👤 Peter Kühnen

A total of 150 clinicians and researchers representing 19 countries came together in person and online to participate in the highly anticipated 2nd International Meeting on Pathway-Related Obesity: Vision & Evidence (IMPROVE), held on 13-15 December 2023 in Paris, France. Building on the success of the inaugural event in 2022, this gathering served as a pivotal platform for attendees to delve into the latest scientific and clinical developments in hyperphagia and early-onset obesity caused by rare melanocortin-4 receptor (MC4R) pathway disease. The central objective of the meeting was to explore the complexities of MC4R pathway-related diseases and generate opportunities for collaborative dialogue among delegates for the advancement of this field. The event unfolded across three distinct sessions, with a dedicated focus on monogenic MC4R pathway disease, Bardet-Biedl syndrome (BBS) and hypothalamic obesity, together with a discussion on the future of the field. Additionally, the agenda featured three insightful workshops designed to facilitate in-depth discussions. One workshop focused on the genetics of monogenic MC4R pathway diseases, another scrutinised the genetics of BBS and the final workshop examined patient management through the exploration of clinical cases. As we reflect on the wealth of information disseminated and the collaborative spirit that permeated the meeting, it becomes clear that IMPROVE 2023 was not merely an assembly of professionals; it was a forum where the future of research in rare MC4R pathway diseases and patient care took centre stage. Here, we encapsulate the key insights, discussions, and initiatives that emerged from this important meeting. Show less

Hyperphagia is a hallmark of both congenital and acquired rare melanocortin-4 receptor (MC4R) pathway diseases. Currently, the medical community has no standard treatment guidelines or approach to establishing treatment benefit. This narrative review discusses current understandings of the pathophysiology, burden, and treatment of hyperphagia and summarizes findings from a systematic literature review of validated instruments for assessing the response to hyperphagia treatment. Hyperphagia can result from dysfunction within, or damage impacting, hypothalamic pathways including the MC4R pathway, a key regulator of energy balance. The burden of hyperphagia is substantial, with negative effects experienced across physiologic, emotional, and social domains. Approaches for hyperphagia management include environmental control, lifestyle intervention, pharmacotherapy, neurocognitive approaches, and neurostimulation. There are varied approaches to determine treatment response; however, standard methodology has not been determined and largely relies on questionnaires. Studies of rare MC4R pathway diseases have improved understanding of the etiology of hyperphagia and established the need for indication-specific treatment. Targeted treatments are limited, and methods for determining treatment efficacy are varied. There is a need for consensus guidelines to establish a standard approach for the management of hyperphagia and related assessment of treatment response to improve patient morbidity. Show less

Monogenic defects in the leptin-melanocortin pathway are associated with hyperphagia and severe, early-onset obesity. Early childhood growth patterns in height, weight, and BMI, might serve as phenotypic markers for specific genetic disorders; however, reliable data are scarce. This study aimed to evaluate the natural history of height, weight, and BMI in early childhood in a large European group of individuals with monogenic obesity. This multicentre observational study analysed height, weight, and BMI from birth to age 5 years in individuals diagnosed with biallelic (likely) pathogenic LEP, LEPR, POMC, PCSK1, or MC4R variants or monoallelic (likely) pathogenic MC4R variants from six European centres (Berlin and Ulm, Germany; Cambridge, UK; Madrid, Spain; Paris, France; Rotterdam, Netherlands). All patient data up to May 31, 2022 were included in this analysis. All individuals had at least two height or weight measurements between birth and age 5 years. Early childhood growth trajectories were compared with those of control children with obesity without a known genetic cause, following a negative next-generation sequencing panel. Diagnostic performance of BMI as a predictor test for monogenic obesity was also evaluated. We included 147 individuals with monogenic obesity. From the age of 6 months onwards, children with biallelic variants (n=88, 55% female vs 45% male) had substantially higher BMIs than those with monoallelic MC4R variants (n=59, 53% female vs 47% male) and control children (n=113, 59% female vs 41% male). Children with biallelic LEP, LEPR, and MC4R variants showed a steep BMI increase during the first year of life, followed by a plateau until age 5 years, whereas those with biallelic POMC variants did not plateau. Accelerated linear growth was only observed in children with biallelic MC4R variants starting from age 1 year. The optimal BMI cut-off for distinguishing individuals with biallelic variants from control individuals was identified at age 2 years, with a test positivity cutoff of 24·0 kg/m This study identified characteristic early childhood BMI trajectories for different forms of monogenic obesity. From age 6 months onwards, individuals with biallelic variants can be distinguished from those with monoallelic variants and common obesity. A BMI ≥24 kg/m Federal Ministry of Education and Research as part of the German Center for Child and Adolescent Health, German Research Foundation, Spanish Ministry of Health, The Wellcome Trust, Botnar Fondation, Leducq Foundation, National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, and NIHR Senior Investigator Award. Show less

Hyperphagia is a condition associated with rare obesity-related diseases, presenting as a pathologic, insatiable hunger accompanied by abnormal food-seeking behaviors. In October 2023, a group of researchers and clinicians with expert knowledge on hyperphagia convened at the annual ObesityWeek meeting to discuss the need for a unified definition of hyperphagia and key items necessary to improve the identification, assessment, and treatment of hyperphagia in patients with melanocortin 4 receptor (MC4R) pathway-associated diseases. The definition of hyperphagia proposed by this group is a pathologic, insatiable hunger accompanied by abnormal food-seeking behaviors. Suggested methods to accurately identify patients with hyperphagia include increased physician and parent/caregiver education and standardized efficient screening procedures for use in the clinic. The etiology of hyperphagia as related to abnormal MC4R signaling was also reviewed and proposed as a central cause of the condition across several underlying diseases. Given this potential unified underlying pathology, the expert group recommends that patients with hyperphagia undergo genetic testing and that treatment include comprehensive weight-management strategies incorporating lifestyle and pharmacotherapies targeted at addressing hyperphagia. Show less

The melanocortin-4 receptor (MC4R) is a key player in the hypothalamic leptin-melanocortin pathway that regulates satiety and hunger. MC4R belongs to the G protein-coupled receptors (GPCRs), which are known to form heterodimers with other membrane proteins, potentially modulating receptor function or characteristics. Like MC4R, thyroid hormones (TH) are also essential for energy homeostasis control. TH transport across membranes is facilitated by the monocarboxylate transporter 8 (MCT8), which is also known to form heterodimers with GPCRs. Based on the finding in single-cell RNA-sequencing data that both proteins are simultaneously expressed in hypothalamic neurons, we investigated a putative interplay between MC4R and MCT8. We developed a novel staining protocol utilizing a fluorophore-labeled MC4R ligand and demonstrated a co-localization of MC4R and MCT8 in human brain tissue. Using in vitro assays such as BRET, IP1, and cAMP determination, we found that MCT8 modulates MC4R-mediated phospholipase C activation but not cAMP formation via a direct interaction, an effect that does not require a functional MCT8 as it was not altered by a specific MCT8 inhibitor. This suggests an extended functional spectrum of MCT8 as a GPCR signaling modulator and argues for the investigation of further GPCR-protein interactions with hitherto underrepresented physiological functions. Show less

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. Show less

Rare homozygous or biallelic variants in To characterize the historical weight trajectory in these patients. This analysis included data from 2 pivotal single-arm, open-label, Phase 3 trials (NCT02896192, NCT03287960). These were multicenter trials. Patients had obesity due to POMC/PCSK1 or LEPR deficiency. During the trial, patients were treated with setmelanotide. Historical data on measured weight and height were obtained during screening. A total of 17 patients (POMC, n = 8; PCSK1, n = 1; LEPR, n = 8) with historical weight and height data were included in this analysis. Before setmelanotide treatment, patients with obesity due to POMC/PCSK1 or LEPR deficiency were above the 95th percentile for weight throughout childhood, demonstrated continuous weight gain, and did not show long-term weight loss upon interventions (eg, diet, surgery, exercise). Setmelanotide treatment attenuated weight and body mass index trajectories over the observation period of 1 year. In patients with POMC, PCSK1, or LEPR deficiency, traditional interventions for weight loss had limited impact on the trajectory of severe early-onset obesity. However, setmelanotide treatment attenuated weight and body mass index trajectories and led to weight loss associated with health benefits in most individuals. Show less

The increasing number of obese children and adolescence is a major problem in health-care systems. Currently, the gold standard for the treatment of these patients with obesity is a multicomponent lifestyle intervention. Unfortunately, this strategy is not leading to a substantial and long-lasting weight loss in the majority of patients. This is the reason why there is an urgent need to establish new treatment strategies for children and adolescents with obesity to reduce the risk for the development of any comorbidities like cardiovascular diseases or diabetes mellitus type 2. In this review, we outline available pharmacological therapeutic options for children and compare the available study data with the outcome of conservative treatment approaches. We discussed, in detail, how knowledge about underlying molecular mechanisms might support the identification of effective antiobesity drugs in the future and in which way this might modulate current treatment strategies to support children and adolescence with obesity to lose body weight. Show less

The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R-Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor-Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs. Show less

In a new paper, Wade et al. (2021) analyzed the frequency of MC4R loss-of-function (LoF) mutations in a population-based Avon Longitudinal Study of Parents and Children. The frequency was 1 in 337 and the authors showed that MC4R LoF variants significantly correlated with increased body weight and fat mass in children and adults (cumulating in additional 17.76 kg weight in adulthood). Hence, the authors provide evidence that MC4R LoF variants are more common than previously expected. Show less

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. To examine bariatric surgery as a therapeutic option for patients with genetic obesity. Three major academic, specialized medical centers. 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). 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. 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. Show less

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. 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. 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. 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. Show less

Pro-opiomelanocortin (POMC) and the melanocortin-4 receptor (MC4R) play a pivotal role in the leptin-melanocortin pathway. Mutations in these genes lead to monogenic types of obesity due to severe hyperphagia. In addition to dietary-induced obesity, a cardiac phenotype without hypertrophy has been identified in MC4R knockout mice. We aimed to characterize cardiac morphology and function as well as tissue Na+ content in humans with mutations in POMC and MC4R genes. A cohort of 42 patients (5 patients with bi-allelic POMC mutations, 6 heterozygous MC4R mutation carriers, 19 obese controls without known monogenic cause, and 12 normal weight controls) underwent cardiac magnetic resonance (CMR) imaging and 23Na-MRI. Monogenic obese patients with POMC or MC4R mutation respectively had a significantly lower left ventricular mass/body surface area (BSA) than nonmonogenic obese patients. Left ventricular end-diastolic volume/BSA was significantly lower in POMC- and MC4R-deficient patients than in nonmonogenic obese patients. Subcutaneous fat and skin Na+ content was significantly higher in POMC- and MC4R-deficient patients than in nonmonogenic obese patients. In these compartments, the water content was significantly higher in patients with POMC and MC4R mutation than in control groups. Patients with POMC or MC4R mutations carriers had a lack of transition to hypertrophy, significantly lower cardiac muscle mass/BSA, and stored more Na+ within the subcutaneous fat tissue than nonmonogenic obese patients. The results point towards the role of the melanocortin pathway for cardiac function and tissue Na+ storage and the importance of including cardiologic assessments into the diagnostic work-up of these patients. Show less

The melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, plays a part in bodyweight regulation. Severe early-onset obesity can be caused by biallelic variants in genes that affect the MC4R pathway. We report the results from trials of the MC4R agonist setmelanotide in individuals with severe obesity due to either pro-opiomelanocortin (POMC) deficiency obesity or leptin receptor (LEPR) deficiency obesity. These single-arm, open-label, multicentre, phase 3 trials were done in ten hospitals across Canada, the USA, Belgium, France, Germany, the Netherlands, and the UK. Participants aged 6 years or older with POMC or LEPR deficiency obesity received open-label setmelanotide for 12 weeks. Participants with at least 5 kg weight loss (or ≥5% if weighing <100 kg at baseline) entered an 8-week placebo-controlled withdrawal sequence (including 4 weeks each of blinded setmelanotide and placebo treatment) followed by 32 additional weeks of open-label treatment. The primary endpoint, which was assessed in participants who received at least one dose of study medication and had a baseline assessment (full analysis set), was the proportion of participants with at least 10% weight loss compared with baseline at approximately 1 year. A key secondary endpoint was mean percentage change in the most hunger score of the 11-point Likert-type scale at approximately 1 year on the therapeutic dose, which was assessed in a subset of participants aged 12 years or older in the full analysis set who demonstrated at least 5 kg weight loss (or ≥5% in paediatric participants if baseline bodyweight was <100 kg) over the 12-week open-label treatment phase and subsequently proceeded into the placebo-controlled withdrawal sequence, regardless of later disposition. These studies are registered with ClinicalTrials.gov, NCT02896192 and NCT03287960. Between Feb 14, 2017, and Sept 7, 2018, ten participants were enrolled in the POMC trial and 11 participants were enrolled in the LEPR trial, and included in the full analysis and safety sets. Eight (80%) participants in the POMC trial and five (45%) participants in the LEPR trial achieved at least 10% weight loss at approximately 1 year. The mean percentage change in the most hunger score was -27·1% (n=7; 90% CI -40·6 to -15·0; p=0·0005) in the POMC trial and -43·7% (n=7; -54·8 to -29·1; p<0·0001) in the LEPR trial. The most common adverse events were injection site reaction and hyperpigmentation, which were reported in all ten participants in the POMC trial; nausea was reported in five participants and vomiting in three participants. In the LEPR trial, the most commonly reported treatment-related adverse events were injection site reaction in all 11 participants, skin disorders in five participants, and nausea in four participants. No serious treatment-related adverse events occurred in both trials. Our results support setmelanotide for the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency. Rhythm Pharmaceuticals. Show less

The leptin melanocortin signaling pathway is playing a pivotal role for body weight regulation. Genetic defects within this cascade are leading to severe hyperphagia and early onset obesity. In most cases, due to persistent hyperphagia the affected patients are not able to stabilize body weight for a longer period of time with conservative treatment strategies based on lifestyle interventions. Therefore, it is of importance to implement alternative treatment options for these patients. This review provides an overview about the published pharmacological treatment attempts in respect to monogenic forms of obesity and summarizes recent research progress about the role of MC4R signaling and POMC derivatives for body weight regulation. Show less

The melanocortin 4 receptor (MC4R) is a key player in hypothalamic weight regulation and energy expenditure as part of the leptin-melanocortin pathway. Mutations in this G protein coupled receptor (GPCR) are the most common cause for monogenetic obesity, which appears to be mediated by changes in the anorectic action of MC4R via G Show less

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that augments insulin secretion in pancreatic β-cells via its glucose-dependent insulinotropic polypeptide receptor (GIPR). Recent genome-wide association studies identified a single nucleotide variant (SNV) in the GIPR encoding gene (GIPR), rs1800437, that is associated with obesity and insulin resistance. In the present study, we tested whether GIPR variants contribute to obesity and disturb glucose homeostasis or diabetes in specific patient populations. Exon sequencing of GIPR was performed in 164 children with obesity and insulin resistance and in 80 children with paediatric-onset diabetes of unknown origin. The Study of Health in Pomerania (SHIP) cohort, comprising 8320 adults, was screened for the GIPR variant Arg217Leu. GIPR variants were expressed in COS-7 cells and cAMP production was measured upon stimulation with GIP. Cell surface expression was determined by ELISA. Protein homology modelling of the GIPR variants was performed to extract three-dimensional information of the receptor. A heterozygous missense GIPR variant Arg217Leu (rs200485112) was identified in a patient of Asian ancestry. Functional characterization of Arg217Leu revealed reduced surface expression and signalling after GIP challenge. The homology model of the GIPR structure supports the observed functional relevance of Arg217Leu. In vitro functional studies and protein homology modelling indicate a potential relevance of the GIPR variant Arg217Leu in receptor function. The heterozygous variant displayed partial co-segregation with diabetes. Based on these findings, we suggest that GIPR variants may play a role in disturbed glucose homeostasis and may be of clinical relevance in homozygous patients. Show less

The melanocortin-4 receptor (MC4R) can be endogenously activated by binding of melanocyte-stimulating hormones (MSH), which mediates anorexigenic effects. In contrast, the agouti-related peptide (AgRP) acts as an endogenous inverse agonist and suppresses ligand-independent basal signaling activity (orexigenic effects). Binding of ligands to MC4R leads to the activation of different G-protein subtypes or arrestin and concomitant signaling pathways. This receptor is a key protein in the hypothalamic regulation of food intake and energy expenditure and naturally-occurring inactivating Show less

The melanocortin-4 receptor (MC4R) - embedded in the leptin-melanocortin pathway - is activated by proopiomelanocortin (POMC)-derived neuropeptides such as α- and β-melanocyte-stimulating hormone (MSH) and plays an important role in hypothalamic body-weight regulation. Accordingly, MC4R is a potential drug target to combat obesity. Previous attempts to develop MC4R agonists failed due to ineffectiveness or severe adverse events. Recently, a new generation of MC4R ligands was developed. Specifically, setmelanotide was found to be effective by inducing biased signalling of the MC4R and thereby reducing feelings of hunger and leading to substantial weight loss in patients with POMC or leptin receptor deficiency. This new potential pharmacological treatment option could be beneficial for further groups of obese patients with defects in the leptin-melanocortin signalling pathway. Show less

Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies. Show less