Therapeutic targeting of PC1/3 deficiency: from obesity to gastrointestinal disorders

PCSK1 encodes the enzyme PC1/3, which is essential for the activation of many prohormones and proneuropeptides. Human subjects with homozygous PCSK1 null mutations suffer from severe intestinal malabsorption, obesity and a complex set of endocrinopathies. In addition, heterozygous common and rare PCSK1 variants/mutations are associated with isolated obesity. We have recently found the first evidence that these variants are prone to misfolding and may cause ER stress in a tissue-dependent fashion.

The aim of this project is to define the role of PC1/3 in obesity and intestinal dysfunction using two Pcsk1 mouse models, a knockout and a hypomorphic variant. Furthermore, we will explore therapeutic approaches to treat the obesity and gastrointestinal phenotypes. In the first objective we will establish whether the obese phenotype is caused by impaired hypothalamic melanocortin tone and we will investigate the effect of the administration of melanocortin agonists on food intake and body weight. In the second objective we will determine the impact of hypothalamic ER stress caused by misfolded PCSK1 mutants on obesity and leptin resistance, and we will explore whether chemical chaperones can alleviate the obese phenotype. In the third objective we will define the impact of the lack of PC1/3 activity on gut endocrine cells and we will investigate the effect of the administration of PC1/3-processed gut peptides on the gastrointestinal phenotype.