👤 Gabriel Ángel Martos-Moreno

Advances in our understanding of hypothalamic control of energy homeostasis have resulted in the identification of genetic forms of obesity, both syndromic and nonsyndromic, with some precision treatments now being employed. In this review article, we examine the progress being made in identifying new genes involved in the hypothalamic leptin-melanocortin system and their possible implications in obesity, as well as other potential clinical features. We include an update on clinical trials in genetic obesity with specific pharmacological treatments, such as agonists for the melanocortin 4 receptor, and for glucagon-like peptide-1 receptor. The possibility of employing new precision drug targets in specific forms of obesity is modifying the approach to disease treatment in the pediatric clinic. 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

To study the prevalence and influence on metabolic profile of the prohormone-convertase-1 (PCSK1) N221D variant in childhood obesity, proven its role in the leptin-melanocortin signaling pathway as in proinsulin and other prohormone cleavage. Transversal study of 1066 children with obesity (mean age and BMI Z-score 10.38 ± 3.44 years and +4.38 ± 1.77, respectively), 51.4 % males, 54.4 % prepubertal, 71.5 % Caucasians and 20.8 % Latinos. Anthropometric and metabolic features were compared between patients carrying the N221D variant in No variants were found in 531 patients (49.8 %), while 68 patients carried the The N221D variant in Show less

Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with hyperphagia and early-onset severe obesity. We aimed to evaluate the effect of setmelanotide on bodyweight in these patients. This multicentre, randomised, 14-week double-blind, placebo-controlled, phase 3 trial followed by a 52-week open-label period, was performed at 12 sites (hospitals, clinics, and universities) in the USA, Canada, the UK, France, and Spain. Patients aged 6 years or older were included if they had a clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome and obesity (defined as BMI >97th percentile for age and sex for those aged 6-15 years and ≥30 kg/m Between Dec 10, 2018, and Nov 25, 2019, 38 patients were enrolled and randomly assigned to receive setmelanotide (n=19) or placebo (n=19; 16 with Bardet-Biedl syndrome and three with Alström syndrome in each group). In terms of the primary endpoint, 32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 years or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight after 52 weeks of setmelanotide. The most commonly reported treatment-emergent adverse events were skin hyperpigmentation (23 [61%] of 38) and injection site erythema (18 [48%]). Two patients had four serious adverse events (blindness, anaphylactic reaction, and suicidal ideation); none were considered related to setmelanotide treatment. Setmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome; however, these results were inconclusive in patients with Alström syndrome. These results support the use of setmelanotide and provided the necessary evidence for approval of this drug as the first treatment for obesity in patients with Bardet-Biedl syndrome. Rhythm Pharmaceuticals. Show less

Obesity is a very heterogeneous disorder at both the clinical and molecular levels and with high heritability. Several monogenic forms and genes with strong effects have been identified for non-syndromic severe obesity. Novel therapeutic interventions are in development for some genetic forms, emphasizing the importance of determining genetic contributions. We aimed to define the contribution of rare single-nucleotide genetic variants (RSVs) in candidate genes to non-syndromic severe early-onset obesity (EOO; body mass index (BMI) >+3 standard deviation score, <3 years). Using a pooled DNA-sequencing approach, we screened for RSVs in 15 obesity candidate genes in a series of 463 EOO patients and 480 controls. We also analysed exome data from 293 EOO patients from the "Viva la Familia" (VLF) study as a replication dataset. Likely or known pathogenic RSVs were identified in 23 patients (5.0%), with 7 of the 15 genes (BDNF, FTO, MC3R, MC4R, NEGR1, PPARG and SIM1) harbouring RSVs only in cases (3.67%) and none in controls. All were heterozygous changes, either de novo (one in BDNF) or inherited from obese parents (seven maternal, three paternal), and no individual carried more than one variant. Results were replicated in the VLF study, where 4.10% of probands carried RSVs in the overrepresented genes. RSVs in five genes were either absent (LEP) or more common in controls than in cases (ADRB3, LEPR, PCSK1 and PCSK2) in both obese datasets. Heterozygous RSVs in several candidate genes of the melanocortin pathway are found in ~5.0% patients with EOO. These results support the clinical utility of genetic testing to identify patients who might benefit from targeted therapeutic intervention. Show less