The role of KLF4 and pregnancy under HFD on energy homeostasis

Abstract

In this thesis we report that hypothalamic KLF4 represents a new transcription factor specifically modulating AgRP expression in vivo. Hypothalamic KLF4 colocalizes with AgRP neurons and is modulated by nutritional status and leptin. KLF4 over-expression in the ARC is sufficient to increase food intake and to blunt the anorectic action of leptin in a FoxO1-independent manner. Moreover hypothalamic KLF4 is regulated by leptin in rats fed a chow diet but not in DIO rats, and KLF4 does not affect HFD-induced leptin resistant. Energy homeostasis in pregnancy is associated to marked changes in the molecular set-point at tissue level as shown here by the finding of decreased BAT and body temperature during pregnancy in order to provide energy resources to the fetus. Metabolic homeostasis undertakes also many adaptive changes as shown by increased liver mass in a diet-independent manner and decreased glucose and increased triglyceride serum levels. In addition there is a pregnancy-induced increase in fat mass that can be mimicked by exposure to HFD before pregnancy. The changes in FGF21 and the likelihood of a pregnancy-induced FGF resistance highlights the adaptive maternal changes in this physiological setting. Although our pregnancy study does not provide clear evidence of the molecular mechanisms involved, it raises the need of further investigation.