Heterozygous pathogenic variants in POMC are not responsible for monogenic obesity: Implication for MC4R agonist use.

PURPOSE: Recessive deficiency of proopiomelanocortin (POMC) causes childhood-onset severe obesity. Cases can now benefit from the melanocortin 4 receptor agonist setmelanotide. Furthermore, a phase 3 clinical trial is evaluating setmelanotide in heterozygotes for POMC. We performed a large-scale genetic analysis to assess the effect of heterozygous, pathogenic POMC variants on obesity. METHODS: A genetic analysis was performed in a family including 2 cousins with childhood-onset obesity. We analyzed the obesity status of heterozygotes for pathogenic POMC variants in the Human Gene Mutation Database. The association between heterozygous pathogenic POMC variants and obesity risk was assessed using 190,000 exome samples from UK Biobank. RESULTS: The 2 cousins carried a compound heterozygous pathogenic variant in POMC. Six siblings were heterozygotes; only 1 of them had obesity. In Human Gene Mutation Database, we identified 60 heterozygotes for pathogenic POMC variants, of whom 14 had obesity. In UK Biobank, heterozygous pathogenic POMC variants were not associated with obesity risk, but they modestly increased body mass index levels. CONCLUSION: Heterozygous pathogenic POMC variants do not contribute to monogenic obesity, but they slightly increase body mass index. Setmelanotide use in patients with obesity, which would only be based on the presence of a heterozygous POMC variant, can be questioned.

Unexpected upper gastrointestinal polyps in patients with short bowel syndrome treated with teduglutide: need for close monitoring.

BACKGROUND: Teduglutide is a GLP-2 analog indicated for the treatment of short bowel syndrome (SBS) since 2015. Its efficacy in reducing parenteral nutrition (PN) has been shown in patients with SBS. OBJECTIVES: Because teduglutide is a trophic factor, the aim of this study was to assess risk of developing polypoid intestinal lesions during treatment. METHODS: A retrospective study was conducted in 35 patients with SBS treated with teduglutide for ≥1 y in a home PN expert center. All patients underwent ≥1 follow-up intestinal endoscopy during treatment. RESULTS: In the 35 patients, the small bowel length was 74 cm (IQR: 25-100), and 23 patients (66%) had a colon in continuity. Upper and lower gastrointestinal endoscopy was performed after a mean treatment duration of 23 mo (IQR: 13-27), and polypoid lesions were found in 10 patients (6 with a colon in continuity, 4 with an end jejunostomy) and no lesion in 25 patients. In 8 out of the 10 patients, the lesion was found in the small bowel. Five of these lesions presented an aspect of hyperplastic polyp without dysplasia, and 3 of a traditional adenoma with low-grade dysplasia. CONCLUSIONS: Our study highlights the importance of performing follow-up upper and lower gastrointestinal endoscopy in SBS patients treated with teduglutide and the potential need to make changes to the recommendations with respect to treatment initiation and follow-up.

Long-Term Weight Outcome After Bariatric Surgery in Patients with Melanocortin-4 Receptor Gene Variants: a Case-Control Study of 105 Patients.

INTRODUCTION: Pathogenic heterozygous MC4R variants are associated with hyperphagia and variable degrees of obesity. Several research groups have reported short-term weight loss outcomes after bariatric surgery in a few patients with MC4R variants, but lack of longer-term data prevents evidence-based clinical decision-making. MATERIALS AND METHODS: Bariatric surgery patients with heterozygous (likely) pathogenic MC4R variants, from three collaborating centers in the Netherlands, France, and the UK, were compared to matched controls (matched 2:1 for age, sex, preoperative BMI, surgical procedure, and diabetes mellitus, but without MC4R mutations). Weight loss and regain outcomes up to 6 years of follow-up were compared. RESULTS: At 60 months of follow-up after RYGB, cases with MC4R variants showed weight regain with a mean of 12.8% (± 10.4 SD) total weight loss (TWL) from nadir, compared to 7.9% (± 10.5 SD) in the controls (p = 0.062). Among patients receiving SG, the cases with MC4R variants experienced inferior weight loss (22.6% TWL) during the first year of follow-up compared to the controls (29.9% TWL) (p = 0.010). CONCLUSIONS: This multicenter study reveals inferior mid-term weight outcomes of cases with MC4R variants after SG, compared to RYGB. Since adequate weight loss outcomes were observed after RYGB, this procedure would appear to be an appropriate surgical approach for this group. However, the pattern of weight regain seen in cases with MC4R variants after both RYGB and SG highlights the need for pro-active lifelong management to prevent relapse, as well as careful expectation management.

[Short bowel syndrome: From intestinal insufficiency to intestinal adaptation]. / Le syndrome de grêle court chez l'adulte - De l'insuffisance intestinale à l'adaptation intestinale.

The short bowel syndrome results from an extensive intestinal resection. When intestinal function is below the minimum necessary for the absorption of macronutrients, water and electrolytes, short small bowel syndrome is responsible for chronic intestinal failure. The management is then parenteral nutrition. The evolution of the short bowel syndrome is schematically divided into three successive periods: (a) Immediate postoperative period lasting 3 to 6 weeks; (b) adaptive period lasting about 2 years and (c) stabilization period. However, the development of hyperphagia, spontaneous intestinal adaptation allowing an increase in the absorption surface area and in secretion of enterohormones and a modification of the microbiota occur spontaneously, improving intestinal absorption and decreasing dependence on parenteral nutrition. This review summarizes the main positive and negative pathophysiological consequences of extensive intestinal resection and the nutritional and drug management of short bowel syndrome in adults.

TITLE: Le syndrome de grêle court chez l'adulte - De l'insuffisance intestinale à l'adaptation intestinale. ABSTRACT: Le syndrome de grêle court, conséquence d'une résection étendue de l'intestin, est la principale cause d'insuffisance intestinale, définie comme la réduction de la fonction intestinale en dessous du minimum nécessaire à l'absorption des macronutriments, de l'eau et des électrolytes. La prise en charge nécessite alors la nutrition parentérale. L'évolution du syndrome de grêle court est schématiquement scindée en trois périodes successives : 1) la période post-opératoire, d'une durée de 3 à 6 semaines ; 2) la période adaptative, d'une durée de 2 ans environ ; et 3) la période de stabilisation, dite séquellaire. Le développement d'une hyperphagie, d'une adaptation intestinale permettant l'augmentation de la surface d'absorption et de la sécrétion d'entérohormones, ainsi qu'une modification du microbiote, se produisent spontanément, améliorant l'absorption intestinale et diminuant la dépendance à la nutrition parentérale. Cet article résume les principales conséquences physiopathologiques (bénéfiques ou délétères) d'une résection étendue de l'intestin grêle et la prise en charge nutritionnelle et médicamenteuse du syndrome de grêle court chez l'adulte.

Orosensory Perception of Fat/Sweet Stimuli and Appetite-Regulating Peptides before and after Sleeve Gastrectomy or Gastric Bypass in Adult Women with Obesity.

The aim of this study was to explore the impact of bariatric surgery on fat and sweet taste perceptions and to determine the possible correlations with gut appetite-regulating peptides and subjective food sensations. Women suffering from severe obesity (BMI > 35 kg/m2) were studied 2 weeks before and 6 months after a vertical sleeve gastrectomy (VSG, n = 32) or a Roux-en-Y gastric bypass (RYGB, n = 12). Linoleic acid (LA) and sucrose perception thresholds were determined using the three-alternative forced-choice procedure, gut hormones were assayed before and after a test meal and subjective changes in oral food sensations were self-reported using a standardized questionnaire. Despite a global positive effect of both surgeries on the reported gustatory sensations, a change in the taste sensitivity was only found after RYGB for LA. However, the fat and sweet taste perceptions were not homogenous between patients who underwent the same surgery procedure, suggesting the existence of two subgroups: patients with and without taste improvement. These gustatory changes were not correlated to the surgery-mediated modifications of the main gut appetite-regulating hormones. Collectively these data highlight the complexity of relationships between bariatric surgery and taste sensitivity and suggest that VSG and RYGB might impact the fatty taste perception differently.

Implication of Heterozygous Variants in Genes of the Leptin-Melanocortin Pathway in Severe Obesity.

CONTEXT: Unlike homozygous variants, the implication of heterozygous variants on the leptin-melanocortin pathway in severe obesity has not been established. OBJECTIVE: To describe the frequency, the phenotype, and the genotype-phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity. METHODS: In this retrospective study, genotyping was performed on at least 1 of the LEP, LEPR, POMC, and PCSK1 genes in 1486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, body mass index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities. RESULTS: The frequency of subjects with homozygous variants was 1.7% (n = 26), and 6.7% (n = 100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 vs 53 kg/m2, P = .015), an earlier onset of obesity (0.4 vs 5.4 years, P < .001), more often food impulsivity (83% vs 42%, P = .04), and endocrine abnormalities (75% vs 26%, P < .01). The BMI was higher for subjects with high-impact heterozygous variants (61 vs 50 kg/m², P = .045) and those with a second heterozygous variant on the pathway (65 vs 49 kg/m², P < .01). In children, no significant differences were found for the age of obesity onset and BMI. CONCLUSION: Heterozygous variants in LEP, LEPR, POMC, and PCSK1 are frequent in severe obesity and sometimes associated with a phenotype close to that of homozygotes. These data suggest a systematic search for variants in severe early-onset obesity, to discuss therapy that targets this key pathway.

Intestinal adaptation in short bowel syndrome. What is new?

Short bowel syndrome (SBS) is a well-known cause of intestinal failure (IF) (1). SBS occurs after extensive resection of the small bowel (RSB) resulting in a bowel length of less than 150/200 cm. The colon may have been partially or completely removed. SBS patients experience severe water and nutrient malabsorption, so that they are often managed with parenteral nutrition (PN) to supplement their oral intake (2-4). A complete understanding of the pathophysiology of SBS and postoperative adaptations may allow identifying the spontaneous processes that compensate for the reduction in absorptive surface. A better knowledge of these adaptive mechanisms may help to improve the management of patient nutrition, to reduce the need for PN and to prevent D-encephalopathy episodes. This review focuses on the overall adaptations described in adult SBS patients but does not review pediatric cases.