LEAP-2, integración funcional tejido específica en el balance energético

Abstract

Ghrelin is an orexigenic hormone with adipogenic functions and favors the release of GH by exerting its actions through the growth hormone secretagogue receptor (GHSR1a). The discovery of LEAP-2 as an endogenous ligand of the ghrelin receptor, showing opposite effects to ghrelin in terms of intake, has opened a new field of study, fostering research on its potential as a possible anti-obesity therapeutic target. In this doctoral thesis we try to elucidate the actions of LEAP-2 in the regulation of energy homeostasis and its effects by antagonizing ghrelin, determining the physiological mechanisms responsible for these effects. Using preclinical mouse models, we analyzed the effect of its central treatment on thermogenesis and hepatic metabolism in different conditions such as diets that induce obesity and resistance to ghrelin and during aging. In order to discern central and peripheral actions of LEAP-2, in vitro experiments were performed with primary cultures of adipose tissue and human hepatocyte cell lines. Our results indicate that LEAP-2 is regulated by nutritional status inversely to ghrelin, and that its central administration exerts important actions on the energy homeostasis of the organism, acting over thermogenesis and fatty acid metabolism in the liver. On the other hand, it also acts peripherally and directly on the liver and adipose tissue, as confirmed by experiments carried out with cells. In conclusion, LEAP-2 is positioned as a counterregulatory hormone, playing a fundamental role in the ghrelin system and could be considered as a new therapeutic target in the treatment of obesity, MAFLD and other metabolic diseases.