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

Leptin receptor deficiency (LEPRD) is a rare recessive genetic disorder causing severe obesity and hyperphagia starting in early childhood. It leads to extreme hunger, high blood sugar, insulin resistance and hyperinsulinemia due to faulty brain and hypothalamic signals that regulate appetite and energy balance. Patients are resistant to lifestyle strategies and bariatric surgery with weight regain. Setmelanotide, a drug approved for LEPRD, reduces hunger effectively but results in less weight loss than other genetic form of obesity. Furthermore, effects on obesity related diseases have not been reported yet. TMPRSS6, a liver-specific protein, has been demonstrated to play a role in adipose tissue and glucose metabolism. Animal studies show that turning off the TMPRSS6 gene improves metabolism and reduces fat accumulation and inflammation, even in LEPRD models. These findings suggest that blocking TMPRSS6 may offer a new therapeutic approach for LEPRD. It could be used by itself, in case of adverse events to setmelanotide, or with setmelanotide to increase treatment effectiveness on peripheral targets apart from the hypothalamus. There is already a safe, tested method to reduce TMPRSS6 activity in the liver, making this a promising dual treatment strategy to manage weight loss and metabolic problems in this severe genetic form of obesity.