Targeting the Hepatic BMP-SMAD Pathway in Leptin Receptor Deficiency (LEPRD)

Leptin receptor deficiency (LEPRD) is an extremely rare autosomal recessive endocrine disorder characterized by severe early-onset obesity, hyperphagia, and metabolic abnormalities resulting from impaired leptin signaling. Genetic forms of lipodystrophy, including generalized and partial lipodystrophy, may also be associated with severe leptin deficiency and impaired leptin signaling, leading to abnormalities in glucose and lipid metabolism and ectopic fat accumulation, particularly in the liver.

Current therapeutic approaches do not fully address the metabolic complications associated with these rare disorders. In patients with LEPRD, setmelanotide, a selective melanocortin-4 receptor (MC4R) agonist, acts downstream of the leptin-melanocortin pathway and can substantially reduce hunger and body weight. However, the response to treatment may be limited in some patients, and metabolic and hepatic abnormalities may persist. Similarly, metreleptin replacement therapy used in selected forms of genetic lipodystrophy may not completely correct all metabolic and hepatic abnormalities. Therefore, identification of additional molecular pathways involved in the metabolic complications of these conditions is needed.

TMPRSS6 is a type II transmembrane serine protease predominantly expressed in hepatocytes. It negatively regulates hepatic BMP-SMAD signaling by cleaving hemojuvelin (HJV), a coreceptor of the BMP pathway, thereby contributing to the regulation of hepcidin production. Preclinical studies have shown that genetic inactivation or antisense oligonucleotide-mediated silencing of Tmprss6 in mice results in activation of the hepatic BMP-SMAD pathway and is associated with beneficial metabolic effects, including improved glucose metabolism, reduced adipose tissue accumulation, and attenuation of inflammation.

Preliminary studies in murine models have identified circulating liver-derived factors, including TMPRSS6-related molecular markers, that may be involved in the metabolic alterations associated with impaired leptin signaling. These findings suggest that TMPRSS6 and the hepatic BMP-SMAD pathway may play a role in the interaction between hepatic function and systemic glucose and lipid metabolism.

The present pilot observational study is designed to investigate whether molecular alterations identified in preclinical models are also detectable in humans with LEPRD or genetic lipodystrophy associated with leptin deficiency. Blood samples will be collected to measure circulating TMPRSS6 and other molecular or metabolic markers previously identified in preclinical studies as being regulated by or associated with TMPRSS6 activity.

The study will integrate these molecular findings with available clinical and biochemical characteristics of the participants. Particular attention will be given to markers of glucose and lipid metabolism and hepatic involvement, in order to explore potential associations between TMPRSS6-related markers and the metabolic phenotype of these rare disorders.

The study is intended to provide preliminary evidence regarding the relevance of the TMPRSS6-related pathway in humans. Identification of a specific circulating molecular signature associated with TMPRSS6 may improve understanding of the mechanisms underlying metabolic and hepatic complications in LEPRD and genetic lipodystrophy and provide a rationale for future translational studies investigating this pathway as a potential therapeutic target.