Previous studies have shown that absence of proneurotensin in mice (knock-out model) protects from high-fat diet induced obesity and liver steatosis, partially through reduced intestinal absorption of fat. Moreover, human studies showed that high plasma concentration of proneurotensin independently predicts obesity, diabetes, liver steatosis, cardiovascular disease and mortality. We therefore tested the therapeutic potential of proneurotensin blockade by administration of a monoclonal antibody (vs control) against proneurotensin in mice, who had been made obese though high fat diet. We found that mice treated with antibodies blocking proneurotensin had greater weight loss, smaller fat depots, increased faecal cholesterol excretion, reduced liver fat and larger muscle fibre size. The results indicate that antibody-based blockade of proneurotensin reduces the adverse cardiometabolic risk associated with high levels of the hormone. To date, antibody-based blockade of proneurotensin is not available in humans. We therefore assess if inhibition of intestinal production and secretion of proneurotensin, using the drug orlistat, may reduce liver steatosis and cardiometabolic risk factors in obese humans with non-alcoholic fatty liver disease and high plasma concentration of proneurotensin (>150 pmol/L). This is the first ever randomized controlled study in humans targeting proneurotensin for cardiometabolic disease prevention. Recruitment is ongoing and results will be available during the last year of this ERC-ADG project.
We and others have shown that high plasma concentration of vasopressin, as measured by copeptin, is consistently independently predictive of future risk of diabetes in healthy individuals. In turn, the most common cause of high vasopressin in the healthy state is a low water intake and in low-water drinkers vasopressin level can be effectively lowered by increasing water intake. In the current project, we therefore undertake a large-scale randomized clinical trial testing if diabetes can be prevented by increasing water intake with 1.5 L daily (vs control therapy) during 12 months in subjects with habitually low water intake and high plasma concentration of vasopressin. Recruitment is finished and results expected Q1 2025.
Studies on the effects of the effects of intravascular compartmentalization and genetic effects on production of bioactive adrenomedullin are ongoing.
