) with SLI (difference, -3.1 kg [95%CI, -5.1 to -1.1]; P = 0.004). No adverse events were reported in any group. Interpretation: Phenotype-tailored lifestyle interventions may result in significant weight loss, but a randomised controlled trial is required to confirm causality. Funding: Mayo Clinic; NIH (K23-DK114460).

Cardiovascular Risk and Diseases in Patients With and Without Leptin-Melanocortin Pathway Variants.

OBJECTIVE: To study differences in cardiovascular risk factors and diseases between patients with and without genetic variants in the leptin-melanocortin pathway. METHODS: A cross-sectional study of patients with a history of severe obesity genotyped in June 2019 as participants of the Mayo Clinic Biobank was conducted in March 2022 to assess differences in cardiovascular risk and diseases between carriers of a heterozygous variant in the leptin-melanocortin pathway and noncarriers. Cardiovascular risk factors included hypertension, diabetes, dyslipidemia, and smoking. Cardiovascular disease includes coronary artery disease, peripheral artery disease, and cerebrovascular accidents. Patients with a history of bariatric surgery were excluded. We used logistic regression models to estimate the odds ratio and 95% CI, adjusting for age, body mass index (BMI), and sex. RESULTS: Among a total of 168 carriers (8%; 121 [72%] female; mean [SD] age, 65.1 [14.9] years; BMI, 44.0 [7.4] kg/m2) and 2039 noncarriers (92%; 1446 [71%] female; mean [SD] age, 64.9 [14.4] years; BMI, 42.9 [6.6] kg/m2), carriers had higher prevalence odds of hypertension (odds ratio, 3.26; 95% CI, 2.31 to 4.61; P<.001) and reported higher number of cardiovascular risk factors compared with noncarriers (2.4 [1.1] vs 2.0 [1.1]; P<.001). There were no significant differences in the adjusted odds associated with diabetes, dyslipidemia, smoking, or cardiovascular disease. CONCLUSION: Despite having similar body weight and BMI, carriers of heterozygous variants in the leptin-melanocortin pathway had higher rates of hypertension than noncarriers. These findings point to an association between hypertension and leptin-melanocortin pathway variants.

Mucosal and hormonal adaptations after Roux-en-Y gastric bypass.

The aim of this study was to perform a comprehensive literature review regarding the relevant hormonal and histologic changes observed after Roux-en-Y gastric bypass (RYGB). We aimed to describe the relevant hormonal (glucagon-like peptides 1 and 2 [GLP-1 and GLP-2], peptide YY [PYY], oxyntomodulin [OXM], bile acids [BA], cholecystokinin [CCK], ghrelin, glucagon, gastric inhibitory polypeptide [GIP], and amylin) profiles, as well as the histologic (mucosal cellular) adaptations happening after patients undergo RYGB. Our review compiles the current evidence and furthers the understanding of the rationale behind the food intake regulatory adaptations occurring after RYGB surgery. We identify gaps in the literature where the potential for future investigations and therapeutics may lie. We performed a comprehensive database search without language restrictions looking for RYGB bariatric surgery outcomes in patients with pre- and postoperative blood work hormonal profiling and/or gut mucosal biopsies. We gathered the relevant study results and describe them in this review. Where human findings were lacking, we included animal model studies. The amalgamation of physiologic, metabolic, and cellular adaptations following RYGB is yet to be fully characterized. This constitutes a fundamental aspiration for enhancing and individualizing obesity therapy.

Effect of caloric intake and macronutrient composition on intestinal cholesterol absorption and bile acids in patients with obesity.

Obesity is associated with alterations in cholesterol and bile acid (BA) metabolism. However, the interaction among dietary intake, cholesterol absorption, and BA metabolism in patients with obesity remains unclear. We conducted a 4-wk nutritional intervention nonrandomized clinical trial with three different sequential diets for a week in the following order: regular diet (RD); high calorie, high-fat diet (HCHF), washout period on RD; and low-calorie, low-fat diet (LCLF). We provided participants with meal replacements during HCHF and LCLF diets. A total of 16 participants completed the study [n = 8 normal weight (NW); n = 8 with obesity (OB)]. Overall, there was a significant increase in intestinal cholesterol uptake when changing from RD to HCHF and a reduction in intestinal cholesterol uptake from HCHF to LCLF. When analyzing by BMI groups, these findings were similar in patients with NW (RD to HCHF: P < 0.007; HCHF to LCLF: P = 0.02); however, in patients with obesity, the change in intestinal cholesterol uptake was only observed when changing from RD to HCHF (P = 0.006). There was no correlation between cholesterol absorption and fecal bile acids or other markers of BA metabolism in all patients or the subgroups. Dietary caloric content had a significant effect on cholesterol absorption, however, this effect is blunted in patients with obesity. These data are consistent with the impaired effect of a low-fat diet on cholesterol absorption in obesity.NEW & NOTEWORTHY We show how switching from a regular diet to an HCHF increases cholesterol absorption in patients with normal weight and obesity. The decrease in cholesterol absorption from an HCHF to an LCLF, on the other hand, was only seen in normal-weight controls, underlining the importance of body weight in this regulation. In addition, changes in caloric and fat content had an immediate and direct effect on hepatic bile acid production.

Effects of Heterozygous Variants in the Leptin-Melanocortin Pathway on Roux-en-Y Gastric Bypass Outcomes: a 15-Year Case-Control Study.

INTRODUCTION: Heterozygous variants in the leptin-melanocortin pathway are associated with obesity. However, their effect on the long-term outcomes after Roux-en-Y gastric bypass (RYGB) is still unknown. METHODS: In this matched case-control study, 701 participants from the Mayo Clinic Biobank with a history of RYGB were genotyped. Sixty-three patients had a heterozygous variant in the leptin-melanocortin pathway. After excluding patients with potential confounders, carriers were randomly matched (on sex, age, body mass index [BMI], and years since surgery) with two non-carrier controls. The electronic medical record of carriers and matched non-carriers was reviewed for up to 15 years after RYGB. RESULTS: A total of 50 carriers and 100 matched non-carriers with a history of RYGB were included in the study. Seven different genes (LEPR, PCSK1, POMC, SH2B1, SRC1, MC4R, and SIM1) in the leptin-melanocortin pathway were identified. At the time of surgery, the mean age was 50.8 ± 10.6 years, BMI 45.6 ± 7.3 kg/m2, and 79% women. There were no differences in postoperative years of follow-up, Roux limb length, or gastric pouch size between groups. Fifteen years after RYGB, the percentage of total body weight loss (%TBWL) in carriers was - 16.6 ± 10.7 compared with - 28.7 ± 12.9 in non-carriers (diff = 12.1%; 95% CI, 4.8 to 19.3) and the percentage of weight regain after maximum weight loss was 52.7 ± 29.7 in carriers compared with 29.8 ± 20.7 in non-carriers (diff = 22.9%; 95% CI, 5.3 to 40.5). The nadir %TBWL was lower - 32.1 ± 8.1 in carriers compared with - 36.8 ± 10.4 in non-carriers (diff = 4.8%; 95% CI 1.8 to 7.8). CONCLUSIONS: Carriers of a heterozygous variant in the leptin-melanocortin pathway have a progressive and significant weight regain in the mid- and long-term after RYGB. Genotyping patients experiencing significant weight regain after RYGB could help implement multidisciplinary and individualized weight loss interventions to improve weight maintenance after surgery.

A Protocol for the Cryopreservation of Human Intestinal Mucosal Biopsies Compatible With Single-Cell Transcriptomics and Ex Vivo Studies.

The heterogeneity of the human intestinal epithelium has hindered the understanding of the pathophysiology of distinct specialized cell types on a single-cell basis in disease states. Described here is a workflow for the cryopreservation of endoscopically obtained human intestinal mucosal biopsies, subsequent preparation of this tissue to yield highly viable fluorescence-activated cell sorting (FACS)isolated human intestinal epithelial cell (IEC) single-cell suspensions compatible with successful library preparation and deep single-cell RNA sequencing (scRNAseq). We validated this protocol in deep scRNAseq of 59,653 intestinal cells in 10 human participants. Furthermore, primary intestinal cultures were successfully generated from cryopreserved tissue, capable of surviving in short-term culture and suitable for physiological assays studying gut peptide secretion from rare hormone-producing enteroendocrine cells in humans. This study offers an accessible avenue for single-cell transcriptomics and ex vivo studies from cryopreserved intestinal mucosal biopsies. These techniques may be used in the future to dissect and define novel aberrations to the intestinal ecosystem that lead to the development and progression of disease states in humans, even in rare IEC populations.

Contamination of single fluid-filled intragastric balloons with orogastric fluid is not associated with hyperinflation: an ex-vivo study and systematic review of literature.

BACKGROUND: Spontaneous hyperinflation is reported to the Food and Drug Administration as a complication of intragastric balloons. It is postulated that orogastric contamination of the intragastric balloon may cause this phenomenon. We sought to investigate the effects of intentional balloon contamination with gastric contents on intragastric balloon perimeter and contents, whether methylene blue plays a role in preventing spontaneous hyperinflation, and review the available literature on spontaneous hyperinflation. METHODS: Four pairs of balloons with different combinations of sterile saline, orogastric contaminants, and methylene blue were incubated in a 37 °C water bath for six months to simulate physiological conditions with serial measurements of balloon perimeter. Our findings were compared against a systematic review across multiple databases to summarize the available literature. RESULTS: Balloon mean perimeter decreased from 33.5 cm ± 0.53 cm to 28.5 cm ± 0.46 cm (p < 0.0001). No significant differences were seen with the methylene blue group. Only 11 cases were found reported in the literature. CONCLUSIONS: Despite contaminating intragastric balloons with gastric aspirates, hyperinflation did not occur, and other factors may be in play to account for this phenomenon, when observed. Rates of hyperinflation remain under-reported in the literature. Further controlled experiments are needed.

Role of Enteroendocrine Hormones in Appetite and Glycemia.

Enteroendocrine cells (EECs) are specialized cells that are widely distributed throughout the gastrointestinal tract. EECs sense luminal content and release hormones, such as: ghrelin, cholecystokinin, glucagon like peptide 1, peptide YY, insulin like peptide 5, and oxyntomodulin. These hormones can enter the circulation to act on distant targets or act locally on neighboring cells and neuronal pathways to modulate food digestion, food intake, energy balance and body weight. Obesity, insulin resistance and diabetes are associated with alterations in the levels of enteroendocrine hormones. Evidence also suggests that modified regulation and release of gut hormones are the result of compensatory mechanisms in states of excess adipose tissue and hyperglycemia. This review collects the evidence available detailing pathophysiological alterations in enteroendocrine hormones and their association with appetite, obesity and glycemic control.

Selection of Antiobesity Medications Based on Phenotypes Enhances Weight Loss: A Pragmatic Trial in an Obesity Clinic.

OBJECTIVE: Little is known about the predictors of response to obesity interventions. METHODS: In 450 participants with obesity, body composition, resting energy expenditure, satiety, satiation, eating behavior, affect, and physical activity were measured by validated studies and questionnaires. These variables were used to classify obesity phenotypes. Subsequently, in a 12-month, pragmatic, real-world trial performed in a weight management center, 312 patients were randomly assigned to phenotype-guided treatment or non-phenotype-guided treatment with antiobesity medications: phentermine, phentermine/topiramate, bupropion/naltrexone, lorcaserin, and liraglutide. The primary outcome was weight loss at 12 months. RESULTS: Four phenotypes of obesity were identified in 383 of 450 participants (85%): hungry brain (abnormal satiation), emotional hunger (hedonic eating), hungry gut (abnormal satiety), and slow burn (decreased metabolic rate). In 15% of participants, no phenotype was identified. Two or more phenotypes were identified in 27% of patients. In the pragmatic clinical trial, the phenotype-guided approach was associated with 1.75-fold greater weight loss after 12 months with mean weight loss of 15.9% compared with 9.0% in the non-phenotype-guided group (difference -6.9% [95% CI -9.4% to -4.5%], P < 0.001), and the proportion of patients who lost >10% at 12 months was 79% in the phenotype-guided group compared with 34% with non-phenotype-guided treatment group. CONCLUSIONS: Biological and behavioral phenotypes elucidate human obesity heterogeneity and can be targeted pharmacologically to enhance weight loss.

Ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic GLP-1-producing enteroendocrine cells in human obesity and diabetes.

BACKGROUND: The bile acid (BA) pathway plays a role in regulation of food intake and glucose metabolism, based mainly on findings in animal models. Our aim was to determine whether the BA pathway is altered and correctable in human obesity and diabetes. METHODS: We conducted 3 investigations: 1) BA receptor pathways were studied in NCI-H716 enteroendocrine cell (EEC) line, whole human colonic mucosal tissue and in human colonic EEC isolated by Fluorescence-activated Cell Sorting (ex vivo) from endoscopically-obtained biopsies colon mucosa; 2) We characterized the BA pathway in 307 participants by measuring during fasting and postprandial levels of FGF19, 7αC4 and serum BA; 3) In a placebo-controlled, double-blind, randomised, 28-day trial, we studied the effect of ileo-colonic delivery of conjugated BAs (IC-CBAS) on glucose metabolism, incretins, and lipids, in participants with obesity and diabetes. FINDINGS: Human colonic GLP-1-producing EECs express TGR5, and upon treatment with bile acids in vitro, human EEC differentially expressed GLP-1 at the protein and mRNA level. In Ussing Chamber, GLP-1 release was stimulated by Taurocholic acid in either the apical or basolateral compartment. FGF19 was decreased in obesity and diabetes compared to controls. When compared to placebo, IC-CBAS significantly decreased postprandial glucose, fructosamine, fasting insulin, fasting LDL, and postprandial FGF19 and increased postprandial GLP-1 and C-peptide. Increase in faecal BA was associated with weight loss and with decreased fructosamine. INTERPRETATIONS: In humans, BA signalling machinery is expressed in colonic EECs, deficient in obesity and diabetes, and when stimulated with IC-CBAS, improved glucose homeostasis. ClinicalTrials.gov number, NCT02871882, NCT02033876. FUNDING: Research support and drug was provided by Satiogen Pharmaceuticals (San Diego, CA). AA, MC, and NFL report grants (AA- C-Sig P30DK84567, K23 DK114460; MC- NIH R01 DK67071; NFL- R01 DK057993) from the NIH. JR was supported by an Early Career Grant from Society for Endocrinology.

Decision making and psychosocial outcomes among living kidney donors: a pilot study.

With an increasing number of available kidney transplant donors comes greater demand for systematic screening of prospective donors to ensure the integrity of the donor's decision and to minimize the risk of a poor postoperative outcome. The present study was intended to explore psychosocial outcomes after kidney donation, aspects of donors' decision making, and donors' experience of the transplantation process. It was hoped that this pilot study would inform the design of a large-scale longitudinal prospective investigation of psychosocial outcomes of kidney donation. In this cross-sectional, retrospective investigation, all patients who had received psychosocial screening before their kidney donation were approached. Seventeen of 43 previous kidney donors responded to a postal questionnaire. Donors' health-related quality of life was higher than population norms on all dimensions. Most participants reported involving someone else in the decision-making process. Donors indicated high levels of satisfaction with virtually all aspects of the donation process. The generalizability of the findings in the context of the limitations of the present pilot study is discussed and specific suggestions for the design of future studies are provided.