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Changes in our lifestyle have resulted in a worldwide increased prevalence of obesity-related metabolic diseases such as type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Besides excessive caloric intake, a high-fructose consumption has been implicated in the accelerated development of metabolic diseases. The small intestine is the major site for fructose uptake and metabolism, while excessive fructose intake is known to cause metabolic adverse effects in the liver. In the first part of the thesis we studied the transcriptional effects of a fructose diet in the small intestine (duodenum) and liver. Fructose as compared to glucose intake has distinct effects on the small intestinal and liver transcriptomes in mice, and these effects were more profound in the small intestine. Systemic activation of nuclear receptors (NRs) has been successfully applied in the pharmaceutical industry to treat various diseases. This strategy, however, often causes major adverse effects due to the pleiotropic target genes of NRs.

Intestinal nutrient uptake and metabolism are important for whole-body energy homeostasis; therefore, we explored the potential of intestinal NR activation in the regulation of whole-body energy homeostasis. We identified several facilitative glucose transporters (GLUT-members) as novel NR target genes.

In addition, we identified the NR PPARdelta as an intestinal regulator of whole-body metabolism by protecting against diet-induced obesity and increasing high-density lipoprotein (HDL) HDL-cholesterol levels. Taken together, selective pharmacologic modulators of NRs that act solely in the gastrointestinal tract are an effective way of inducing beneficial effects on whole-body metabolism while minimising systemic adverse effects.