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Four European Reference Networks (ERN-EYE, ERKNet, Endo-ERN, ERN-ITHACA) have teamed up to establish a consensus statement and recommendations for Bardet-Biedl syndrome (BBS). BBS is an autosomal recessive ciliopathy with at least 26 genes identified to date. The clinical manifestations are pleiotropic, can be observed in utero and will progress with age. Genetic testing has progressively improved in the last years prompting for a revision of the diagnostic criteria taking into account clinical Primary and Secondary features, as well as positive or negative molecular diagnosis. This consensus statement also emphasizes on initial diagnosis, monitoring and lifelong follow-up, and symptomatic care that can be provided to patients and family members according to the involved care professionals. For paediatricians, developmental anomalies can be at the forefront for diagnosis (such as polydactyly) but can require specific care, such as for associated neuro developmental disorders. For ophthalmology, the early onset retinal degeneration requires ad hoc functional and imaging technologies and specific care for severe visual impairment. For endocrinology, among other manifestations, early onset obesity and its complications has benefited from better evaluation of eating behaviour problems, improved lifestyle programs, and from novel pharmacological therapies. Kidney and urinary track involvements warrants lifespan attention, as chronic kidney failure can occur and early management might improve outcome. This consensus recommends revised diagnostic criteria for BBS that will ensure certainty of diagnosis, giving robust grounds for genetic counselling as well as in the perspective of future trials for innovative therapies., (© 2024. The Author(s).)

Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up., (Copyright © 2024. Published by Elsevier Masson SAS.)

Importance: A major issue in the management of craniopharyngioma-related obesity (CRO) is the ineffectiveness of the current therapeutic approaches., Objective: To study the efficacy of glucagon-like peptide-1 analogs compared with placebo in adults with obesity CRO., Design: A double-blind multicenter superiority randomized clinical in trial in two parallel arms., Setting: Eleven French University Hospital Centers., Participants: Adults with CRO (body mass index > 30 kg/m²) without the sign of recurrence of craniopharyngioma in the past year., Interventions: Exenatide or placebo injected subcutaneously twice a day during 26 weeks., Main Outcomes and Measures: The primary outcome was the mean change in body weight at week 26 in the intention-to-treat population. Secondary outcomes were eating behavior, calories intake, energy expenditure, cardiovascular, metabolic risk factor, quality of life, and the tolerance profile., Results: At week 26, weight decreased from baseline by a mean of -3.8 (SD 4.3) kg for exenatide and -1.6 (3.8) kg for placebo. The adjusted mean treatment difference was -3.1 kg (95% confidence interval [CI] -7.0 to 0.7, P = 0.11). Results were compatible with a higher reduction of hunger score with exenatide compared with placebo (estimated treatment difference in change from baseline to week 26: -2.3, 95% CI -4.5 to -0.2), while all other outcomes did not significantly differ between groups. Adverse events were more common with exenatide versus placebo, and occurred in, respectively, 19 (95%) participants (108 events) and 14 (70%) participants (54 events)., Conclusions and Relevance: Combined with intensive lifestyle interventions, a 26-week treatment with exenatide was not demonstrated superior to placebo to treat craniopharyngioma-related obesity., Competing Interests: Conflict of interest: G.R. is on the editorial board of EJE. He was not involved in the review or editorial process for this paper, on which he is listed as an author. The other authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The determinants of early-onset obesity (< 6 years) are not completely elucidated, however eating behavior has a central role. To date no study has explored eating behavior in children with severe, early-onset obesity. Self-administered questionnaire data from these children were examined to evaluate eating behavior and the etiology of early-onset obesity., Methods: Children with severe, early-onset obesity (body mass index [BMI] > International Obesity Task Force [IOTF] 30) of different etiologies (hypothalamic obesity [HO], intellectual disability with obesity [IDO], common polygenic obesity [CO]) were prospectively included. BMI history and responses from the Dykens' Hyperphagia Questionnaire and an in-house Impulsivity Questionnaire at first visit were compared between groups., Results: This cohort of 75 children (39 girls; mean age ± standard deviation [SD] 10.8 ± 4.4 years) had severe, early-onset obesity at an age of 3.8 ± 2.7 years, with a BMI Z-score of 4.9 ± 1.5. BMI history varied between the 3 groups, with earlier severe obesity in the HO group versus 2 other groups (BMI > IOTF40 at 3.4 ± 1.6 vs. 4.6 ± 1.6 and 8.4 ± 4.1 years for the IDO and CO groups, respectively [P < 0.01]). Absence of adiposity rebound was more prevalent in the HO group (87% vs. 63% and 33% for the IDO and CO groups, respectively [P < 0.01]). The Dykens' mean total score for the cohort was 22.1 ± 7.2 with no significant between-group differences. Hyperphagia (Dykens' score > 19) and impulsivity (score > 7) were found in 50 (67%) and 11 children (15%), respectively, with no difference between the HO, IDO and CO groups regarding the number of patients with hyperphagia (10 [67%], 14 [74%], and 26 [63%] children, respectively) or impulsivity (2 [13%], 1 [7%], and 8 [19%] children, respectively). Children with food impulsivity had significantly higher total and severity scores on the Dykens' Questionnaire versus those without impulsivity., Conclusion: The Dykens' and Impulsivity questionnaires can help diagnose severe hyperphagia with/without food impulsivity in children with early-onset obesity, regardless of disease origin. Their systematic use can allow more targeted management of food access control in clinical practice and monitor the evolution of eating behavior in the case of innovative therapeutic targeting hyperphagia., (© 2024. The Author(s).)

Background: Bariatric surgery (BS) results in major and sustained weight loss and improves comorbidities in patients with obesity but can also lead to malnutrition, especially through severe malabsorption and/or surgical complications. Little is known about the efficacy of artificial nutrition (AN) in this setting., Methods: In this case series, we describe data from consecutive severely malnourished patients after BS (resectional and non-resectional), managed by AN at our hospital unit over a 4-year period., Results: Between January 2018 and June 2022, 18 patients (mean ± SD age 42.2 ± 10.4 years, 94% women) required AN following BS complications. At the time of AN initiation, more than half of the patients (53%) had multiple revisional surgeries (up to four). Mean BMI was 49.7 ± 11.3 kg/m 2 before BS and 29.6 ± 9.6 kg/m 2 when AN was initiated. Most patients (n=16, 90%) received enteral nutrition. AN management resulted in weight regain (+4.7kg ± 8.0, p=0.034), increased serum albumin (+28%, p=0.02), pre-albumin (+88%, p=0.002), and handgrip strength (+38%, p=0.078). No major AN complication nor death was observed. Median total AN duration was 4.5 months [1-12]. During follow-up, the cumulative duration of hospitalization was 33 days [4-88] with a median of 2.5 hospitalizations [1-8] per patient., Conclusion: Malnutrition can occur after any BS procedure, and AN when required in this setting appears safe and effective on nutritional parameters. It is important to recognize the potential risk factors for malnutrition, which include excessive weight loss resulting from surgical complications, eating disorders, multiple revisional BS, and pregnancy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Obesity is associated with low-grade inflammation, including intestinal inflammation based on fecal or serum calprotectin (FC-SC) measurement. Roux-en-Y gastric bypass (RYGB) improves obesity-related parameters. However, the association between FC-SC levels and postoperative course and the link with metabolic and inflammatory phenotypes before and after RYGB remains unclear., Methods: We determined SC levels in 48 patients before (T0) and 6 months after (T6M) RYGB. We then analyzed postoperative changes in FC-SC levels and the relationship with inflammation and metabolic status., Results: Twenty-three patients (48%) had elevated SC levels (˃2.9 μg/mL) at T0 and T6M. Six of 29 patients (20.7%) had elevated FC concentrations (>50 μg/g) at T0 vs. 16 of 17 patients (94.1%) at T6M (p=0.006). At T0, FC levels correlated with BMI (Rho=0.63; p=0.001) and systemic inflammation (CRP: Rho=0.66, p=0.0006; IL-6: Rho=0.48, p=0.03; haptoglobin: Rho=0.75; p= 0.0006). SC tended to be positively associated with triglyceride levels (Rho=0.34; p=0.08), BMI (Rho=0.34; p=0.08), and inflammatory markers (CRP: Rho=0.33; p=0.09; IL-6: Rho=0.36; p=0.06). FC levels were associated with increased jejunal IL-17+CD8+ T-cell densities (Rho:0.90; p=0.0002). FC and SC were correlated together at T0 (Rho=0.83; p<0.001) but not at T6M. At T6M, SC decreased by 53.6%, whereas FC increased by 79.7%. SC and FC were not associated with any of the variables studied at T6M., Conclusion: FC is a surrogate marker of systemic and intestinal inflammation and adiposity, whereas SC only tends to correlate with systemic inflammation. At 6 months after RYGB, SC-based systemic inflammation decreased, whereas FC-based intestinal inflammation increased. FC and SC levels follow different trajectories and are unrelated to improvements following bariatric surgery., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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) 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Mutations in genes encoding proteins located in the leptin/melanocortin pathway have been identified in the rare cases of genetic obesities. Heterozygous variants of MRAP2, encoding a G coupled-protein receptor accessory protein implicated in energy control notably via the melanocortin-4 receptor, have been recently identified. A 24-year-old patient with early-onset severe obesity (body mass index [BMI]: 64 kg/m2) associated with hypertension, respiratory complications, nonalcoholic fatty liver disease, and type 2 diabetes was referred to our department. Sleeve gastrectomy was successful. A new heterozygous variant in MRAP2 (NM&#95;138409.4: c.154G>C/p.G52R) variant was identified in the patient DNA. Functional assessment confirmed that this new variant was pathogenic. We report a new pathogenic loss-of-function mutation in MRAP2 in a patient suffering from a severe multicomplicated obesity. This confirms the metabolic phenotype in patients with this monogenic form of obesity. Longer follow-up will be necessary. Our finding will allow a personalized medicine., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Sleeve gastrectomy (SG) is a popular surgical weight-loss procedure, but there are increasing reports of revisional Roux-Y-gastric-bypass (R-RYGB) to manage weight-loss failure (WLF) or proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) after SG, with little data available in these settings., Methods: This retrospective study included all consecutive patients undergoing R-RYGB for WLF or RGERD after SG in two bariatric care centers from 2012 to 2018., Results: Of 720 patients, 46 (3.6%) underwent R-RYGB (RGERD, n = 25; 54.4%; WLF, n = 21; 45.6%) within 44.8 ± 27.5 months post-SG. SG had enabled 27% ± 11.6 total weight loss (TWL) in the RGERD group vs. 7.2% ± 12.5% TWL in the WLF group (p < 0.001). At R-RYGB, WLF-group patients had a higher BMI (47.8 ± 8.4 vs. 34.7 ± 6.1 kg/m 2 ; p < 0.001) and a higher number of comorbidities (2.4 ± 1.5 vs 1.5 ± 1.2; p < 0.02) compared to RGERD-group patients, while severe morbidity (Clavien-Dindo ≥ IIIb) was not significantly different between groups (6.5% vs 2.1%, p = 0.6). %TWL was still higher in the RGERD group at 12 months post-R-RYGB (35.6% ± 10.4 vs. 23.8% ± 9.2; p < 0.01) but not after 24 months post-R-RYGB. R-RYGB corrected reflux symptoms in 32 (94%) patients and reduced PPI use in 29 (97%) patients (p < 0.001), with no significant between-group difference. A history of adjustable gastric banding (AGB) (N = 8;17.4%) prior to SG was associated with a similar prevalence of GERD at R-RYGB and a lower %TWL (AGB:13.1 ± 10.2 vs. No AGB:31.6 ± 8.5; p < 0.05) at 3 years post-R-RYGB., Conclusion: R-RYGB following SG provides remission of reflux symptoms in 94% of patients and extra weight loss in patients with WLF, except in patients with a history of AGB prior to SG., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Explicit weight bias is an underlying cause of weight stigma, but its associations with individual characteristics are not well known. This study aimed to assess explicit weight bias in French adults and to explore the associations with weight status and sociodemographic characteristics., Methods: Adults from the NutriNet-Santé cross-sectional study (France, 2020, n=33,948, 52% women after weighting procedures) completed the Anti-Fat Attitudes Questionnaire assessing three dimensions: Dislike (antipathy toward people with obesity), Fear of fat (concerns about body weight), and Willpower (belief in weight controllability). Associations with weight status and sociodemographic characteristics were examined using multivariable ANCOVA models in 2022., Results: Fear of fat and Willpower scores were higher than Dislike scores (mean [SD]=4.0 [2.0], 3.3 [1.7] and 1.9 [1.3], respectively). Fear of fat was higher among women, whereas Dislike and Willpower were higher among men (all p<0.0001). Obesity was associated with greater Fear of fat scores (p<0.0001, mean difference versus normal-weight participants [95% CI]=0.35 [0.24, 0.46] in women, 0.36 [0.17, 0.56] in men), lower Dislike scores (-0.38 [-0.45, -0.32] in women, -0.43 [-0.56, -0.30] in men), and lower Willpower scores (-1.00 [-0.18, -0.90] in women, -0.40 [-0.57, -0.23] in men). In both genders, lower income was associated with lower Dislike, Fear of fat, and Willpower scores (all p<0.0001), and lower education was associated with greater Fear of fat and Willpower scores (all p<0.0001)., Conclusions: Explicit weight bias was driven by the fear of gaining weight and the belief in weight controllability. This study provides new insights into which population subgroups should be targeted by interventions aimed at reducing explicit weight bias., (Copyright © 2023 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Prader-Willi syndrome (PWS) is a rare, complex, genetic disorder characterized by hyperphagia, hypotonia, delayed psychomotor development, low muscle mass and hypothalamic dysfunction. Adults with PWS often have obesity, hypertension and type 2 diabetes mellitus (DM2), known risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Early symptoms of CVD and CKD may be masked by intellectual disability and inability to express physical complaints. Furthermore, kidney diseases are often asymptomatic. Therefore, renal and cardiovascular disease might be missed in patients with PWS. Microalbuminuria is an early sign of microvascular damage in the kidneys and other vascular beds. Therefore, we screened our adult PWS cohort for the presence of elevated urinary albumin and (micro)albuminuria., Methods: We retrospectively collected anthropometric measurements, blood pressure, medical history, medication use, urine dipstick and biochemical measurements form electronic patient files. In addition, we performed a systematic literature review on kidney disease in PWS., Results: We included 162 adults with genetically confirmed PWS (56% male, median age 28 years), of whom 44 (27%) had DM2. None had known CVD. All subjects had normal estimated glomerular filtration rate (eGFR) according to non-PWS reference intervals. Elevated urinary albumin or (micro)albuminuria was present in 28 (18%); 19 out of 75 (25%) had an increased urinary albumin-to-creatinine ratio (UACR) and 10 out of 57 (18%) had an increased urinary protein-to-creatinine ratio. Elevated urinary albumin was present at a young age (median age 26 (IQR 24-32) years) and was associated with an significantly higher BMI and LDL-cholesterol levels and higher prevalence of DM2, hypertension and dyslipidemia than those with normal UACR ( p =0.027, p =0.019, p <0.001, p <0.001, p =0.011 and respectively)., Conclusion: Upon screening, one in every five adults with PWS had increased urinary albumin or (micro)albuminuria, early signs of microvascular disease. All had normal eGFR, according to non-PWS reference intervals, and none had a formal diagnosis of CVD. As muscle mass is low in PWS, creatinine levels and eGFR may be spuriously normal. Urinalysis in this patient group can be used as a screening tool for microvascular (kidney) disease. We propose an algorithm for the detection and management of microvascular disease in adults with PWS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 van Abswoude, Pellikaan, Nguyen, Rosenberg, Davidse, Hoekstra, Rood, Poitou, Grugni, Høybye, Markovic, Caixàs, Crinò, van den Berg, van der Lely and de Graaff.)

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., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Obesity derives from impaired central control of body weight, implying interaction between environment and an individual genetic predisposition. Genetic obesities, including monogenic and syndromic obesities, are rare and complex neuro-endocrine pathologies where the genetic contribution is predominant. Severe and early-onset obesity with eating disorders associated with frequent comorbidities make these diseases challenging. Their current estimated prevalence of 5-10% in severely obese children is probably underestimated due to the limited access to genetic diagnosis. A central alteration of hypothalamic regulation of weight implies that the leptin-melanocortin pathway is responsible for the symptoms. The management of genetic obesity has so far been only based, above all, on lifestyle intervention, especially regarding nutrition and physical activity. New therapeutic options have emerged in the last years for these patients, raising great hope to manage their complex situation and improve quality of life. Implementation of genetic diagnosis in clinical practice is thus of paramount importance to allow individualized care. This review describes the current clinical management of genetic obesity and the evidence on which it is based. Some insights will also be provided into new therapies under evaluation., (©Copyright 2023 by Turkish Society for Pediatric Endocrinology and Diabetes | The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.)

Study Objectives: To evaluate sleep, sleepiness, and excessive need for sleep in patients with craniopharyngioma (a suprasellar tumor which can affect sleep-wake systems)., Methods: A retrospective study of all adult patients living with craniopharyngioma referred to the sleep clinic, who received a sleep interview, nocturnal polysomnography, multiple sleep latency tests (MSLT), and 18-h bed rest polysomnography. Their sleep measurements were compared with those of age- and sex-matched healthy controls., Results: Of 54 patients screened with craniopharyngioma, 42 were analyzed, 80% of whom complained of excessive daytime sleepiness. Sleep testing revealed that 6 (14.3%) of them had secondary narcolepsy (including one with cataplexy), and 11 (26.2%) had central hypersomnia associated with a medical disorder. Compared with controls, patients were more frequently obese, had a shorter mean sleep latency on MSLT, and slept longer on the first night. There was a nonsignificant trend for patients with (vs. without) narcolepsy and hypersomnia to be younger, to have a higher body mass index, to be more likely to have received radiation therapy, and to have more severe damage to the hypothalamus after surgery. Treatment with stimulants (modafinil, pitolisant, and methylphenidate) was beneficial in 9/10 patients., Conclusions: Nearly half of the patients with craniopharyngioma and sleep disorders have a central disorder of hypersomnolence (narcolepsy and hypersomnia), which should be investigated and lead to considerations beyond sleep apnea syndrome in these obese patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The better understanding of the molecular causes of rare genetic obesities and its associated phenotype involving the hypothalamus allows today to consider innovative therapeutics focused on hunger control. Several new pharmacological molecules benefit patients with monogenic or syndromic obesity. They are likely to be among the treatment options for these patients in the coming years, helping clinicians and patients prevent rapid weight progression and eventually limit bariatric surgery procedures, which is less effective in these patients. Their positioning in the management of such patients will be needed to be well defined to develop precision medicine in genetic forms of obesity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dubern reports a relationship with rhythm Pharmaceuticals, Novo Nordisks that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The COVID-19 pandemic was initially responsible for a global restricted access to healthcare resources including the follow-up of at-risk populations such as bariatric patients. We substituted face-to-face bariatric follow-up outpatient clinics (FTFC) with teleclinics (TC) during the lockdown., Material and Methods: We retrospectively reviewed data collected on all patients scheduled for TC during the French lockdown period (March 15 to May 15, 2020) (N = 87). Our aims were to present the patients' outcomes at one and 2 years post-TC implementation and describe patient/practitioner satisfaction., Results: Seven (8%) patients required FTFC, and 80 (92%) underwent TC (study population) for preoperative bariatric assessment (N = 3) and postoperative follow-up (N = 77) after 23.6 ± 29 months following surgery. TC was performed with video and audio (N = 46; 57.5%) or audio alone when video was impossible (N = 34; 42.5%). Sixteen (20%) patients presented at least one complication identified at the first TC and were managed accordingly. There were no readmissions at 30/90 days post-TC. At 1-year after the first TC, overall follow-up rate was 94.9% (TC: 73% vs FTFC: 27%). Patients surveyed on the main advantages of TC over FTFC (N = 46) cited: saving time (97.8%) at a mean 3.9 ± 6.4 h saved per TC, work-advantages (94.3%), and comparable relevance of TC (84.8%). At 2 years post-TC implementation, follow-up rate was 93.5% and satisfaction rate was 80%, with 33% of patients preferring to return to FTFC., Conclusions: TC is a satisfactory substitute for FTFC, enabling continued bariatric follow-up during and beyond the pandemic setting without compromising patient safety. However, the modest satisfaction outcomes at 2 years highlight a need to discuss follow-up preferences in order to achieve optimal outcomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The adipogenic PPARG-encoded PPARγ nuclear receptor also displays essential placental functions. We evaluated the metabolic, reproductive, and perinatal features of patients with PPARG-related lipodystrophy., Methods: Current and retrospective data were collected in patients referred to a National Rare Diseases Reference Centre., Results: 26 patients from 15 unrelated families were studied (18 women, median age 43 years). They carried monoallelic PPARG variants except a homozygous patient with congenital generalized lipodystrophy. Among heterozygous patients aged 16 or more (n = 24), 92% had diabetes, 96% partial lipodystrophy (median age at diagnosis 24 and 37 years), 78% hypertriglyceridaemia, 71% liver steatosis, and 58% hypertension. The mean BMI was 26 ± 5.0 kg/m2. Women (n = 16) were frequently affected by acute pancreatitis (n = 6) and/or polycystic ovary syndrome (n = 12). Eleven women obtained one or several pregnancies, all complicated by diabetes (n = 8), hypertension (n = 4), and/or hypertriglyceridaemia (n = 10). We analysed perinatal data of patients according to the presence (n = 8) or absence (n = 9) of a maternal dysmetabolic environment. The median gestational age at birth was low in both groups (37 and 36 weeks of amenorrhea, respectively). As expected, the birth weight was higher in patients exposed to a foetal dysmetabolic environment of maternal origin. In contrast, 85.7% of non-exposed patients, in whom the variant is, or is very likely to be, paternally-inherited, were small for gestational age., Conclusions: Lipodystrophy-related PPARG variants induce early metabolic complications. Our results suggest that placental expression of PPARG pathogenic variants carried by affected foetuses could impair prenatal growth and parturition. This justifies careful pregnancy monitoring in affected families., Competing Interests: Conflicts of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Prader-Willi Syndrome (PWS) is a rare genetic condition, which affects one in 25,000 births and results in various phenotypes. It leads to a wide range of metabolic and endocrine disorders including growth delay, hypogonadism, narcolepsy, lack of satiety and compulsive eating, associated with mild to moderate cognitive impairment. Prognosis is especially determined by the complications of obesity (diabetes, cardiorespiratory diseases) and by severe behavioral disorders marked by impulsivity and compulsion. This heterogeneous clinical picture may lead to mis- or delayed diagnosis of comorbidities. Moreover, when diagnosis is made, treatment remains limited, with high interindividual differences in drug response. This may be due to the underlying genetic variability of the syndrome, which can involve several different genetic mutations, notably deletion or uniparental disomy (UPD) in a region of chromosome 15. Here, we propose to determine whether subjects with PWS differ for clinical phenotype and treatment response depending on the underlying genetic anomaly., Methods: We retrospectively included all 24 PWS patients who were referred to the Reference Center for Rare Psychiatric Disorders (GHU Paris Psychiatrie and Neurosciences) between November 2018 and July 2022, with either deletion ( N = 8) or disomy ( N = 16). The following socio-demographic and clinical characteristics were recorded: age, sex, psychiatric and non-psychiatric symptoms, the type of genetic defect, medication and treatment response to topiramate, which was evaluated in terms of eating compulsions and impulsive behaviors. We compared topiramate treatment doses and responses between PWS with deletion and those with disomy. Non-parametric tests were used with random permutations for p -value and bootstrap 95% confidence interval computations., Results: First, we found that disomy was associated with a more severe clinical phenotype than deletion. Second, we observed that topiramate was less effective and less tolerated in disomy, compared to deletion., Discussion: These results suggest that a pharmacogenomic-based approach may be relevant for the treatment of compulsions in PWS, thus highlighting the importance of personalized medicine for such complex heterogeneous disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Louveau, Turtuluci, Consoli, Poitou, Coupaye, Krebs, Chaumette and Iftimovici.)

Context: Prader-Willi syndrome (PWS) is a rare complex genetic syndrome, characterized by delayed psychomotor development, hypotonia, and hyperphagia. Hormone deficiencies such as hypogonadism, hypothyroidism, and growth hormone deficiency are common. The combination of hypotonia, low physical activity, and hypogonadism might lead to a decrease in bone mass and increase in fracture risk. Moreover, one would expect an increased risk of scoliosis due to hypotonia and low physical activity., Objective: To study the prevalence and risk factors for skeletal problems (reduced bone mineral density, fractures, and scoliosis) in adults with PWS., Methods: We retrospectively collected patient characteristics, medical history, medication, biochemical measurements, dual-energy X-ray absorptiometry scans, and spinal X-rays and reviewed the current literature., Results: We included 354 adults with PWS (median age 31 years; 43% males), of whom 51 (14%) had osteoporosis (T-score below -2.5) and 143 (54%) had osteopenia (T-score -1 to -2.5). The most prevalent modifiable risk factors for osteoporosis were hypogonadism, insufficient dairy intake, sedentary lifestyle, and corticosteroid use. Male sex was associated with osteoporosis (P = .005). Growth hormone treatment was not associated with osteoporosis. A history of vertebral fractures was present in 10 (3%) and nonvertebral fractures in 59 (17%). Scoliosis was present in 263 (80%), but no modifiable risk factors were identified., Conclusion: Besides scoliosis, osteoporosis is common in adults with PWS. Based on the literature and the risk factors for osteoporosis found in our cohort, we provide practical clinical recommendations to avoid skeletal complications in these vulnerable patients., Competing Interests: Conflict of Interest The authors have no conflict of interest to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Prader-Willi syndrome (PWS), the most common form of syndromic obesity, is a complex neurodevelopmental genetic disorder including obesity with hyperphagia, endocrine and metabolic disorders and also psychiatric disorders. The most frequent endocrine disturbances include hypogonadism and growth hormone (GH) deficiency. Hypothyroidism and central adrenal insufficiency can also be observed but are less frequent. The transition of individuals with PWS from adolescence to adult life is challenging because of multiple comorbidities and complex disabilities. Individuals and caregivers face psychological, medical and social issues. This period of profound changes is thus prone to disruptions, and the main risks being the worsening of the medical situation and loss to follow-up of the individuals. Medical care may be poorly adapted to the needs of individuals because of a lack of knowledge concerning the syndrome and also lack of the necessary specific skills. A multidisciplinary panel composed of several experts in PWS met in November 2021 during an European Reference Network on Rare Endocrine Conditions (Endo-ERN) webinar. They presented complementary aspects of PWS from the perspective of the transition including psychiatric, pediatric and adult endocrinological and parent's and patient's points of view and shed light on the best way to approach this pivotal period.

Background: Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with hyperphagia and early-onset severe obesity. We aimed to evaluate the effect of setmelanotide on bodyweight in these patients., Methods: This multicentre, randomised, 14-week double-blind, placebo-controlled, phase 3 trial followed by a 52-week open-label period, was performed at 12 sites (hospitals, clinics, and universities) in the USA, Canada, the UK, France, and Spain. Patients aged 6 years or older were included if they had a clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome and obesity (defined as BMI >97th percentile for age and sex for those aged 6-15 years and ≥30 kg/m 2 for those aged ≥16 years). Patients were randomly assigned (1:1) using a numerical randomisation code to receive up to 3·0 mg of subcutaneous setmelanotide or placebo once per day during the 14-week double-blind period, followed by open-label setmelanotide for 52 weeks. The primary endpoint, measured in the full analysis set, was the proportion of patients aged 12 years or older who reached at least a 10% reduction in bodyweight from baseline after 52 weeks of setmelanotide treatment. This study is registered with ClinicalTrials.gov, NCT03746522., Findings: Between Dec 10, 2018, and Nov 25, 2019, 38 patients were enrolled and randomly assigned to receive setmelanotide (n=19) or placebo (n=19; 16 with Bardet-Biedl syndrome and three with Alström syndrome in each group). In terms of the primary endpoint, 32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 years or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight after 52 weeks of setmelanotide. The most commonly reported treatment-emergent adverse events were skin hyperpigmentation (23 [61%] of 38) and injection site erythema (18 [48%]). Two patients had four serious adverse events (blindness, anaphylactic reaction, and suicidal ideation); none were considered related to setmelanotide treatment., Interpretation: Setmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome; however, these results were inconclusive in patients with Alström syndrome. These results support the use of setmelanotide and provided the necessary evidence for approval of this drug as the first treatment for obesity in patients with Bardet-Biedl syndrome., Funding: Rhythm Pharmaceuticals., Competing Interests: Declaration of interests RMH received study medication, grant support for clinical trials of setmelanotide, payments for lectures and expert testimony, and support for attending meetings from Rhythm Pharmaceuticals; consulting fees from Rhythm Pharmaceuticals and Axovia Therapeutics; participated in the data safety monitoring board for Rhythm Pharmaceuticals; and is a stockholder in Rhythm Pharmaceuticals. AMH received grants from the Weston Family Microbiome Initiative and Canadian Institutes of Health Research, payment as a speaker for Pfizer Canada, is a member of the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals and the 2021 Somatrogon advisory board for Pfizer, and head of the scientific advisory board for the Prader-Willi Syndrome Association USA. WKC received study funding, consulting fees, and payment for speaker bureaus from Rhythm Pharmaceuticals. HD received consulting fees and participated in the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals. GÁM-M received payment for lectures and participated in the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals. CP received support for attending meetings and grant funding for clinical trials of setmelanotide from Rhythm Pharmaceuticals; clinical trials of Prader-Willi syndrome from Millendo; and clinical trials of obesity from Novo Nordisk. JAY received grant support for clinical trials of setmelanotide from Rhythm Pharmaceuticals, grant support for clinical trials of diazoxide choline-controlled release in Prader-Willi syndrome from Soleno Therapeutics, and study medication for clinical trials from Hikma Pharmaceuticals and Versanis Bio. RSM and GY are employees and stockholders of Rhythm Pharmaceuticals. EF received consulting fees and participated in the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals and is a clinical investigator for clinical trials of setmelanotide in Bardet-Biedl syndrome for Rhythm Pharmaceuticals. KC received grant funding from Ysopia, Integrative Phenomics, and Confo Therapeutics; and is a clinical investigator for clinical trials of setmelanotide in Bardet-Biedl syndrome for Rhythm Pharmaceuticals. JA received payment for lectures and participated in the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aim: To describe baseline characteristics and follow-up data in patients with lipodystrophy syndromes treated with metreleptin in a national reference network, in a real-life setting., Patients and Methods: Clinical and metabolic data from patients receiving metreleptin in France were retrospectively collected, at baseline, at 1 year and at the latest follow-up during treatment., Results: Forty-seven patients with lipodystrophy including generalized lipodystrophy (GLD; n = 28) and partial lipodystrophy (PLD; n = 19) received metreleptin over the last decade. At baseline, the median (interquartile range [IQR]) patient age was 29.3 (16.6-47.6) years, body mass index was 23.8 (21.2-25.7) kg/m 2 and serum leptin was 3.2 (1.0-4.9) ng/mL, 94% of patients had diabetes (66% insulin-treated), 53% had hypertension and 87% had dyslipidaemia. Metreleptin therapy, administered for a median (IQR) of 31.7 (14.2-76.0) months, was ongoing in 77% of patients at the latest follow-up. In patients with GLD, glycated haemoglobin (HbA1c) and fasting triglyceride levels significantly decreased from baseline to 1 year of metreleptin treatment, from 8.4 (6.5-9.9)% [68 (48-85) mmol/mol] to 6.8 (5.6-7.4)% [51(38-57) mmol/mol], and 3.6 (1.7-8.5) mmol/L to 2.2 (1.1-3.7) mmol/L, respectively (P < 0.001), with sustained efficacy thereafter. In patients with PLD, HbA1c was not significantly modified (7.7 [7.1-9.1]% [61 (54-76) mmol/mol] at baseline vs. 7.7 [7.4-9.5]% [61(57-80) mmol/mol] at 1 year), and the decrease in fasting triglycerides (from 3.3 [1.9-9.9] mmol/L to 2.5 [1.6-5.3] mmol/L; P < 0.01) was not confirmed at the latest assessment (5.2 [2.2-11.3] mmol/L). However, among PLD patients, at 1 year, 61% were responders regarding glucose homeostasis, with lower baseline leptin levels compared to nonresponders, and 61% were responders regarding triglyceridaemia. Liver enzymes significantly decreased only in the GLD group., Conclusions: In this real-life setting study, metabolic outcomes are improved by metreleptin therapy in patients with GLD. The therapeutic indication for metreleptin needs to be clarified in patients with PLD., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background and Objectives: We previously showed in a 6-month randomized controlled trial that resistance training and protein supplementation after bariatric surgery (Roux-en-Y gastric bypass, RYGB) improved muscle strength without significant effect on weight loss and body composition changes. We performed a 5-year follow-up study in these subjects with the aim 1) to assess the long-term effect of this exercise training intervention and 2) to analyze associations between habitual physical activity (PA) and weight regain at 5 years., Methods: Fifty-four out of 76 initial participants (follow-up rate of 71%) completed the 5-year follow-up examination (controls, n = 17; protein supplementation, n = 22; protein supplementation and resistance training, n = 15). We measured body weight and composition (DXA), lower-limb strength (leg-press one-repetition maximum) and habitual PA (Actigraph accelerometers and self-report). Weight regain at 5 years was considered low when <10% of 12-month weight loss., Results: Mean (SD) time elapse since RYGB was 5.7 (0.9) y. At 5 years, weight loss was 32.8 (10.1) kg, with a mean weight regain of 5.4 (SD 5.9) kg compared with the 12-month assessment. Moderate-to-vigorous PA (MVPA) assessed by accelerometry did not change significantly compared with pre-surgery values (+5.2 [SD 21.7] min/d, P = 0.059), and only 4 (8.2%) patients reported participation in resistance training. Muscle strength decreased over time (overall mean [SD]: -49.9 [53.5] kg, respectively, P<0.001), with no statistically significant difference between exercise training intervention groups. An interquartile increase in MVPA levels was positively associated with lower weight regain (OR [95% CI]: 3.27 [1.41;9.86])., Conclusions: Early postoperative participation in a resistance training protocol after bariatric surgery was not associated with improved muscle strength after 5 years of follow-up; however, increasing physical activity of at least moderate intensity may promote weight maintenance after surgery. PA may therefore play an important role in the long-term management of patients with obesity after undergoing bariatric procedure., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Craniopharyngiomas are tumors located in the hypothalamic region which leads to obesity in about 50% of cases. Long-term efficacy and safety of bariatric surgery are lacking in this peculiar population. The aim of this study is to determine the 5-year weight loss and resolution of type 2 diabetes (T2D) after bariatric surgery in patients operated on craniopharyngioma who had developed hypothalamic obesity., Materials and Methods: This is a multicenter french retrospective case-control study. Subjects with craniopharyngioma (n = 23) who underwent sleeve gastrectomy (SG) (n = 9) or Roux-en-Y gastric bypass (RYGB) (n = 14) (median age 35 years [25;43] and BMI 44.2 kg/m 2 [40.7; 51.0]; 8/23 with T2D) were individually matched to 2 subjects with common obesity for age, gender, preoperative body mass index, T2D, and type of surgery., Results: TWL% after 1 and 5 years was lower in the craniopharyngioma group than in the control group: 23.1 [15.4; 31.1] (23/23) vs 31.4 [23.9; 35.3] at 1 year (p = 0.008) (46/46) and 17.8 [7.1; 21.9] (23/23) vs 26.2 [18.9; 33.9] at 5 years (p = 0.003) (46/46). After RYGB, TWL% was lower in the craniopharyngioma group compared to the control group (p < 0.001) and comparable after SG both at 1 and 5 years. No difference between the two groups was observed in T2D remission rate and in early and late adverse events. No hormonal deficiency-related acute disease was reported., Conclusions: Bariatric surgery induced a significant weight loss in the craniopharyngioma group at 1 and 5 years, but less than in common obesity. SG may be more effective than RYGB but this remains to be demonstrated in a larger cohort., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Little is known about the consequences of COVID-19 lockdowns on physical activity (PA), eating behavior, and mental health in post-bariatric surgery (BS) patients. We aimed to analyze the relations between changes in PA during COVID-19 lockdowns and changes in body weight and a comprehensive set of lifestyle and psychological outcomes in patients who have undergone BS., Material and Methods: In April-May 2020 (lockdown#1), we performed an online survey in a cohort of 937 adults who underwent BS and were followed-up at our university medical center for at least one year. We assessed changes in PA, eating behavior, body weight, fatigue, and depression (PHQ-9). In November-December 2020 (lockdown#2), we recorded body weight in 280 patients who had reported decreased PA during lockdown #1., Results: During lockdown #1 (N = 420 patients included, 44% response rate), decreased PA was reported by 67% patients. Compared to those who reported increased or unchanged PA, patients with decreased PA were more likely to report a ≥ 5% weight gain (OR (95% CI): 3.15 (1.46-7.65), increased fatigue (2.08 (1.36-3.23)), a worsening of eating behavior (2.29 (1.47-3.58)), and moderate-to-severe depressive symptoms (4.74 (2.14-11.76)). During lockdown #2 (N = 225 patients, 80% response rate), significant weight gain since before lockdown #1 was reported (+ 2.8 (95% CI: 1.7-3.8) kg, p < 0.001), with 36% patients reporting a ≥ 5% weight gain., Conclusions: PA may counteract detrimental effects of COVID-19 lockdown on post-BS weight trajectories and mental health outcomes. Follow-up measures are needed in this setting to assess the long-term impact of lockdown., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Prader-Willi syndrome (PWS) is a rare, genetic, multisymptomatic, neurodevelopmental disease commonly associated with sleep alterations, including sleep-disordered breathing and central disorders of hypersomnolence. Excessive daytime sleepiness represents the main manifestation that should be addressed by eliciting the detrimental effects on quality of life and neurocognitive function from the patients' caregivers. Patients with PWS have impaired ventilatory control and altered pulmonary mechanics caused by hypotonia, respiratory muscle weakness, scoliosis and obesity. Consequently, respiratory abnormalities are frequent and, in most cases, severe, particularly during sleep. Adults with PWS frequently suffer from sleep apnoea syndrome, sleep hypoxemia and sleep hypoventilation. When excessive daytime sleepiness persists after adequate control of sleep-disordered breathing, a sleep study on ventilatory treatment, followed by an objective measurement of excessive daytime sleepiness, is recommended. These tests frequently identify central disorders of hypersomnolence, including narcolepsy, central hypersomnia or a borderline hypersomnolent phenotype. The use of wake-enhancing drugs (modafinil, pitolisant) is discussed in multidisciplinary expert centres for these kinds of cases to ensure the right balance between the benefits on quality of life and the risk of psychological and cardiovascular side effects.

Context: Serum propeptides of type III and type VI collagen (PRO-C3 and PRO-C6) are elevated in advanced nonalcoholic fatty liver disease (NAFLD), but their value in patients with severe obesity and their evolution after bariatric surgery (BS) is unknown. It is unclear if these markers of fibrogenesis are affected by adipose tissue fibrosis (ATF)., Objective: We studied the association of PRO-C3 and PRO-C6 with liver fibrosis before BS, examined their evolution after BS, and evaluated how much patients' ATF contribute to their levels., Methods: Serum PRO-C3 and PRO-C6 were measured in 158 BS patients and compared with liver, subcutaneous, and omental adipose tissue histology obtained during surgery. PRO-C3 and PRO-C6 levels of 63 patients were determined in follow-up at 3 and 12 months post-BS., Results: Patients in the highest quartile of PRO-C3 had a higher risk of advanced liver fibrosis (stage F3-4; odds ratio 5.8; 95% CI [1.5-29.9]; P = 0.017) vs the lowest quartile (adjustment for age, gender, and BMI). PRO-C3 was positively correlated with markers of insulin resistance and liver enzymes. After BS, PRO-C3 levels decreased in patients with high baseline liver fibrosis. This decrease correlated with improvement of metabolic and liver parameters. PRO-C6 was not related to stage of liver fibrosis. ATF did not correlate with PRO-C3 or PRO-C6 levels at baseline or after BS., Conclusion: PRO-C3 was associated with advanced liver fibrosis in patients with severe obesity, and decreased after BS, without being affected by ATF. These data suggest that BS prominently eliminates drivers of hepatic fibrogenesis in NAFLD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Individuals with proopiomelanocortin (POMC) or leptin receptor (LEPR) deficiency are young and experience severe obesity, hyperphagia, and comorbidities, which can impair quality of life (QOL)., Methods: Two pivotal Phase 3 trials explored the effect of setmelanotide on body weight and hunger in individuals with obesity due to POMC (NCT02896192) or LEPR (NCT03287960) deficiency. QOL and depression were investigated in parallel using the disease-specific, age-appropriate Impact of Weight on Quality of Life-Lite (IWQOL-Lite), Pediatric Quality of Life Inventory (PedsQL), and Patient Health Questionnaire-9 (PHQ-9)., Results: In total, the POMC and LEPR trials enrolled 21 patients. Adults (≥ 18 years old; n = 7) had moderate-to-severe impairment in QOL at baseline, with mean (standard deviation [SD]) IWQOL-Lite total score 60.3 (13.2; maximum IWQOL-Lite total score = 100). The effect of setmelanotide on IWQOL-Lite total score was observed as soon as Week 5. Among those with scores at Week 52, 5 of 6 adults experienced a clinically meaningful improvement, with mean (SD) total scores increased from baseline by 24.2 (12.1) points. Children (6-12 years old; n = 2) and adolescents (13-17 years old; n = 4) had impaired QOL at baseline, with mean (SD) self-reported PedsQL total scores 53.3 (6.2) and 63.3 (29.1), respectively (maximum PedsQL total score = 100). Three of 5 patients experienced clinically meaningful improvement in PedsQL, with 2 children whose PedsQL total score increased by 28.3 and 3.3 points and 3 adolescents whose mean (SD) total score increased from baseline by 5.8 (18.3) points. Baseline mean (SD) PHQ-9 score (in those ≥ 12 years old) was 5.3 (3.8) and was generally maintained through Week 52., Conclusions: Patients with POMC or LEPR deficiency had impaired, and in some cases severely impaired, QOL before setmelanotide treatment. Setmelanotide improved QOL in patients as early as Week 5, with some patients no longer experiencing impaired QOL at Week 52. Improvements in QOL may be related to a reduction in hunger and body weight associated with setmelanotide. Because of the highly complex psychological consequences of rare genetic diseases of obesity, some patients may require a long period of treatment to improve QOL and benefit from interdisciplinary care., (© 2022. The Author(s).)

Rare genetic forms of obesity are linked to impaired energy balance (i.e., eating behaviour and energy expenditure) involving hypothalamic pathways. More than 60 genes coding for proteins located in the hypothalamic leptin/melanocortin pathway contribute to the development of these rare forms of obesity. The ambition of the French National Protocol for the Diagnosis and Care (PNDS) of Obesity of Rare Causes was to establish practical recommendations for assessment and management at all ages. This report is available on the website of the French Health Authority (HAS). In addition to severe obesity, patients often display obesity-related comorbidities and neuropsychological/psychiatric disorders. These complex conditions make clinical management particularly challenging. Early diagnosis is critical for the organization of coordinated specialized multidisciplinary care, with mandatory interaction between caregivers, social partners and families. Strategies to prevent aggravation of obesity consist in limiting access to food, establishing a reassuring daily eating environment, and the practice of sustained adapted supervised daily physical activity. The implementation of genetic diagnosis in clinical practice now enables a personalized medicine approach with access to new drug therapies, and improves the analysis of the risk/benefit ratio of bariatric surgery., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Roux-en-Y gastric bypass (RYGB) is efficient at inducing drastic albeit variable weight loss and type-2 diabetes (T2D) improvements in patients with severe obesity and T2D. We hypothesized a causal implication of the gut microbiota (GM) in these metabolic benefits, as RYGB is known to deeply impact its composition. In a cohort of 100 patients with baseline T2D who underwent RYGB and were followed for 5-years, we used a hierarchical clustering approach to stratify subjects based on the severity of their T2D (Severe vs Mild) throughout the follow-up. We identified via nanopore-based GM sequencing that the more severe cases of unresolved T2D were associated with a major increase of the class Bacteroidia, including 12 species comprising Phocaeicola dorei, Bacteroides fragilis , and Bacteroides caecimuris . A key observation is that patients who underwent major metabolic improvements do not harbor this enrichment in Bacteroidia, as those who presented mild cases of T2D at all times. In a separate group of 36 patients with similar baseline clinical characteristics and preoperative GM sequencing, we showed that this increase in Bacteroidia was already present at baseline in the most severe cases of T2D. To explore the causal relationship linking this enrichment in Bacteroidia and metabolic alterations, we selected 13 patients across T2D severity clusters at 5-years and performed fecal matter transplants in mice. Our results show that 14 weeks after the transplantations, mice colonized with the GM of Severe donors have impaired glucose tolerance and insulin sensitivity as compared to Mild-recipients, all in the absence of any difference in body weight and composition. GM sequencing of the recipient animals revealed that the hallmark T2D-severity associated bacterial features were transferred and were associated with the animals' metabolic alterations. Therefore, our results further establish the GM as a key contributor to long-term glucose metabolism improvements (or lack thereof) after RYGB.

Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Prader-Willi syndrome (PWS) is a rare neuroendocrine genetic syndrome. Characteristics of PWS include hyperphagia, hypotonia, and intellectual disability. Pituitary hormone deficiencies, caused by hypothalamic dysfunction, are common and hypogonadism is the most prevalent. Untreated hypogonadism can cause osteoporosis, which is already an important issue in PWS. Therefore, timely detection and treatment of hypogonadism is crucial. To increase understanding and prevent undertreatment, we (1) performed a cohort study in the Dutch PWS population, (2) thoroughly reviewed the literature on female hypogonadism in PWS and (3) provide clinical recommendations on behalf of an international expert panel. For the cohort study, we retrospectively collected results of a systematic health screening in 64 female adults with PWS, which included a medical questionnaire, medical file search, medical interview, physical examination and biochemical measurements. Our data show that hypogonadism is frequent in females with PWS (94%), but is often undiagnosed and untreated. This could be related to unfamiliarity with the syndrome, fear of behavioral changes, hygienic concerns, or drug interactions. To prevent underdiagnosis and undertreatment, we provide practical recommendations for the screening and treatment of hypogonadism in females with PWS.

Type 2 diabetes mellitus (T2DM) affects 20% of patients with Prader-Willi syndrome (PWS), with many cases diagnosed during the transition period. Our aim was to describe the natural history of T2DM in patients with PWS before the age of 25 years and to develop screening and preventive strategies. Thirty-nine patients followed in the French PWS Reference Center were included (median age 25.6 years [23.7; 31.7]). Twenty-one had been treated with growth hormone (GH), fifteen had not, and three had an unknown status. The median age at T2DM diagnosis was 16.8 years (11-24) and the median BMI was 39 kg/m 2 [34.6; 45], with 34/35 patients living with obesity. The patients displayed frequent psychiatric (48.3% hospitalization,) and metabolic (56.4% hypertriglyceridemia,) comorbidities and a parental history of T2DM (35.7%) or overweight (53.6%) compared to the PWS general population. There was no difference in BMI and metabolic complications between the GH-treated and non-GH-treated groups at T2DM diagnosis. Patients with PWS who develop early T2DM have severe obesity, a high frequency of psychiatric and metabolic disorders, and a family history of T2DM and overweight. These results underline the need for early identification of patients at risk, prevention of obesity, and repeated blood glucose monitoring during the transition period.

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Prader-Willi syndrome (PWS) is a complex genetic syndrome characterized by hyperphagia, intellectual disability, hypotonia and hypothalamic dysfunction. Adults with PWS often have hormone deficiencies, hypogonadism being the most common. Untreated male hypogonadism can aggravate PWS-related health issues including muscle weakness, obesity, osteoporosis, and fatigue. Therefore, timely diagnosis and treatment of male hypogonadism is important. In this article, we share our experience with hypogonadism and its treatment in adult males with PWS and present a review of the literature. In order to report the prevalence and type of hypogonadism, treatment regimen and behavioral issues, we retrospectively collected data on medical interviews, physical examinations, biochemical measurements and testosterone replacement therapy (TRT) in 57 Dutch men with PWS. Fifty-six (98%) of the patients had either primary, central or combined hypogonadism. Untreated hypogonadism was associated with higher body mass index and lower hemoglobin concentrations. TRT was complicated by behavioral challenges in one third of the patients. Undertreatment was common and normal serum testosterone levels were achieved in only 30% of the patients. Based on the Dutch cohort data, review of the literature and an international expert panel discussion, we provide a practical algorithm for TRT in adult males with PWS in order to prevent undertreatment and related adverse health outcomes.

In Prader-Willi syndrome (PWS), conditions that are associated with hyponatremia are common, such as excessive fluid intake (EFI), desmopressin use and syndrome of inappropriate antidiuretic hormone (SIADH) caused by psychotropic medication. However, the prevalence of hyponatremia in PWS has rarely been reported. Our aim was to describe the prevalence and severity of hyponatremia in PWS. In October 2020, we performed a retrospective study based on the medical records of a large cohort of children and adults with PWS from seven countries. Among 1326 patients (68% adults), 34 (2.6%) had at least one episode of mild or moderate hyponatremia (125 ≤ Na < 135 mmol/L). The causes of non-severe hyponatremia were often multi-factorial, including psychotropic medication in 32%, EFI in 24% and hyperglycemia in 12%. No obvious cause was found in 29%. Seven (0.5%) adults experienced severe hyponatremia (Na < 125 mmol/L). Among these, five recovered completely, but two died. The causes of severe hyponatremia were desmopressin treatment for nocturnal enuresis ( n = 2), EFI ( n = 2), adrenal insufficiency ( n = 1), diuretic treatment ( n = 1) and unknown ( n = 1). In conclusion, severe hyponatremia was very rare but potentially fatal in PWS. Desmopressin treatment for nocturnal enuresis should be avoided. Enquiring about EFI and monitoring serum sodium should be included in the routine follow-ups of patients with PWS.

Background: Gene mutations in the leptin-melanocortin signaling cascade lead to hyperphagia and severe early onset obesity. In most cases, multimodal conservative treatment (increased physical activity, reduced caloric intake) is not successful to stabilize body weight and control hyperphagia., Objectives: To examine bariatric surgery as a therapeutic option for patients with genetic obesity., Setting: Three major academic, specialized medical centers., Methods: In 3 clinical centers, we retrospectively analyzed the outcomes of bariatric surgery performed in 8 patients with monogenic forms of obesity with bi-allelic variants in the genes LEPR (n = 5), POMC (n = 2), and MC4R (n = 1)., Results: In this group of patients with monogenic obesity, initial bariatric surgery was performed at a median age of 19 years (interquartile range [IQR], 16-23.8 yr). All patients initially experienced weight loss after each bariatric surgery, which was followed by substantial weight regain. In total, bariatric surgery led to a median maximum reduction of body weight of -21.5 kg (IQR, -36.3 to -2.9 kg), median percent excess weight loss (%EWL) of -47.5 %EWL (IQR, -57.6 to -28.9 %EWL). This body weight reduction was followed by median weight regain of 24.1 kg (IQR: 10.0 to 42.0 kg), leading to a final weight change of -24.2 % EWL (IQR: -37.6 to -5.4 %EWL) after a maximum duration of 19 years post surgery. In one patient, bariatric surgery was accompanied by significant complications, including vitamin deficiencies and hernia development., Conclusion: The indication for bariatric surgery in patients with monogenic obesity based on bi-allelic gene mutations and its benefit/risk balance has to be evaluated very cautiously by specialized centers. Furthermore, to avoid an unsuccessful operation, preoperative genetic testing of patients with a history of early onset obesity might be essential, even more since novel pharmacological treatment options are expected., (Copyright © 2021 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Patients with Prader-Willi syndrome (PWS) often have comorbidities, especially obesity, that may constitute a risk factor for severe forms of COVID-19. We aimed to assess prevalence and medical course of SARS-CoV-2 infection in children and adults with PWS. From November 2020 to January 2021, we performed a detailed medical survey on 342 adults and 305 children with PWS followed in the French reference center., Results: We obtained responses from 288 adults (84%) and 239 children (78%). From March 2020 to January 2021, 38 adults (13.2%) and 13 children (5.4%) with PWS had SARS-CoV-2 infection. Mean age of adults was 34.1 ± 11.9 years and mean body mass index was 40.6 ± 12.7 kg/m 2 ; 82% had obesity and 37% had diabetes. Only 3 children (23%) had obesity and none had diabetes. Similar to the general population, the most frequent symptoms of COVID-19 were asthenia, fever, cough, headache and shortness of breath. All patients had a favorable outcome., Conclusion: PWS itself is not a risk factor for severe COVID-19 in children and adults. On the contrary, evolution of SARS-CoV-2 infection in adults with PWS seems more favorable than expected, given their comorbidities., (© 2021. The Author(s).)

Physical activity (PA) is an important aspect of the management of patients with Prader-Willi syndrome (PWS). However, the day-to-day implementation of PA programs is particularly challenging in these patients. This systematic review aimed (1) to describe habitual PA and sedentary behavior and (2) to assess the effects of PA interventions and to describe their implementation process, in children and adults with PWS. A systematic search of controlled trials, single-group interventions, observational, and qualitative studies published up to December 2020 was performed. Twenty-five studies were included. Habitual PA was found to be lower in patients with PWS compared to controls without obesity or with non-syndromic obesity. Habitual PA was positively associated with lean body mass and bone parameters in children with PWS, and these finding were strengthened by intervention studies reporting an increase in both outcomes after a PA program. PA programs also improved physical function (muscle strength, walking distance, and coordination), without significant effect on weight and fat mass. Attendance to exercise sessions was usually high and no serious adverse effect was reported. In conclusion, supervised PA programs are beneficial for children and adults with PWS. Support should be provided to families to facilitate their implementation in real-life settings.

Background: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with hypothalamic dysfunction leading to obesity and behavioral disabilities, including eating disorders (EDs). We evaluated the effects of the COVID-19 infection and lockdown on mental and physical health in PWS. At the end of April, 85 adults with PWS completed a self-administered questionnaire, including lockdown conditions, physical activity (PA), ED, and medical and behavioral outcomes. Body weight was measured at home and self-reported., Results: Patients (52.9% women, 44.8% disomic) were assessed, with a mean age of 28.05 ± 8.73 years and body mass index (BMI) of 36.76 ± 10.74 kg/m 2 . Seventy percent lived in the Paris region (France) and were confined with their parents. The mean weight change was 0.96 ± 3.28 kg. We compared patients showing weight loss (n = 39, - 3.30 ± 2.93 kg) to patients showing weight gain (n = 22, + 2.35 ± 1.54 kg): the BMI was lower (34.60 ± 9.18 versus 40.45 ± 9.45 kg/m 2 , p = 0.02), PA increased (25.6% versus 4.5%, p = 0.04), and EDs improved (51.3% versus 13.6%, p = 0.005). Behavioral disorders increased for 12.9% of the cohort. Three individuals (3.5%) were diagnosed with non-severe COVID-19., Conclusion: Lockdown during the COVID-19 pandemic was associated with positive effects for most French adults with PWS, with weight loss probably associated with a more favourable environment during this period. We observed no severe forms of COVID-19.

Introduction/ Purpose: Sleeve gastrectomy (SG), the most frequently performed bariatric procedure, induces marked weight-loss, but with high inter-individual variability. Since type 2 diabetes (T2D) negatively impacts weight-loss outcomes after Roux-en-Y gastric bypass (RYGB), we herein aimed to evaluate whether and how T2D status may influence weight-loss and body composition changes in individuals with or without T2D after SG., Material and Methods: We retrospectively included individuals with obesity operated from SG and prospectively followed at our center: 373 patients including 152 with T2D (40%). All subjects' clinical characteristics were collected before and during 4 years of follow-up post-SG. Linear mixed models were applied to analyze weight-loss trajectories post-surgery., Results: Compared to individuals with obesity but no T2D, those with T2D before SG displayed lower weight-loss at 1 year (21 vs. 27% from baseline, p < 10 -3 ). This difference was accentuated in patients with poorer glucose control (HbA1c > 7%) at baseline. Furthermore, patients with T2D underwent less favorable body composition changes at 1-year post-SG compared to individuals without T2D (% fat mass reduction: 28 vs. 37%, p < 10 -3 respectively)., Conclusion: When undergoing SG, subjects with obesity and T2D who have poor pre-operative glycemic control display reduced weight-loss and less improvement in body composition compared to patients with obesity but without T2D. This result suggests that glycemic control prior to surgery is important to take into account for the outcome of bariatric surgery.

Insulin resistance (IR), currently called prediabetes (PD), affects more than half of the adult population worldwide. Type 2 diabetes (T2D), which often follows in the absence of treatment, affects more than 475 million people and represents 10-20% of the health budget in industrialized countries. A preventive public health policy is urgently needed in order to stop this constantly progressing epidemic. Indeed, early management of prediabetes does not only strongly reduce its evolution toward T2D but also strongly reduces the appearance of cardiovascular comorbidity as well as that of associated cancers. There is however currently no simple and reliable test available for the diagnosis or screening of prediabetes and it is generally estimated that 20-60% of diabetics are not diagnosed. We therefore developed an ELISA for the quantitative determination of serum Insulin-Regulated AminoPeptidase (IRAP). IRAP is associated with and translocated in a stoechiometric fashion to the plasma membrane together with GLUT4 in response to insulin in skeletal muscle and adipose tissue which are the two major glucose storage sites. Its extracellular domain (IRAPs) is subsequently cleaved and secreted in the blood stream. In T2D, IRAP translocation in response to insulin is strongly decreased. Our patented sandwich ELISA is highly sensitive (≥10.000-fold "normal" fasting concentrations) and specific, robust and very cost-effective. Dispersion of fasting plasma concentration values in a healthy population is very low (101.4 ± 15.9 μg/ml) as compared to those of insulin (21-181 pmol/l) and C-peptide (0.4-1.7 nmol/l). Results of pilot studies indicate a clear correlation between IRAPs levels and insulin sensitivity. We therefore think that plasma IRAPs may be a direct marker of insulin sensitivity and that the quantitative determination of its plasma levels should allow large-scale screening of populations at risk for PD and T2D, thereby allow the enforcement of a preventive health policy aiming at efficiently reducing this epidemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Trocmé, Gonnet, Di Tommaso, Samouda, Cracowski, Cracowski, Lambert-Porcheron, Laville, Nobécourt, Gaddhab, Le Lay, Bohn, Poitou, Clément, Al-Mulla, Bitar and Bottari.)

Weight gain is often associated with the pleasure of eating food rich in calories. This idea is based on the findings that people with obesity showed increased neural activity in the reward and motivation systems of the brain in response to food cues. Such correlations, however, overlook the possibility that obesity may be associated with a metabolic state that impacts the functioning of reward and motivation systems, which in turn could be linked to reactivity to food and eating behaviour and weight gain. In a study involving 44 female participants [14 patients with obesity, aged 20-63 years (mean: 42, SEM: 3.2 years), and 30 matched lean controls, aged 22-60 years (mean: 37, SEM: 1.8 years)], we investigated how ventromedial prefrontal cortex seed-to-voxel resting-state connectivity distinguished between lean and obese participants at baseline. We used the results of this first step of our analyses to examine whether changes in ventromedial prefrontal cortex resting-state connectivity over 8 months could formally predict weight gain or loss. It is important to note that participants with obesity underwent bariatric surgery at the beginning of our investigation period. We found that ventromedial prefrontal cortex-ventral striatum resting-state connectivity and ventromedial-dorsolateral prefrontal cortex resting-state connectivity were sensitive to obesity at baseline. However, only the ventromedial prefrontal cortex-ventral striatum resting-state connectivity predicted weight changes over time using cross-validation, out-of-sample prediction analysis. Such an out-of-sample prediction analysis uses the data of all participants of a training set to predict the actually observed data in one independent participant in the hold-out validation sample and is then repeated for all participants. In seeking to explain the reason why ventromedial pre-frontal cortex-ventral striatum resting-state connectivity as the central hub of the brain's reward and motivational system may predict weight change over time, we linked weight loss surgery-induced changes in ventromedial prefrontal cortex-ventral striatum resting-state connectivity to surgery-induced changes in homeostatic hormone regulation. More specifically, we focussed on changes in fasting state systemic leptin, a homeostatic hormone signalling satiety, and inhibiting reward-related dopamine signalling. We found that the surgery-induced increase in ventromedial prefrontal cortex-ventral striatum resting-state connectivity was correlated with a decrease in fasting-state systemic leptin. These findings establish the first link between individual differences in brain connectivity in reward circuits in a more tonic state at rest, weight change over time and homeostatic hormone regulation., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objectives: Altered enteroendocrine cell (EEC) function in obesity and type 2 diabetes is not fully understood. Understanding the transcriptional program that controls EEC differentiation is important because some EEC types harbor significant therapeutic potential for type 2 diabetes., Methods: EEC isolation from jejunum of obese individuals with (ObD) or without (Ob) type 2 diabetes was obtained with a new method of cell sorting. EEC transcriptional profiles were established by RNA-sequencing in a first group of 14 Ob and 13 ObD individuals. EEC lineage and densities were studied in the jejunum of a second independent group of 37 Ob, 21 ObD and 22 non obese (NOb) individuals., Results: The RNA seq analysis revealed a distinctive transcriptomic signature and a decreased differentiation program in isolated EEC from ObD compared to Ob individuals. In the second independent group of ObD, Ob and NOb individuals a decreased GLP-1 cell lineage and GLP-1 maturation from proglucagon, were observed in ObD compared to Ob individuals. Furthermore, jejunal density of GLP-1-positive cells was significantly reduced in ObD compared to Ob individuals., Conclusions: These results highlight that the transcriptomic signature of EEC discriminate obese subjects according to their diabetic status. Furthermore, type 2 diabetes is associated with reduced GLP-1 cell differentiation and proglucagon maturation leading to low GLP-1-cell density in human obesity. These mechanisms could account for the decrease plasma GLP-1 observed in metabolic diseases.

Background and Objectives: Gene mutations within the leptin-melanocortin signaling pathway lead to severe early-onset obesity. Recently, a phase 2 trial evaluated new pharmacological treatment options with the MC4R agonist setmelanotide in patients with mutations in the genes encoding proopiomelanocortin (POMC) and leptin receptor (LEPR). During treatment with setmelanotide, changes in skin pigmentation were observed, probably due to off-target effects on the closely related melanocortin 1 receptor (MC1R). Here, we describe in detail the findings of dermatological examinations and measurements of skin pigmentation during this treatment over time and discuss the impact of these changes on patient safety., Methods: In an investigator-initiated, phase 2, open-label pilot study, 2 patients with loss-of-function POMC gene mutations and 3 patients with loss-of-function variants in LEPR were treated with the MC4R agonist setmelanotide. Dermatological examination, dermoscopy, whole body photographic documentation, and spectrophotometric measurements were performed at screening visit and approximately every 3 months during the course of the study., Results: We report the results of a maximum treatment duration of 46 months. Skin pigmentation increased in all treated patients, as confirmed by spectrophotometry. During continuous treatment, the current results indicate that elevated tanning intensity levels may stabilize over time. Lips and nevi also darkened. In red-haired study participants, hair color changed to brown after initiation of setmelanotide treatment., Discussion: Setmelanotide treatment leads to skin tanning and occasionally hair color darkening in both POMC- and LEPR-deficient patients. No malignant skin changes were observed in the patients of this study. However, the results highlight the importance of regular skin examinations before and during MC4R agonist treatment., (© 2021 S. Karger AG, Basel.)