Targeting the Hepatic BMP-SMAD Pathway in Leptin Receptor Deficiency (LEPRD): A New Strategy for Treating Severe PediatricObesity

Leptin receptor deficiency (LEPRD) is a rare genetic disorder causing severe early-onset obesity, hyperphagia, hyperglycemia, hyperinsulinemia, and insulin resistance (IR) due to impaired leptin–melanocortin signalling. This results in abnormal feeding behaviour. Unfortunately, standard interventions such as energy restriction and bariatric surgery often fail or are contraindicated due to the persistent hyperphagia. Setmelanotide (SET), an MC4R agonist that bypasses the defective leptin receptor, has been recently approved for LEPRD and effectively reduces hunger. However, it induces only modest weight loss and can cause dose-limiting adverse events, highlighting the need for complementary therapies. The crosstalk between hepatocytes and metabolic organs (e.g., adipose tissue and skeletal muscle) governs lipid and glucose homeostasis. TMPRSS6, a hepatocyte-specific protease that suppresses BMP–SMAD signalling, has emerged as a potential metabolic regulator. Indeed, Tmprss6-KO mice on a high-fat diet exhibit reduced adiposity and improved insulin sensitivity, while Tmprss6 downregulation via antisense oligonucleotides counteracts diet-induced metabolic disorders. Interestingly, our preliminary studies show that Tmprss6 downregulation in adult LEPRD mice mitigates the steatotic phenotype and adipose tissue inflammation. These findings position TMPRSS6 as a key modifier of the metabolic phenotype in LEPRD. We therefore propose TMPRSS6 inhibition as a novel therapeutic strategy for LEPRD, either as monotherapy or in combination with SET to enhance efficacy while allowing lower SET doses. A validated siRNA-based method for selective hepatic TMPRSS6 silencing offers a feasible translational approach, potentially enabling a dual strategy, targeting both hyperphagia and peripheral metabolic dysfunction in this severe genetic obesity.