Metabolic disorders: role of pregnane X receptor, fibroblast growth factor 19 and persistent organic pollutants

Abstract

The incidence of obesity and correlated metabolic abnormalities has increased dramatically in the last decades and constitutes a huge burden on healthcare systems and economies. It is therefore important to increase our understanding of the mechanisms that underlie obesity and to develop safe and effective treatments for the management of these disorders. Paper I focus on the role of the pregnane X receptor (PXR), which is encoded by the Nr1i2 gene, in the regulation of whole-body metabolism. We carried out an extensive metabolic phenotyping of these mice to improve our understanding of the anti-obesity and anti-diabetic effects of PXR ablation. Our findings suggest that deletion of PXR improves metabolism through enhancement of skeletal muscle mass, which is associated with increased plasma levels of fibroblast growth factor (FGF) 15. We suggest that this hormone may be responsible for the stimulation of skeletal muscle growth in Nr1i2-/- mice. Larger skeletal muscles of PXR knockout mice suggest that pharmacological interventions to increase muscle size may be exploited for the management of metabolic disorders. Paper II investigates the ability of FGF19, the human orthologue of FGF15, to promote skeletal muscle growth, given the importance of this organ in general metabolism and health. We demonstrated that human recombinant FGF19 promotes skeletal muscle growth by increasing the size of skeletal muscle fibers, but without affecting their number and type. In addition, we characterized the signaling pathway required for FGF19 hypertrophic activity. Importantly, we showed that treatment with FGF19 protects from skeletal muscle loss in animal models of muscle atrophy. Our results suggest potential therapeutic application of FGF19 to stimulate skeletal muscle growth and to protect from muscle-atrophy-related conditions. Paper III examines the impact of a dietary mixture of persistent organic pollutants (POPs) at environmentally relevant levels on intestinal inflammation and immune system in the context of obesity. We revealed that, during obesity, exposure to a mixture of POPs stimulated further adipose tissue accumulation and affected the immune system. In addition, POPs promoted intestinal inflammation and influenced faecal production. In obese mice with established intestinal inflammation (induced by treatment with dextran sodium sulphate), consumption of dietary POPs further aggravated it. These data suggest that dietary exposure to a mixture of POPs can impact health and metabolic outcome in obesity.