Changes of the Concentration of Short-Chain Fatty Acids in the Intestines of Mice with Different Types of Obesity.

We studied the production of short-chain fatty acids (SCFA) by the intestinal microbiota in mice with obesity caused by a diet and a genetic defect in the leptin receptor gene. In mice, intestinal contents were examined and SCFA were quantitatively assayed by gas chromatography. SCFA concentration in the intestinal contents of mice with alimentary obesity model was significantly lower in the first phase of the experiment (day 14), and the change in their production in dynamics was fundamentally different from this process in the control group (standard diet). The dynamics of the concentration of these metabolites in the model of genetic obesity was similar to that in the control, but the production of SCFA was significantly reduced in mice with leptin resistance in the middle phase (day 60) of the experiment. These findings indicate that the production of SCFA is more influenced by the diet than by leptin resistance.

Body composition and obstructive sleep apnoea assessment in adult patients with Prader-Willi syndrome: a case control study.

INTRODUCTION: In Prader-Willi syndrome (PWS) adult patients, sleep-breathing disorders, especially obstructive sleep apnoea syndrome (OSAS), are very common, whose missed or delayed diagnosis can contribute to further increase cardiovascular morbidity and mortality. PURPOSE: The aim of this cross-sectional study was to evaluate differences in sleep-breathing parameters obtained by overnight cardiorespiratory polygraphy in 13 adult PWS patients and 13 individuals with non-syndromic obesity as controls matched by age, sex, and BMI. METHODS: In all subjects' anthropometric parameters, body composition using bioimpedance analysis and overnight cardiorespiratory monitoring parameters were obtained. RESULTS: Ten (76.9%) PWS patients were diagnosed with OSAS, most notably nine (69.2%) and one PWS (7.7%) with mild and severe OSAS, respectively. Compared with the control group, PWS patients had evidence of higher apnoea-hypopnea index (AHI) (p = 0.04) and oxyhaemoglobin desaturation index (ODI) (p = 0.009). However, no differences were found between the two groups regarding OSAS categories or diagnosis of nocturnal respiratory failure. In the PWS group, there were no significant correlations among AHI, ODI and hypoxemia index (T90) and anthropometric measurements, fat mass (FM), and FM percentage (%). Conversely, in the control group, the sleep-related respiratory indices evaluated correlated positively with BMI, waist circumference, FM and FM%. CONCLUSIONS: This study confirmed that AHI and ODI indices were worse in PWS than in age, sex and BMI-matched controls. The lack of their significant association with the anthropometric parameters and FM supported the existence of PWS-related mechanisms in OSAS pathophysiology that are independent of visceral obesity and FM.

Kisspeptin and the Genetic Obesity Interactome.

BACKGROUND: Kisspeptin (encoded by the KISS1 gene in humans) is an excitatory neuromodulatory peptide implicated in multiple homeostatic systems, including anti-oxidation, glucose homeostasis, nutrition, locomotion, etc. Therefore, in the current obesity epidemic, kisspeptin is gaining increasing interest as a research objective. AIM: To construct an updated interactome of genetic obesity, including the kisspeptin signal transduction pathway. METHODS: Kisspeptin and obesity-related genes or gene products were extracted from the biomedical literature, and a network of functional associations was created. RESULTS: The generated network contains 101 nodes corresponding to gene/gene products with known and/or predicted interactions. In this interactome, KISS1 and KISS1R are connected directly to the luteinizing hormone receptor (LHCGR), gonadotropin-releasing hormone receptor (GNRH1), and indirectly, through the latter, to proopiomelanocortin (POMC), glucagon, leptin (LEP), and/or pro-protein convertase subtilisin/kexin-type 1 (PCSK1), all of which are critically implicated in obesity disorders. CONCLUSIONS: Our updated obesidome includes kisspeptin and its connections to the genetic obesity signalosome with 12 major hubs: glucagon (GCG), insulin (INS), arginine vasopressin (AVP), G protein subunit beta 1 (GNB1) and proopiomelanocortin (POMC), melanocortin 4 receptor (MC4R), leptin (LEP), gonadotropin-releasing hormone 1 (GNRH1), adrenoceptor beta 2 and 3 (ADRB2-3), glucagon-like peptide 1 receptor (GLP1R), and melanocortin 3 receptor (MC3R) genes were identified as major "hubs" for genetic obesity, providing novel insight into the body's energy homeostasis.

Dietary Hemp Seeds More Effectively Attenuate Disorders in Genetically Obese Rats than Their Lipid Fraction.

BACKGROUND: Hemp seeds are rich in PUFAs and other bioactives that can attenuate the development of obesity-related disorders; however, the extent to which their lipid fraction is responsible for this effect is unknown. OBJECTIVE: We hypothesized that hemp seed or hemp oil supplementation can attenuate genetically determined disorders and that the former are more effective in doing so. METHODS: Lean and obese male Zucker rats, aged 8 wk, weighing 174 ± 4.2 g and 223 ± 3.8 g, respectively, were allocated to 4 groups. The lean (LC) and obese controls (OC) were fed a standard diet, whereas the other 2 obese groups were fed a modified diet in which hemp oil (4% diet; O + HO) or hemp seeds (12% diet; O + HS) were included. All diets had the same proportions of protein (18%), fat (8%), and fiber (5%) and a similar carbohydrate proportion (∼52%). Diets fed to O + HO and O + HS had similar fatty acid profiles. After 4 wk, markers of gut and liver function, antioxidant status, and lipid metabolism were measured. RESULTS: The total SCFA concentration in the cecal digesta was lower in OC (64.8 ± 4.21 µmol/g) compared with LC (78.1 ± 2.83 µmol/g) (P ≤ 0.05), whereas it was greater in O + HS (89 ± 4.41 µmol/g) compared with LC, OC, and O + HO (69.7 ± 2.68 µmol/g) (P ≤ 0.05). Plasma total cholesterol was greater in OC (6.20 ± 0.198 mmol/L) and O + HO (5.60 ± 0.084 mmol/L) compared with LC (2.71 ± 0.094 mmol/L) (P ≤ 0.05); in O + HS, the concentration did not differ from the other groups (5.16 ± 0.278 mmol/L). The liver cholesterol concentration was greater in OC (1.79 ± 0.379 mg/g) compared with the other groups (1.28-1.43 mg/g) (P ≤ 0.05). Hepatic expression of peroxisome proliferator-activated receptor γ was lower in OC (11.9 ± 0.93 units) compared with LC (17.3 ± 1.3 units) (P ≤ 0.05), whereas it was greater in O + HS (19.2 ± 1.04 units) compared with OC and O + HO (14.0 ± 1.33 units) (P ≤ 0.05). CONCLUSIONS: Dietary hemp seeds more effectively attenuate metabolic disorders in genetically obese rats than the oil extracted from them, which suggests that the lipid fraction is only partly responsible for these effects.

Genetic obesity: next-generation sequencing results of 1230 patients with obesity.

BACKGROUND: Obesity is a global and severe health problem. Due to genetic heterogeneity, the identification of genetic defects in patients with obesity can be time consuming and costly. Therefore, we developed a custom diagnostic targeted next-generation sequencing (NGS)-based analysis to simultaneously identify mutations in 52 obesity-related genes. The aim of this study was to assess the diagnostic yield of this approach in patients with suspected genetic obesity. METHODS: DNA of 1230 patients with obesity (median BMI adults 43.6 kg/m2; median body mass index-SD children +3.4 SD) was analysed in the genome diagnostics section of the Department of Genetics of the UMC Utrecht (The Netherlands) by targeted analysis of 52 obesity-related genes. RESULTS: In 48 patients pathogenic mutations confirming the clinical diagnosis were detected. The majority of these were observed in the MC4R gene (18/48). In an additional 67 patients a probable pathogenic mutation was identified, necessitating further analysis to confirm the clinical relevance. CONCLUSIONS: NGS-based gene panel analysis in patients with obesity led to a definitive diagnosis of a genetic obesity disorder in 3.9% of obese probands, and a possible diagnosis in an additional 5.4% of obese probands. The highest yield was achieved in a selected paediatric subgroup, establishing a definitive diagnosis in 12 out of 164 children with severe early onset obesity (7.3%). These findings give a realistic insight in the diagnostic yield of genetic testing for patients with obesity and could help these patients to receive (future) personalised treatment.

A cafeteria diet triggers intestinal inflammation and oxidative stress in obese rats.

The gastrointestinal alterations associated with the consumption of an obesogenic diet, such as inflammation, permeability impairment and oxidative stress, have been poorly explored in both diet-induced obesity (DIO) and genetic obesity. The aim of the present study was to examine the impact of an obesogenic diet on the gut health status of DIO rats in comparison with the Zucker (fa/fa) rat leptin receptor-deficient model of genetic obesity over time. For this purpose, female Wistar rats (n 48) were administered a standard or a cafeteria diet (CAF diet) for 12, 14·5 or 17 weeks and were compared with fa/fa Zucker rats fed a standard diet for 10 weeks. Morphometric variables, plasma biochemical parameters, myeloperoxidase (MPO) activity and reactive oxygen species (ROS) levels in the ileum were assessed, as well as the expressions of proinflammatory genes (TNF-α and inducible nitric oxide synthase (iNOS)) and intestinal permeability genes (zonula occludens-1, claudin-1 and occludin). Both the nutritional model and the genetic obesity model showed increased body weight and metabolic alterations at the final time point. An increase in intestinal ROS production and MPO activity was observed in the gastrointestinal tracts of rats fed a CAF diet but not in the genetic obesity model. TNF-α was overexpressed in the ileum of both CAF diet and fa/fa groups, and ileal inflammation was associated with the degree of obesity and metabolic alterations. Interestingly, the 17-week CAF group and the fa/fa rats exhibited alterations in the expressions of permeability genes. Relevantly, in the hyperlipidic refined sugar diet model of obesity, the responses to chronic energy overload led to time-dependent increases in gut inflammation and oxidative stress.

Interactome of Obesity: Obesidome : Genetic Obesity, Stress Induced Obesity, Pathogenic Obesity Interaction.

Obesity is a chronic disease of increasing prevalence reaching epidemic proportions. Genetic defects as well as epigenetic effects contribute to the obesity phenotype. Investigating gene (e.g. MC4R defects)-environment (behavior, infectious agents, stress) interactions is a relative new field of great research interest. In this study, we have made an effort to create an interactome (henceforth referred to as "obesidome"), where extrinsic stressors response, intrinsic predisposition, immunity response to inflammation and autonomous nervous system implications are integrated. These pathways are presented in one interactome network for the first time. In our study, obesity-related genes/gene products were found to form a complex interactions network.

High Prevalence of Positive Genetic Obesity Variants in Postoperative Bariatric Surgery Patients with Weight Regain Presenting for Medical Obesity Intervention.

INTRODUCTION: Genetic obesity susceptibility in postoperative bariatric surgery weight regain (PBSWR) remains largely unexplored. METHODS: A retrospective case series of adult (N = 27) PBSWR patients who had undergone genetic obesity testing was conducted between Sept. 2020 and March 2022. PRIMARY OUTCOME: frequency of genetic variants in patients experiencing weight regain following bariatric surgery. SECONDARY OUTCOMES: prevalence of obesity-related comorbidities, nadir BMI achieved post-bariatric surgery, and percent total body weight loss (%TBWL) achieved with obesity pharmacotherapies. RESULTS: Heterozygous mutations were identified in 22 (81%) patients, with the most prevalent mutations occurring in CEP290, RPGR1P1L, and LEPR genes (3 patients each). Median age was 56 years (interquartile range (IQR) 46.8-65.5), 88% female. Types of surgery were 67% RYGB, 19% SG, 4% gastric band, and 13% revisions. Median nadir BMI postoperatively was 34.0 kg/m2 (IQR 29.0-38.5). A high prevalence of metabolic derangements was noted; patients presented median 80 months (IQR 39-168.5) postoperative for medical weight management with 40% weight regain. BMI at initiation of anti-obesity medication (AOMs) was 41.7 kg/m2 (36.8-44.4). All received AOM and required at least 3 AOMs for weight regain. Semaglutide (N = 21), topiramate (N = 14), and metformin (N = 12) were most prescribed. Median %TBWL for the cohort at the first, second, and third visit was 1.7, 5.0, and 6.5 respectively. Fourteen (52%) achieved 5%TBWL, 10 (37%) achieved 10%TBWL, and 4 (15%) achieved 15%TBWL with combination AOMs and supervised medical intervention. CONCLUSION: An unusually high prevalence of genetic obesity variants in PBSWR was found, warranting further research.

Treatment with liraglutide or naltrexone-bupropion in patients with genetic obesity: a real-world study.

Background: Rare genetic obesity commonly features early-onset obesity, hyperphagia, and therapy-resistance to lifestyle interventions. Pharmacotherapy is often required to treat hyperphagia and induce weight loss. We describe clinical outcomes of glucagon-like peptide-1 analogue liraglutide or naltrexone-bupropion treatment in adults with molecularly confirmed genetic obesity (MCGO) or highly suspected for genetic obesity without definite diagnosis (HSGO). Methods: We conducted a real-world cohort study at the Obesity Center CGG at Erasmus University Center, Rotterdam, Netherlands, between March 19, 2019, and August 14, 2023. All patients with MCGO and HSGO who were treated with either liraglutide or naltrexone-bupropion were included. Liraglutide 3 mg and naltrexone-bupropion were administered according to the manufacturer's protocol. Treatment evaluation occurred short-term, after 12 weeks on maximum or highest-tolerated dose, preceded by the 4-5 week dose escalation phase. Differences in anthropometrics, body composition, metabolic markers, self-reported appetite, eating behaviour, and quality of life (QoL) were evaluated. Findings: Ninety-eight adults were included in the analysis: 23 patients with MCGO and 75 patients with HSGO, with median BMI of 42.0 kg/m2 (IQR 38.7-48.2) and 43.7 kg/m2 (IQR 38.0-48.7), respectively. After liraglutide treatment, median weight at evaluation significantly decreased compared to baseline in both groups: -4.7% (IQR -6.0 to -1.5) in patients with MCGO and -5.2% (IQR -8.1 to -3.5) in patients with HSGO. Additionally, improvements were observed in appetite, fat mass, fasting glucose, and HbA1c in both patients with MCGO and with HSGO. Patients with HSGO also reported significant improvements in several domains of QoL and eating behaviour. In patients with MCGO and HSGO treated with naltrexone-bupropion, mean weight at evaluation significantly differed from baseline: -5.2% ± 5.8 in patients with MCGO and -4.4% ± 4.7 in patients with HSGO. Appetite, fat mass, and waist circumference significantly decreased in both groups. Obesity-related comorbidities improved in significant proportions of patients treated with liraglutide or naltrexone-bupropion. Interpretation: In conclusion, our short-term findings show potential of liraglutide and naltrexone-bupropion as treatment options for adults with (a clinical phenotype of) genetic obesity. Funding: MB, EvdA, and EvR are supported by the Elisabeth Foundation, a non-profit foundation supporting academic obesity research.

GNB1 and obesity: Evidence for a correlation between haploinsufficiency and syndromic obesity.

Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1 encephalopathy caused by haploinsufficiency have been reported that also show a Prader-Willi-like phenotype of childhood hypotonia and severe obesity. Here we present three new cases from our expert centre for genetic obesity in which GNB1 truncating and splice variants, probably leading to haploinsufficiency, were identified. They all have obesity, hyperphagia and intellectual deficit. The clinical cases and their weight courses are presented, together with a review of all 68 published cases with GNB1 encephalopathy. Information on weight was not mentioned in most of these articles, so we contacted authors for additional clinical information on weight status and hyperphagia. Of the 42 patients whose weight status we could determine, obesity was present in 8 patients (19%). Obesity is significantly over-represented in the group with truncating and splicing variants. In this group, we see an obesity prevalence of 75%. Since GNB1 has been linked to several key genes in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure, our data support the potential association between GNB1 haploinsufficiency and genetic obesity. We also suggest GNB1 is a candidate gene for the known obesity phenotype of the 1p36 microdeletion syndrome given this chromosomal region includes the GNB1 gene. Knowledge of an additional obesity phenotype is important for prognosis, early interventions against obesity and awareness when prescribing weight-inducing medication.

IMPROVE 2022 International Meeting on Pathway-Related Obesity: Vision of Excellence.

Nearly 90 clinicians and researchers from around the world attended the first IMPROVE 2022 International Meeting on Pathway-Related Obesity. Delegates attended in person or online from across Europe, Argentina and Israel to hear the latest scientific and clinical developments in hyperphagia and severe, early-onset obesity, and set out a vision of excellence for the future for improving the diagnosis, treatment, and care of patients with melanocortin-4 receptor (MC4R) pathway-related obesity. The meeting co-chair Peter Kühnen, Charité Universitätsmedizin Berlin, Germany, indicated that change was needed with the rapidly increasing prevalence of obesity and the associated complications to improve the understanding of the underlying mechanisms and acknowledge that monogenic forms of obesity can play an important role, providing insights that can be applied to a wider group of patients with obesity. World-leading experts presented the latest research and led discussions on the underlying science of obesity, diagnosis (including clinical and genetic approaches such as the role of defective MC4R signalling), and emerging clinical data and research with targeted pharmacological approaches. The aim of the meeting was to agree on the questions that needed to be addressed in future research and to ensure that optimised diagnostic work-up was used with new genetic testing tools becoming available. This should aid the planning of new evidence-based treatment strategies for the future, as explained by co-chair Martin Wabitsch, Ulm University Medical Center, Germany.

Blind to the perils of pursuing food: Behaviors of individuals with Smith-Magenis Syndrome.

Purpose: Discrepancies exist between the need to lock food away and satiety scores in the Smith-Magenis syndrome (SMS) population. This study sought to uncover food-related behaviors within this unique group of individuals. Methods: Caregivers (N = 24) representing 21 individuals with SMS, recruited from the Parents and Researchers Interested in SMS national meeting and social media platforms, participated in semistructured interviews. Interviews were digitally recorded, transcribed verbatim, coded, and analyzed using hybrid thematic analysis. Results: This study identified a global theme of "Blind to the perils while pursuing their goals," supported by 5 organizing themes: (1) Biology-impacting behaviors, (2) Need for personalized strategies, (3) Controlling food experiences, (4) Need for parents to orchestrate life, and (5) Surprising resourcefulness. Subthemes within these organizing themes highlighted that individuals with SMS have unique food-related behaviors and often fixate on certain types of foods. Their constant obsession with food for many of them is driven by hunger, obsessive characteristics, a need for autonomy, and a need for fairness. Caregivers must put multiple guardrails in place and remain constantly vigilant to prevent overeating in these individuals. Conclusion: Individuals with SMS often perseverate on food and display unique food-related behaviors. Treating obesity in this population is likely to be ineffective without multicomponent, individualized strategies. Additionally, research in this population will likely require targeted instruments for the SMS population to more clearly define the underlying etiologies and to track changes over time in therapeutic trials.

Syndromic and Monogenic Obesity: New Opportunities Due to Genetic-Based Pharmacological Treatment.

Obesity is a significant health problem with a continuously increasing prevalence among children and adolescents that has become a modern pandemic during the last decades. Nowadays, the genetic contribution to obesity is well-established. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles, and meta-analyses regarding the genetics of obesity and current pharmacological treatment, published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Our research was conducted between December 2022 and December 2023. We used the terms "obesity", "genetics", "monogenic", "syndromic", "drugs", "autosomal dominant", "autosomal recessive", "leptin-melanocortin pathway", and "children" in different combinations. Recognizing the genetic background in obesity can enhance the effectiveness of treatment. During the last years, intense research in the field of obesity treatment has increased the number of available drugs. This review analyzes the main categories of syndromic and monogenic obesity discussing current data on genetic-based pharmacological treatment of genetic obesity and highlighting the necessity that cases of genetic obesity should follow specific, pharmacological treatment based on their genetic background.

Genetic Contributors to Obesity.

Genetic forms of obesity contribute to ∼7% of severe obesity in children and adolescents. The exact global prevalence of monogenic and syndromic forms of obesity is not well established, most likely due to missed or delayed diagnosis. The challenge in determining the prevalence can be attributed to the lack of consensus on identifying and evaluating symptoms of genetic defects in a timely manner and hence a vastly undertested patient population. Further large-scale and long-term studies are needed to advance the understanding of this unique phenotype of obesity and effective treatment options."

Metabolomic Study of Aging in fa/fa Rats: Multiplatform Urine and Serum Analysis.

Zucker fatty (fa/fa) rats represent a well-established and widely used model of genetic obesity. Because previous metabolomic studies have only been published for young fa/fa rats up to 20 weeks of age, which can be considered early maturity in male fa/fa rats, the aim of our work was to extend the metabolomic characterization to significantly older animals. Therefore, the urinary profiles of obese fa/fa rats and their lean controls were monitored using untargeted NMR metabolomics between 12 and 40 weeks of age. At the end of the experiment, the rats were also characterized by NMR and LC-MS serum analysis, which was supplemented by a targeted LC-MS analysis of serum bile acids and neurotransmitters. The urine analysis showed that most of the characteristic differences detected in young obese fa/fa rats persisted throughout the experiment, primarily through a decrease in microbial co-metabolite levels, the upregulation of the citrate cycle, and changes in nicotinamide metabolism compared with the age-related controls. The serum of 40-week-old obese rats showed a reduction in several bile acid conjugates and an increase in serotonin. Our study demonstrated that the fa/fa model of genetic obesity is stable up to 40 weeks of age and is therefore suitable for long-term experiments.

Obesity Characteristics Are Poor Predictors of Genetic Mutations Associated with Obesity.

BACKGROUND: The genetic contribution to obesity is substantial and may underpin the altered pathophysiology. One such pathway involves melanocortin signaling in the hypothalamus. Genetic variants can cause dysregulation in the central melanocortin pathway that can result in early onset of hyperphagia and obesity. Clinically identifying patients who are at risk of known genetic mutations is challenging. The main purpose of this study was to identify associations between the clinico-demographical characteristics and the presence of a genetic mutation associated with obesity. METHODS: We tested samples from 238 adult patients with class III obesity between October 2021 to February 2023 using next-generation sequencing (NGS) (Illumina, NovaSeq 6000 Sequencing System). The results were classified as "no variant identified" or "variant identified". RESULTS: 107 patients (45%) had one or more gene mutation in the leptin-melanocortin pathway. All variants were heterozygous. The patients with a gene mutation had a BMI of 48.4 ± 0.8 kg/m2 (mean ± SEM), and those without a gene mutation had a BMI of 49.4 ± 0.7 kg/m2 (p = 0.4). The mean age of onset of obesity in patients with a gene mutation was 13.9 ± 1.3 years and for those without gene mutations was 11.5 ± 0.9 years (p = 0.1). The incidence of hyperphagia as a child was also not predictive (p = 0.4). CONCLUSIONS: Gene mutations associated with obesity in patients with a BMI > 40 kg/m2 are common. However, a patient's BMI, age of onset of obesity, or age of onset of hyperphagia did not help to differentiate which patients may be more likely to have genetic mutations associated with obesity.

Current Treatments for Patients with Genetic Obesity

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.

Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet-Biedl syndrome: phase 3 trial results.

BACKGROUND: Bardet-Biedl syndrome is a rare genetic disease associated with hyperphagia and early-onset, severe obesity. There is limited evidence on how hyperphagia and obesity affect health-related quality of life in patients with Bardet-Biedl syndrome, and on how management of these symptoms may influence disease burden. This analysis evaluated changes in health-related quality of life in adults and children with Bardet-Biedl syndrome in a Phase 3 trial following 1 year of setmelanotide treatment (ClinicalTrials.gov identifier: NCT03746522). METHODS: Patients with Bardet-Biedl syndrome and obesity received 52 weeks of treatment with setmelanotide and completed various self-reported health-related quality of life measures. Patients aged < 18 years or their caregiver completed the Pediatric Quality of Life Inventory (PedsQL; meaningful improvement, 4.4-point change); adults aged ≥ 18 years completed the Impact of Weight on Quality of Life Questionnaire-Lite (IWQOL-Lite; meaningful improvement range, 7.7-12-point change). Descriptive outcomes were reported in patients with data both at active treatment baseline and after 52 weeks of treatment. RESULTS: Twenty patients (< 18 years, n = 9; ≥ 18 years, n = 11) reported health-related quality of life at baseline and 52 weeks. For children and adolescents, PedsQL score mean change from baseline after 52 weeks was + 11.2; all patients with PedsQL impairment at baseline (n = 4) experienced clinically meaningful improvement. In adults, IWQOL-Lite score mean change from baseline was + 12.0. Of adults with IWQOL-Lite impairment at baseline (n = 8), 62.5% experienced clinically meaningful improvement. In adults, IWQOL-Lite score was significantly correlated with changes in percent body weight (P = 0.0037) and body mass index (P = 0.0098). CONCLUSIONS: After 1 year of setmelanotide, patients reported clinically meaningful improvements across multiple health-related quality of life measures. This study highlights the need to address the impaired health-related quality of life in Bardet-Biedl syndrome, and supports utility of setmelanotide for reducing this burden. Trial Registration NCT03746522. Registered November 19, 2018, https://clinicaltrials.gov/ct2/show/NCT03746522 .

A novel pathogenic variant in MRAP2 in an obese patient with successful outcome of bariatric surgery.

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_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.

The Narrative of a Patient with Leptin Receptor Deficiency: Personalized Medicine for a Rare Genetic Obesity Disorder.

Leptin receptor (LEPR) deficiency is a rare genetic disorder that affects the body's ability to regulate appetite and weight. For patients and their families, the disorder seriously disrupts daily life; however, little is published about this impact. We here report the experiences of a 10.5-year-old girl with leptin receptor deficiency and her family. The diagnosis of this rare genetic obesity had a deep impact on the life of the child and her family. It led to a better understanding of the cause of the impaired appetite regulation and early-onset obesity with subsequently less judgement by others and improved cooperation of their social network and school on maintaining a healthy lifestyle for this girl. A strict eating regimen and lifestyle measures resulted in the first year after diagnosis in a significantly decreased body mass index (BMI), followed by BMI stabilization, still categorized as obesity class three. However, the troublesome challenge of how to manage the disruptive behaviour due to hyperphagia remained. Eventually, due to treatment with targeted pharmacotherapy, i.e., melanocortin-4 receptor agonists, her BMI continued to decrease due to resolving hyperphagia. The daily routine of the family and the atmosphere at home positively changed as they were no longer dominated by the food-focused behaviour of the child and the adherence to the strict eating regimen. This case report demonstrates the importance and impact of a rare genetic obesity disorder diagnosis in a family. Additionally, it highlights the value of genetic testing in patients with a high suspicion of a genetic obesity disorder as it can eventually lead to personalized treatment, such as guidance by specialized healthcare professionals and educated caregivers or targeted pharmacotherapy.