IMPROVE 2023: The 2nd International Meeting on Pathway‐Related Obesity: Vision & Evidence

ABSTRACT

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.

1. Introduction

The International Meeting on Pathway‐Related Obesity: Vision & Evidence (IMPROVE) 2023, held in Paris on December 13–15, convened 150 clinicians and researchers from 19 countries, both in‐person and online. The central objective of the meeting was to explore the complexities of melanocortin‐4 receptor (MC4R) pathway‐related diseases and generate opportunities for collaborative dialogue among delegates for the advancement of this field. This second annual meeting included sessions on monogenic MC4R pathway disease, Bardet‐Biedl syndrome (BBS), and hypothalamic obesity. The meeting underscored the importance of inter‐disciplinary dialogue and set the stage for future collaborative efforts to tackle these complex diseases. Here, we encapsulate the key insights, discussions and initiatives that emerged from this meeting.

2. Monogenic MC4R Pathway Disease

2.1. Clinical Aspects

2.1.1. Professor Martin Wabitsch, Ulm University, Germany

In 2015, a biologically inactive leptin variant (D100Y) was first described [1]. Since then, research into rare human variants in the leptin gene has been conducted, particularly exploration of the functional aspects and impact of leptin as a pharmacotherapy. It has been hypothesised that there are leptin variants that block the leptin receptor when metreleptin treatment is initiated, behaving like antagonising ligands [2]. This hypothesis was studied in two patients, each presenting a unique leptin variant: P64S and G59S [2].

In vitro studies revealed that these leptin variants are secreted but fail to activate intracellular phosphorylated signal transducer and activator of transcription 3 (pSTAT3) signalling [2]. Notably, these variants demonstrate antagonist behaviour at the receptor level, as increasing doses of non‐variant leptin did not elicit a pSTAT3 response [2]. This discovery is pivotal in understanding the therapeutic application of metreleptin in patients with this variant. The in vitro findings suggest that higher levels of metreleptin are necessary to compete with these native, mutant leptins, which act as partial antagonists [2].

Based on the in vitro results, both patients were treated successfully with a marked increase in the dose of metreleptin, followed by a tapering, to overcome the effects of the endogenous antagonist [2]. This research represents a novel understanding in the biological realm of endogenous antagonising hormone variants, a phenomenon not described previously in humans. This research offers significant implications for the treatment of diseases related to leptin dysfunction and points to a new classification of congenital leptin deficiency [3].

2.1.2. Professor Erica LT van den Akker, Erasmus University Rotterdam, the Netherlands

Phenotype is critical in identifying patients for genetic testing in the context of rare MC4R pathway diseases [4, 5, 6, 7, 8, 9]. Research by Abawi et al. focused on the body mass index (BMI) characteristics of children and adolescents with these diseases, investigating whether growth‐chart characteristics could guide decisions about who should be referred for genetic testing [10].

The study included patients with MC4R pathway diseases diagnosed when a pathogenic or likely pathogenic variant or copy number variation was identified that matched the patient's clinical phenotype [11]. These were either non‐syndromic (n = 32) or syndromic (n = 32). A control group from a population‐based study, Generation R, provided a comparative baseline [11]. Key findings included the observation that patients with non‐syndromic MC4R pathway disease displayed severe obesity from an early age, with a more pronounced BMI increase in patients with biallelic variants compared with patients with heterozygous variants. In contrast, patients with syndromic MC4R pathway disease showed a higher BMI trajectory overall versus controls, but the increase varied depending on the specific syndrome [10].

Notably, the age of onset of obesity was largely under the recommended cut‐off point of 5 years of age for genetic testing for non‐syndromic diseases and some of the syndromic diseases, such as BBS [10]. Some others, such as 16p11.2del and Temple syndrome (caused by aberrant expression of imprinted genes at chromosome region 14q32), demonstrated higher variability in the age of onset [10]. The study suggested an optimal age of onset cut‐off of ≤ 3.9 years for non‐syndromic and ≤ 4.7 years for syndromic MC4R pathway disease to determine the need for genetic testing [10]. This research highlights the potential of utilising a lower age of onset as an indicator for genetic testing in infants now and in the future.

2.1.3. Professor Erica LT van den Akker, Erasmus University Rotterdam, the Netherlands; Professor Martin Wabitsch, Ulm University, Germany

Early childhood height and weight in children with monogenic MC4R pathway disease were evaluated for 150 patients from six European centres [12]. The study included patients with biallelic (likely) pathogenic variants in leptin (LEP), leptin receptor (LEPR), proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) and MC4R, or monoallelic (likely) pathogenic variants in the MC4R gene [12].

The research highlighted that early childhood BMI development in patients with monogenic MC4R pathway disease is characterised by a steep BMI increase in the first year of life (biallelic LEP, LEPR and MC4R variants) or in the first 2 years of life (biallelic POMC variants), followed by a plateau in BMI [12]. Notably, patients with biallelic MC4R variants experienced accelerated growth from 6 months of age, while those with LEP/LEPR variants showed normal growth patterns [12]. The study underlines that a normal BMI at 1 year of age makes the presence of biallelic variants in the leptin‐melanocortin pathway unlikely [12].

This research underscores the need for further international, multicentre studies to fully understand the natural course of monogenic MC4R pathway disease, a rare and complex disease.

2.2. Obesity Genetics: Relevance for Clinical Practice

2.2.1. Professor Sadaf Farooqi, University of Cambridge, UK

Obesity is complex and arises from the interaction of social, environmental and genetic factors. Central to the development of obesity is dysfunction in the hypothalamic control of eating behaviour, an interaction of innate and learned behaviours. Severe obesity is driven strongly by genetic factors, and genes regulate weight across the whole spectrum, with thinness also being heritable [13]. With the increased accessibility of genetic testing, there is a growing number of identified MC4R pathway diseases. As such, it is important to understand the clinical spectrum arising from different types of variants, which may share a common root cause. Furthermore, specialist clinical services for people with MC4R pathway diseases are needed, particularly as new therapies emerge.

Additional genes in which both common and rare variants contribute to obesity are likely to be identified. For instance, new data investigating 16p11.2 BP2‐3 deletion carriers (n = 60) in the UK Biobank study of 0.5 million people reported an association with measures such as increased BMI, body‐fat percentage, weight and body size. When compared with a control group matched for age and BMI, deletion carriers had an increased body size at 10 years of age, type 2 diabetes prevalence, elevated glycated haemoglobin and glucose, and a lower age of onset of type 2 diabetes, and had received diabetes medications. Another example shows that the targeted deletion of microRNA‐7 in single‐minded family basic helix‐loop helix transcription factor 1 (SIM1) neurons, a critical component of the hypothalamic melanocortin pathway, causes hyperphagia, obesity, and increased linear growth [14]. Genetic discoveries not only benefit clinical outcomes but also provide crucial insights into disease mechanisms and potential new targets for weight loss therapy.

2.3. Clinical Trials: The Leptin‐Melanocortin Pathway as a Therapeutic Target

2.3.1. Professor Peter Kühnen, Charité Universitätsmedizin Berlin, Germany

Treatments developed to date originate from an understanding of the leptin‐melanocortin pathway (see Figure 1) [15, 16, 17, 18]. Notably, setmelanotide, an MC4R agonist, has been shown to be effective in patients with POMC, PCSK1 or LEPR variants, or BBS [19, 20]. Understanding the underlying mechanisms of regulation of satiety and of energy expenditure is crucial for the further development of effective pharmacological treatment strategies.

FIGURE 1.

The leptin‐melanocortin pathway and associated treatments [15, 16, 17, 18]. LEPR, leptin receptor; MC4R, melanocortin‐4 receptor; POMC, proopiomelanocortin.

The discovery of multiple layers of complexity within the leptin‐melanocortin pathway presents promising avenues for novel therapeutic strategies in obesity treatment. For example, single‐nucleus analysis has been instrumental in uncovering more than three distinct clusters of POMC neuronal populations in the hypothalamus [21]. This differentiation in neuronal clusters could lead to more targeted approaches in obesity management [21].

Further complexity is evident in the differential signalling of MC4R [22]. Understanding the nuanced signalling mechanisms of MC4R can elucidate the safety and efficacy profiles of MC4R agonists, pivotal to developing safe and effective obesity treatments [22].

Cryo‐electron microscopy has further advanced our understanding by detailing the activation and inhibition mechanisms of MC4R [23]. This structural insight is crucial for fine‐tuning receptor‐signalling pathways, thereby paving the way for the creation of tailored anti‐obesity drugs [23].

Lastly, mouse genetics studies have highlighted the indispensable role of cilia on MC4R‐expressing neurons in maintaining energy homeostasis [24]. Targeted deletion of primary cilia on these neurons leads to hyperphagia and obesity, indicating a novel therapeutic target within these neural pathways [24]. These varied complexities not only deepen our understanding of obesity pathophysiology but also open new possibilities for targeted, effective hyperphagia and obesity treatments.

2.4. Paediatric Patient Management: Lessons Learned

2.4.1. Professor Jesús Argente, Hospital Infantil Universitario Niño Jesús, Madrid, Spain

When measuring change in obesity in children, it is important to consider the impact of puberty. In some instances, an increase in weight occurring during a high growth spurt because of puberty could result in a decrease in BMI. As such, BMI, rather than weight, should be considered the most appropriate metric for obesity in children.

While individual variants associated with MC4R pathway diseases are uncommon, rare genetic causes that lead to obesity are likely not uncommon among individuals with early‐onset obesity. Approximately 7% of children globally are affected by early‐onset, severe obesity before reaching 4 years of age [25]. Of those, monogenic MC4R pathway disease accounts for ~5%–7% of patients [18, 26]. Furthermore, in Europe, genetic factors are believed to be the underlying cause of obesity in approximately 13% of children [27]. We have started to unravel the pathophysiological basis of syndromic and monogenic MC4R pathway disease; however, further research is needed.

Monogenic MC4R pathway diseases are a clinical reality [28]. Clinical features complement the diagnosis and help to identify which patients should be referred for genetic testing. Syndromic and non‐syndromic forms of MC4R pathway disease should be differentiated: in non‐syndromic MC4R pathway disease, clinical features include hyperphagia and endocrine abnormalities in addition to early‐onset, severe obesity, whereas syndromic MC4R pathway disease is associated with a range of clinical features in addition to early‐onset obesity.

Genetic testing of patients with early‐onset, severe obesity may be an important component of understanding the aetiology of these patients' disease and could potentially affect their course of care. For example, an analysis of data from the Rare Obesity Advanced Diagnosis genetic testing programme revealed ~31% (n = 707/2253) of patients with early‐onset, obesity carried potentially actionable variants [29].

Further translational research in monogenic and syndromic MC4R pathway disease is a scientific necessity as many questions remain. Case studies of patients with monogenic or syndromic MC4R pathway disease demonstrate the efficacy of setmelanotide, indicate a possibility of reduction of complications later in life when setmelanotide is initiated early, and reveal current, clinically relevant questions regarding the management of hyperpigmentation in responding patients, varying disease evolution in patients with identical variants and environment, and the influence of multiple variants in the leptin‐melanocortin pathway on the outcome of treatment.

2.5. Adult Patient Management: Lessons Learned

2.5.1. Professor Béatrice Dubern, Sorbonne Université, Paris, France; Professor Christine Poitou, INSERM/Sorbonne Université and Pitié‐Salpêtrière Hospital, Paris, France; Professor Karine Clément, INSERM/Sorbonne Université and Pitié‐Salpêtrière Hospital, Paris, France

Accurate phenotype characterisation is essential for enhancing genetic diagnosis in adults. Despite the challenges posed by the lack of early childhood data, it is recommended to explore the patient's history beyond standard clinical records. This includes engaging with family members and requesting childhood photographs to gain insights into early signs of corpulence aggravation. Hyperphagia is often difficult to diagnose with the available tools (e.g., self‐questionnaires) and requires a specific expertise and a multidimensional approach. Recurrent stigma experience and repeated and inappropriate management since childhood, such as restrictive diets, can aggravate eating disorders. Additionally, there is a pressing need for updated diagnostic criteria to facilitate better access to genetic diagnosis for adults. In order to help clinicians who suspect a genetic origin for their patient's obesity, the French team at the Rare Obesity Reference Centre has developed a web‐based tool called Obsgen to provide diagnostic guidance and improve diagnosis of early‐onset obesity in adults [30].

The effectiveness of bariatric surgery in patients with monogenic MC4R pathway disease is limited. While initial weight loss can be achieved, long‐term data reveal a tendency for weight regain, underscoring the need for alternative or supplementary treatment approaches [31, 32]. Bariatric surgery can be discussed on an individual basis in patients with heterozygous variants in the leptin‐melanocortin pathway, taking into account that results from pharmacological trials are pending.

Monogenic MC4R pathway disease are multifaced diseases that require medical and psychosocial expertise. Beyond the increased morbidity and mortality related to obesity, the stigma associated with obesity also contributes to the burden of disease [33, 34, 35]. Management of monogenic MC4R pathway diseases should be holistic, involve multiple disciplines, and have a coordinated approach. Beyond medical treatment of the disease and any complications, management of patients with monogenic MC4R pathway diseases should include behavioural/psychological intervention, as well as familial and social support.

Quality of life benefit can be independent of weight loss [36]. Even if weight‐loss objectives are not reached, the effect of treatment on hyperphagia is dramatic and could explain the overall improvement in quality of life in these patients, their families and caregivers [36]. As such, a recent case study showed that the improvement of patient BMI following initiation of setmelanotide resulted in a simultaneous and major improvement in the quality of life of caregivers [37].

Transitioning from paediatric to adult care in rare MC4R pathway‐related hyperphagia and obesity is complex, necessitating comprehensive medication and coordinated care [38, 39, 40]. The medical condition of these patients is very complex and includes severe hyperphagia, lack of control or impulsivity, cognitive disorders and social‐interaction disorders. These symptoms are responsible for major vulnerability and worsening of medical conditions. For example, rapid weight gain is often observed during the transition to adult care and the start of obesity‐related complications, such as diabetes. A coordinated approach to transition is needed, and this can take several years to complete for each patient.

3. Bardet–Biedl Syndrome

3.1. Clinical Aspects

3.1.1. Professor Hélène Dollfus, INSERM‐Université de Strasbourg, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

BBS, a ciliopathy, is diagnosed using clinical characteristics, as described in Beales' modified diagnostic criteria [41]. New diagnostic criteria for BBS, with a clear role for genetic testing, are currently in development. Primary features of BBS, as described in Beales' modified diagnostic criteria, include retinal dystrophy (> 90%), obesity (> 80%), polydactyly (> 75%), hypogonadism or genitourinary anomaly (~60%), neurodevelopmental disorder (~50%) and/or kidney anomaly (< 50%) [41, 42, 43, 44, 45]. Importantly, patients with BBS typically also present with hyperphagia, which is considered a key feature of the disease. Hyperphagia, resulting from the dysfunction of primary cilia in the hypothalamic MC4R pathway of patients with BBS, manifests as insatiable, pathological hunger and food‐seeking behaviours that drive the development of obesity early in childhood. Hyperphagic behaviour impacts patients across multiple aspects of their lives, as well as the lives of their parents and carers [46]. Many patients feel stigmatised due to these behaviours and the resulting obesity, exacerbating the impact of hyperphagia on quality of life [46]. Due to the autosomal recessive nature of BBS, genetic testing should be performed where possible, and should be accompanied by genetic counselling for patients and family.

The diagnosis of BBS is highly dependent on age. In utero, key characteristics include nephromegaly and polydactyly; however, at birth, patients with BBS are typically of normal weight. During the first 2 years of life, patients are characterised by early‐onset obesity, kidney dysfunction, and retinal dystrophy, and during childhood, patients are characterised by obesity, retinal dystrophy and neurodevelopmental disorders. Diagnosis in adulthood is very difficult given the full spectrum of symptoms, highlighting the importance of early genetic testing.

It is crucial to distinguish between ciliopathies, despite their phenotypic similarities, and genetic testing is key to obtaining an accurate diagnosis. For example, Alström syndrome is a monogenic disease that should not be confused with BBS: it does not present with polydactyly, but does present with insulin resistance and cardiomyopathy. Patients with BBS may exhibit developmental anomalies in the hands and feet, neurodevelopmental features and endocrine dysfunctions. Although neurodevelopmental features are frequent in patients with BBS, they are not automatic [47]; they can present as hyper emotivity, slow reactivity, intellectual disability, autistic features and psychiatric traits, such as anxiety and obsessive‐compulsive behaviour.

Obesity is a central characteristic of BBS; normal birth weight is followed by rapid weight gain. Hyperphagia, a key clinical feature of BBS, critically affects the patient's weight gain and drives the development of obesity early in childhood. Together, hyperphagia and obesity result in a significant quality of life burden for patients with BBS. Hyperphagia and obesity in patients with BBS have been shown to be centrally caused by dysfunction in the cilia [48], as opposed to peripherally dysfunction.

Retinal dystrophy is the most penetrant feature of BBS and starts early in the patient's life, with legal blindness occurring at approximately 15 years of age. Ophthalmological issues in patients with BBS, such as retinal dystrophy, are a direct result of cilia dysfunction in photoreceptors. This dysfunction results in accumulation of proteins in the inner segment and/or unwanted proteins in the outer segment that cannot return to the inner segment, leading to degeneration of cellular structures [49]. Diagnosis of retinal dystrophy can often be overlooked in early life; progressive visual field reduction is often characterised as clumsiness, and central vision can be affected early. Besides retinal imaging, electrocardiograms are an important part of the diagnostic procedure for retinal dystrophy.

3.2. Kidney and Bardet‐Biedl Syndrome

3.2.1. Dr. Metin Cetiner, University of Duisburg‐Essen, Essen, Germany

Ultrasound has emerged as a crucial diagnostic tool to differentiate BBS from other ciliopathies. Approximately 50% of patients with BBS have structural renal abnormalities that can be identified through ultrasound [50].

The risk of end‐stage renal disease (ESRD) is highest in the first year of life and during pre‐school years [50]. ESRD in adults is less common; however, it can occur at any age. Specific BBS gene variants (e.g., BBS2, BBS3, BBS6, BBS9, BBS10, BBS12 and BBS16) have been associated with a higher risk of kidney failure, whereas others (BBS1, BBS4 and BBS8) have been linked to fewer kidney anomalies [51]. Kidney failure is also more prevalent in females than males, and it increases with age [51].

The key characteristics of the kidney to identify when using ultrasound include its shape (including the regression of lobulation, which typically disappears in the first year of life), its position, parenchymal echogenicity and corticomedullary differentiation and perfusion. Persistent foetal lobulation, increased echogenicity (in ~50% of patients), and lifted corticomedullary differentiation (in ~1/3 patients) are characteristic of BBS.

The management of chronic kidney disease (CKD) in patients with BBS is the same as with other causes of CKD, and current guidelines should be adhered to. When considering kidney transplantation, there is no evidence that patients with BBS should not be candidates for a kidney transplant, with the caveat that severe obesity is a relative contraindication to kidney transplant in adults. In situations of inappropriate BMI increase post‐transplant, sparing of steroid regimen might be considered. Intellectual disabilities and familial support should be considered when ensuring adherence to immunosuppressive medication.

Advances in ultrasound technology now permit the non‐invasive measurement of elasticity and fat content in the liver. This technology may represent a promising tool for imaging diagnostics and improve the diagnostic relevance of liver ultrasound in early childhood and some syndrome conditions, such as ciliopathies [52, 53].

3.3. MC4R and Primary Cilia

3.3.1. Professor Christian Vaisse, University of California, San Francisco, USA

Ciliopathies, such as BBS or Alström syndrome, are a group of diseases caused by genetic alterations to a specific cellular organelle—the primary cilia [54, 55, 56]. Primary cilia are present on most eukaryotic cells, and all neurons have cilia, including those in the hypothalamus [56]. Cilia function as cellular antennae informing the cell of changes in the environment [57], by compartmentalising and organising signalling cascades [57, 58]. Specific proteins structure the cilium shaft, transport proteins along the cilium, and control the exit of proteins from the cilium [58].

Genetic ablation of primary cilia in neurons of adult mice caused obesity, suggesting that one or more receptors at the primary cilium of differentiated neurons are required for long‐term regulation of energy homeostasis [24, 59]. Recent data suggest that this receptor is MC4R as it localises and functions exclusively at the primary cilia.

Both in vitro and in vivo studies in mice indicate that MC4R localises to primary cilia [60]. Ablation of primary cilia exclusively from MC4R neurons mimics loss of MC4R in mice, demonstrating that the primary cilia of MC4R neurons are required for MC4R activity, food intake and body weight regulation [24].

In addition, inhibition of adenylate‐cyclase signalling specifically in the primary cilia of MC4R neurons is sufficient to abolish MC4R activity, identifying this signalling modality as the one utilised by MC4R in neurons [24].

3.4. Novel Therapies and Clinical Trials for Bardet‐Biedl Syndrome

3.4.1. Professor Phil Beales, UCL Great Ormond Street Institute of Child Health, London, UK

There are significant challenges in developing treatments for rare diseases. Over 90% of rare diseases lack a dedicated treatment [61] with around 150 conditions comprising most of the rare disease patient population [62].

Approximately 85% of conditions fall into the very rare/ultra rare category creating skewed investments into therapeutic research [63]. While current systems, such as the Orphan Drug Act, work well, they incentivise orphan drug development for more ‘common’ rare diseases. Development of therapies for very rare/ultra rare diseases also needs to be incentivised.

Many governments have already committed to national rare disease frameworks and should now go further to establish Offices for Rare Diseases focused on innovation support for new therapies. However, at the current rate [64], only 600 new therapies for specific rare diseases will emerge in the next decade.

Stratification of patients by genetic therapy reveals that most patients with BBS would benefit from gene therapy (43%), with fewer patients benefitting from readthrough therapy (11%) and antisense oligonucleotide therapy (9%). There are > 300 gene‐therapy trials worldwide, with clinical trials for a BBS1 gene therapy following preclinical studies underway. This gene therapy uses an adeno‐associated virus vector (AAV9) to deliver a functional copy of the faulty BBS1 gene in key tissues, resulting in normal protein synthesis and restoration of cell function. Subretinal injections with BBS1 gene therapy in M390R mice were shown to prevent vision loss, and CNS delivery of this therapy normalised weight and leptin levels. Human Phase 1 trials are anticipated to enrol mid‐2025 [65].

4. Workshop Highlights

4.1. Workshop 1: Genetics: Obesity Due to Monogenic Disease

4.1.1. Dr. Johanne Le Beyec, Hôpital La Pitié Salpêtrière, Paris, France and Dr. Louis Lebreton, Centre Hospitalier Universitaire de Bordeaux, France

This workshop aimed to define current practice with regard to inclusion criteria for gene testing and gather interest from attendees to develop a ClinGen Gene Curation Expert Panel for obesity due to monogenic disease obesity.

Despite using a decision tree to determine which patients should be referred for genetic testing, Pitié‐Salpêtrière Hospital in Paris experiences a positive rate of < 10% for gene variants possibly or likely pathogenic. Discussion around decision trees and rates of positivity for gene variants among those tested revealed that other hospitals experience the same frustration with negative results. However, some people recognise the limitations of testing in diagnosis. It is therefore useful to refine the eligibility criteria for the molecular diagnosis of obesity due to monogenic disease, also taking into account the recognised symptoms of monogenic disease beyond hyperphagia and early onset of obesity. The age threshold for early‐onset obesity ranged from 4 to 6 years, while hyperphagia was recognised as hard to define. Testing approaches differ by region; for example, Argentina faces hurdles in accessing genetic testing and often relies on commercial panels capable of testing up to 70 genes. Interest was shown in investigating epigenetic factors like methylation, but this exploration is also constrained by current testing capacities.

The proposal to develop a ClinGen Gene Curation Expert Panel for obesity due to monogenic disease was met with enthusiasm, attracting interest from 60 clinicians. The group acknowledged that many genes could be included. It was noted that obesity has not been curated in ClinGen, presenting a significant opportunity to apply a robust methodology, with one suggestion being to adopt a broad approach by first identifying which genes to exclude. There was consensus on the considerable time investment required, with one participant drawing on past experiences with a cardiovascular expert panel. Successfully curating these genes will clarify their relation to obesity, a crucial factor for appropriate diagnoses and reimbursement of medications.

4.2. Workshop 2: Genetics: Bardet–Biedl Syndrome

4.2.1. Dr. Jean Muller and Dr. Aurélie Gouronc, Les Hôpitaux Universitaires de Strasbourg, France

This workshop covered the genetics of BBS including the diagnostic process and challenges, the diversity of genetic variants associated with the disease and the functional testing of variants. Emphasis was placed on two main genes (BBS1 and BBS10) and two founder variants (c.1169T>G and c.271dupT) that account for ~30% of patients, suggesting a more practical approach to genetic testing. The importance of considering the geographic origin of patients was noted, as other founder variants prevalent in certain regions could be more relevant. Based on the European Reference Networks consensus statement on diagnosis criteria and management of BBS [66], early information about gene categories was discussed with three categories of BBS genes: genes with strong evidence (‘Core’), genes requiring additional evidence (‘Need replication’), and genes with weak evidence (‘Questioned’). Whole‐genome sequencing was favoured over exome sequencing because it provides a broader scope of genetic information, including better structural variant discovery and intronic‐region exploration. Such comprehensive genetic analysis is game‐changing for patients, allowing for a deeper exploration of the nuances of variants of uncertain significance (VUS) that are still to be resolved, and enhancing our understanding of cilia biogenesis and functioning, which is crucial for the progression of BBS research and treatment.

4.3. Workshop 3: Patient Management With Clinical Cases

4.3.1. Professor Béatrice Dubern, Sorbonne Université, Paris, France; Professor Christine Poitou, INSERM/Sorbonne Université, Pitié‐Salpêtrière Hospital, Paris, France; and Professor Martin Wabitsch, Ulm University, Germany

This workshop focused on the clinical management of severe MC4R pathway diseases. Discussions centred around therapy with setmelanotide, the impact on hyperphagia, varying dosing strategies for weight stabilisation, and the role of combination therapies. Debate arose around dose adjustment of setmelanotide for weight stabilisation in children, with some clinicians opting to escalate the dose up to a maximum of 3 mg, if needed, to achieve the best possible reduction in weight to prevent secondary diseases. Other clinicians would opt not to escalate the dose of setmelanotide to the maximum permitted too early, given that children are still growing and weight loss is not the only goal. Discussion regarding who should make therapy decisions emphasised the need for a balance between medical guidance and parental input. The workshop featured case studies, illustrating challenges, such as managing complications like diabetes and the influence of stigmatisation on treatment outcomes. Key takeaways included the need for tailored management, early access to testing and treatment, transition care and a coordinated care network for the patient. As part of the concluding remarks, the need for long‐term follow‐up data and international collaboration was highlighted.

5. Future of the Field

5.1. Rhythm Clinical Development Update

5.1.1. David Meeker, Rhythm Pharmaceuticals, Boston, USA

Clinical trials performed by Rhythm Pharmaceuticals have provided positive and elucidative updates. The Phase 3 VENTURE trial enrolled 12 patients (2–< 6 years of age) with obesity due to either biallelic variants of POMC, PCSK1 or LEPR genes or BBS [67]. Overall, 83.3% (n = 10/12) achieved ≥ 0.2 reduction in BMI z‐score from baseline to Week 52 and the mean percent change from baseline in BMI at Week 52 was −18.4% (n = 12), with a mean change in BMI z‐score of −3.4 [67]. The pattern of response in these patients was highlighted as particularly important given the rarity of the diseases; it indicated that patients with a very severe starting point had the largest response. Two patients did not achieve ≥ 0.2 reduction in BMI z‐score because of either non‐compliance or early discontinuation, demonstrating the importance of adherence to the treatment protocol. Patients also showed improvements in hunger scores, and caregivers reported an improved quality of life. The non‐compliant patient had an initial response, with a return to baseline following non‐compliance. The safety profile remained consistent with past trials evaluating setmelanotide in patients ≥ 6 years of age [67].

Long‐term (≥ 1 year) data from a Phase 2 trial [68] of setmelanotide in 14 patients with acquired hypothalamic obesity, typically resulting from hypothalamic damage, have been analysed. The majority (n = 12/14) of patients enrolled were children 10–18 years of age. Most patients had craniopharyngioma (n = 11/14). The mean percent change in BMI from baseline to week 16 and month 12 was −17.7% and −25.5%, respectively. All patients experienced ≥ 5% BMI reduction from baseline to month 12, and individual patient analysis revealed a varying BMI change trajectory over 12 months, with some patients' BMI reducing more rapidly than others. Analysis of dose modification in a patient who ultimately discontinued treatment because of an adverse event (AE) revealed a positive relationship between treatment dose and overall BMI change. Most patients (91.7%; n = 11/12) experienced ≥ 1 weight class improvement from baseline. Body composition changes were favourable, with larger percentage decreases in total fat mass compared with lean muscle mass. The two patients with the lowest percentage change in BMI from baseline to month 12 were two teenage males who had the greatest increase in lean muscle mass, indicating a very positive response to treatment. Enrolment for the Phase 3 trial for hypothalamic obesity has now reached the desired target of 120 patients.

DAYBREAK is a Phase 2 trial designed to evaluate setmelanotide across 24 genes with strong relevance to the MC4R pathway [69]. Results from stage 1 (open‐label run‐in) were presented. Out of 164 enrolled patients, 112 completed stage 1, with 49 progressing to stage 2. The trial revealed that 25.0%–56.3% of patients per gene showed a positive response with ≥ 5% reduction in BMI, indicating a gene‐specific response to treatment. Among patients with semaphorin 3A (SEMA3) and pleckstrin homology domain‐interacting protein (PHIP) variants, 61.5% (n = 16/26) and 69.2% (n = 9/13) of completers, respectively, responded with ≥ 5% reduction in BMI. Variability in BMI reduction was noted, with an average decrease of ~5% across all genes. Significantly, following the reclassification of 90 variants of uncertain significance through functional characterisation, response rates among SIM1 variants increased from 31.3% (n = 5/16) to 45.4% (n = 5/11) and response rates among SEMA3G variants increased from 57.1% (n = 8/14) to 77.8% (n = 7/9). In vitro functional characterisation of missense variants enables us to understand their direct impact on protein functionality and assess how these variants contribute to disease manifestation and, potentially, setmelanotide response. This approach also allows for high throughput and assistance of clinical genetic laboratories in reclassifying variants of uncertain significance (VUS). Individual patient analysis for individual gene variants may reveal clues for identifying patients likely to respond to treatment with setmelanotide.

5.2. Hypothalamic Obesity: Clinical Aspects

5.2.1. Professor Hermann L. Müller, Carl von Ossietzky Universität Oldenburg, Germany

Hypothalamic syndrome is an umbrella term describing multiple clinical symptoms and complaints that frequently occur in patients with damage or dysfunction of hypothalamic structures. Hypothalamic syndrome is not synonymous with acquired hypothalamic obesity, but surveys in patients and caregivers have shown that hypothalamic obesity is the major contributor to hypothalamic syndrome [70, 71].

A score for hypothalamic syndrome has been developed [72], which encompasses clinical criteria (hyperphagia, diencephalic syndrome, BMI, behavioural problems, sleep disorders, temperature regulation disorder, and pituitary dysfunction) and radiological magnetic resonance imaging (MRI) criteria. This score offers the potential for more accurate diagnostics, facilitates comparisons between different diseases in randomised trials, and enables the identification of disease‐specific profiles. The potential application of this score in trials for hypothalamic obesity was discussed, albeit with acknowledgement of the challenges associated with integrating it into study protocols.

Approximately 50% of patients with craniopharyngioma develop hypothalamic obesity [73, 74, 75]. Analysing anthropometric data before and after a diagnosis of craniopharyngioma in 90 patients, Müller et al. showed that BMI increases slightly 2–3 years before a craniopharyngioma diagnosis, and that the major weight gain resulting in the development of obesity occurs during the first 12 months following diagnosis/surgery [76]. Other studies also showed that the major and clinically most significant increase in BMI (mean BMI standard deviation score [SDS] increase: +2 SD) occurred during the first 12 months following neurosurgical intervention leading to hypothalamic lesions [75, 77, 78]. Patients with craniopharyngioma and damage to the posterior hypothalamic structures due to neurosurgical interventions develop a mean BMI increase of +3.2 SD during the 36 months following neurosurgery, which approximates a 50%–80% weight gain [78]. During long‐term follow‐up, BMI SDS of patients with craniopharyngioma and hypothalamic obesity stabilised at a high plateau (BMI SDS increase of approximately +5.0 SD) without a trend towards further BMI increase [79]. Surgical hypothalamic lesions have been shown to impact BMI, social function, physical function, and autonomy [77]. The largest BMI increase after surgery is seen in patients with lesions to both the anterior and posterior hypothalamus compared to those without lesions, or those patients with lesions to the anterior hypothalamus only [77].

When compared with healthy controls, patients with craniopharyngioma and hypothalamic obesity show similar energy intake but lower overall movement per minute [80]. A potential explanation for this is the increased daytime sleepiness observed with some patients [81]. A study of 79 patients with childhood craniopharyngioma found associations between decreased nocturnal melatonin levels and increased daytime sleepiness, BMI, and hypothalamic tumour diagnosis [82]. Long‐term sequelae of hypothalamic obesity were also associated with more radical surgical treatment approaches, performed more frequently in centres with lower patient load, indicating that therapeutic expertise might be a relevant prognostic factor [78, 83].

Treatment for childhood‐onset craniopharyngioma should employ a hypothalamus‐sparing strategy because of the impaired prognosis resulting from neuroendocrine sequelae such as hypothalamic obesity. Further research on targeted therapy and treatment of hypothalamic obesity is needed, and treatment should be facilitated by a multidisciplinary expert team.

5.3. Early Onset of Obesity Model: Impact of Early‐Onset Obesity on Life Expectancy and Risks of Complications

5.3.1. Patrick Sleiman, Director of Genetics, Rhythm Pharmaceuticals, Boston, USA

A systematic model has been developed to assess the impact of early‐onset obesity on life expectancy and the risk of complications. This model is the first of its kind, enabling the estimation of the impact of early‐onset obesity on life expectancy, disability‐adjusted life years, and complications. Data from published clinical studies and demographic information were adopted to estimate the effect of weight trajectories including weight gain/loss at different ages on complication development, disease burden, and mortality. It underscores the finding that both the magnitude and duration of obesity are crucial determinants of health outcomes. Notably, it reveals that the age at which obesity begins has a profound effect on life expectancy, with earlier onset leading to more significant years of life lost. For example, the average life expectancy was 39 years in patients with a BMI z‐score of 3.5 by age 4 years versus 56 years in patients with a BMI z‐score of 3.5 by age 45 years. The severity of BMI z‐score at an early age also has a large impact on average life expectancy, with higher scores resulting in shorter life expectancy. For example, average life expectancy was shortened by 26 years in a 12‐year‐old patient with a BMI z‐score of 4 versus 2. The model is set to be utilised in characterising and quantifying the benefits of early weight loss interventions in paediatric patients.

However, the model has some limitations. It does not allow for ethnic or gender‐specific variations in the development of complications, nor does it consider specific complications that arise due to obesity caused by monogenic, syndromic, or hypothalamic diseases. The model is restricted to assessing the impact of six complications on life expectancy and considers each complication individually, failing to account for their potential synergistic impact. Additionally, it sets upper limits with a BMI z‐score > 4 and a BMI > 50, due to a lack of source data for higher obesity severity. Furthermore, the model does not consider recent advancements in managing complications that might reduce mortality risk.

This model not only reinforces the urgency of treating early‐onset obesity as a severe disease but also highlights the necessity of early diagnosis and treatment. This approach is crucial to prevent the development of complications and minimise long‐term negative health outcomes.

5.4. Perspectives in Neuroendocrinology

5.4.1. Professor Jacques Young, Hôpitaux de Paris, France

Congenital hypogonadotropic hypogonadism (CHH) is a rare endocrine disorder characterised by a deficiency in gonadotropin‐releasing hormone (GnRH) leading to low levels of pituitary gonadotropins and subsequent hypogonadism [84]. It has heterogenous presentations and is often diagnosed during puberty [84]. CHH can affect fertility, which may be restorable by GnRH or gonadotropin administration [84]. Genetic analysis is crucial for patient care to assess the risk of transmission to offspring. Advances in genomics and shifting from Sanger sequencing to exome analysis have uncovered additional genes, increased the understanding of the neuroendocrine hierarchy in humans, and aided the development of novel therapies like kisspeptin and neurokinin B.

The progression in our understanding of CHH mirrors the advancements being made in understanding genetic and complex forms of obesity. There is a pressing need for more research to deepen our knowledge of human biology, particularly regarding the mechanisms behind early‐onset, severe obesity. Such insights could pave the way for the development of new and effective treatments.

6. Summary and Meeting Close

The IMPROVE 2023 meeting highlighted the significant progress made in understanding the complex genetic and clinical aspects of MC4R pathway‐related obesity. This year's meeting emphasised the importance of interdisciplinary and international collaboration in advancing knowledge and developing treatments for rare diseases associated with the MC4R pathway.

Global and cross‐disciplinary cooperation is vital for conducting comprehensive research, sharing best practices, and innovating new treatment strategies. Such collaboration can deepen our understanding of the genetic and environmental factors influencing the MC4R pathway‐related hyperphagia and obesity, ultimately enhancing patient care worldwide.

Key discussions and presentations underscored the urgent need for early diagnosis and prompt treatment. Integrating genetic testing into diagnostic protocols is crucial for identifying patients with MC4R pathway disease, enabling more targeted and effective treatments. Early intervention can significantly alter the disease's trajectory and improve long‐term patient outcomes.

A particularly notable finding was the impact of treatment on hyperphagia, even when substantial weight loss was not achieved. The reduction in hyperphagia is closely linked to improved quality of life, demonstrating the broad benefits of treatment beyond conventional weight metrics. However, the meeting also highlighted the importance of treatment adherence in achieving positive outcomes. While maintaining treatment regimens is essential, potential AEs may lead to discontinuation, presenting a challenge for ongoing patient management.

The discussions also highlighted the multifaceted nature of these diseases, involving genetic, environmental, psychological, and social components, which call for a holistic approach to treatment. Effective management of MC4R pathway diseases requires the coordinated efforts of various healthcare professionals, including geneticists, endocrinologists, dietitians, and psychologists.

Overall, IMPROVE 2023 has advanced our understanding and approach to MC4R pathway diseases. The meeting laid the foundation for more collaborative, patient‐centred, and multifaceted treatment strategies, essential for addressing the complexities of these diseases. The insights gained serve as a guiding light for future research and clinical practice, paving the way for improved outcomes and quality of life for affected patients.

Conflicts of Interest

All presenters received speaker fees and travel reimbursement from Rhythm Pharmaceuticals for speaking at the meeting.

Clément K., van den Akker E. L. T., Argente J., et al., “ IMPROVE 2023: The 2nd International Meeting on Pathway‐Related Obesity: Vision & Evidence,” Clinical Obesity 15, no. 5 (2025): e70029, 10.1111/cob.70029.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this article.