ESPE Abstracts

Clinical and experimental evidence supports the important contribution of brain circuits in the pathogenesis of obesity. While functional perturbation of hypothalamic pathways could underlie common forms of obesity, the term “hypothalamic obesity” has been coined to define rare forms of severe overweight where a clear hypothalamic substrate, either genetic or acquired, can be identified. Addressing the problem of early-onset, severe obesity in children is of utmost importance as it is associated with reduced quality of life and increased morbidity and mortality. Approximately 7% of children with severe obesity may carry rare genetic variants, including those that affect key components of the melanocortin-4 receptor (MC4R) signaling pathway which regulates hunger, satiety, and energy expenditure via neural circuits in the hypothalamus. Monogenic obesity can be caused by variants in proopiomelanocortin (POMC), the proprotein convertase subtilisin/kexin type 1 (PCSK1), and the leptin receptor (LEPR). Bardet-Biedl syndrome (BBS) is caused by disruption of primary cilia and is associated with multifactorial organ dysfunction. Variants in some BBS genes have been shown to negatively impact LEPR trafficking. These MC4R pathway diseases commonly result in hyperphagia and early-onset severe obesity, often beginning in the first years of life, and are likely underdiagnosed. Indeed, identifying patients to provide early intervention can be challenging in these rare diseases. Use of an MC4R agonist has been associated with reduced weight-related measures and favorable tolerability in patients ≥ 6 years of age with POMC (including PCSK1) deficiency, LEPR deficiency, or BBS and is currently approved for use by the FDA and EMA. Recent evidence also supports its efficacy and safety in pediatric patients aged 2 to <6 years with obesity due to either biallelic variants in POMC, PCSK1, or LEPR or in patients with BBS. This conference will discuss the diagnosis and medical treatment of genetic and acquired hypothalamic obesity.