Endocrine Abstracts

Introduction: Rare genetic causes of obesity result from disruption of the melanocortin-4 receptor (MC4R) pathway, a regulator of energy balance. Patients with obesity due to variants in multiple genes, including POMC, LEPR, SRC1, and SH2B1, have shown weight and hunger reductions after treatment with setmelanotide, an MC4R agonist. DAYBREAK is a Phase 2 trial of setmelanotide in patients with additional gene variants with suggested relevance to the...

Background: Proopiomelanocortin (POMC; including biallelic variants in PCSK1) and leptin receptor (LEPR) deficiency are associated with hyperphagia and early-onset, severe obesity. Treatment with the melanocortin-4 receptor agonist setmelanotide for 1 year results in significant and sustained improvements in weight (POMC, −25.6%; LEPR, −12.5%), hunger, and quality of life. We used the metabolic syndrome Z score based on body mass index (MetS-Z-BMI) to asse...

Background: Rare variants in the melanocortin-4 receptor (MC4R) pathway are associated with early-onset, severe obesity and hyperphagia. Setmelanotide, an MC4R agonist, reduced body mass index (BMI) and decreased hunger in patients with obesity due to biallelic variants in genes encoding proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) in Phase 3 trials. The current analysis assesses the durability of setmelanotide ef...

Objective: Ideally, treatment strategies designed to reduce weight or body mass index in patients with obesity should reduce fat mass while preserving lean mass because reduced lean mass can negatively impact overall health and energy expenditure, thus favoring weight regain. In Phase 3 trials, 1 year of treatment with the melanocortin-4 receptor agonist setmelanotide led to weight reduction in patients with obesity due to biallelic variants in the genes encoding proopiomelano...

Background: Patients with proopiomelanocortin (POMC; including variants in POMC or PCSK1) or leptin receptor (LEPR) deficiency due to biallelic gene variants have impaired melanocortin-4 receptor signaling that leads to hyperphagia and early-onset, severe obesity. Setmelanotide treatment in this population improved weight-related measures and hunger severity and was well tolerated. Reported here are long-term extension (LTE) outcomes after 4 years of setmelan...

Objective: Treatment with metreleptin ameliorates hepatic steatosis in patients with lipodystrophy. The anti-steatotic effect of metreleptin is partially independent of its anorexic action, which suggests a direct effect of metreleptin on hepatic lipid metabolism. However, this mechanism is unknown. Based on previous findings in rodents, we hypothesized that metreleptin reduces hepatic lipid content by stimulating very-low density lipoprotein triglyceride (VLDL1-TG) secretion,...