Metabolic adaptation to nutritional changes that occurs at birth is essential for newborn mammal survival. This is particularly crucial for newborn mice in which glucose availability from milk is low. Numerous signalling pathways and transcription factors are involved in these postnatal adaptations. The work presented in this thesis shows that nuclear receptor COUP-TFII (Chicken Ovalbumin Upstream Promoter, Transcription Factor II) plays a central role in this nutritional adaptation. Indeed, its hepatic gene expression increases during the rst days after birth. Two factors are involved in this postnatal increase : glucagon and nuclear receptor PPAR that directly controls COUP-TFII gene expression secondarily to its binding to DNA consensus responsive element (DR-1). To study COUP-TFII function, two strategies (shRNA mediating invalidation and functional invalidation using a dominant negative COUP-TFII protein) were used in 4 day-old suckling mice. Hepatic invalidation of COUP-TFII induces a marked hypoglycaemia and hypoketonemia. At this developmental stage, hepatic glucose production is ensured by gluconeogenesis that is energetically dependant of fatty acid oxidation that provide cofactors (NADH, H+ and acetyl-CoA) required for speci c gluconeogenic enzymes activities. Using the crossover plot technique, we showed that pyruvate carboxylase (acetyl-CoA dependant) and glycerad ehyde-3- phosphate dehydrogenase (NADH, H+ dependant) are involved in the inhibition of hepatic gluconeogenesis in COUP-TFII invalidated mice.Moreover, hepatic COUP-TFII invalidation reduces key gluconeogenic (PEPCK, glucose-6-phosphatase) and fatty acid oxidation (CPT-1, mHMG-CoA synthase, FABP-1) gene expression. The hypoglycaemic and hypoketonemic phenotype is reversed by pharmacologic activation of PPAR (a major factor in the regulation of fatty acid oxidation gene expression) suggesting that inhibition of gluconeogenesis is mainly due to the reduction of fatty acid oxidation. All together, these data provide evidences that COUP-TFII is a major actor in the regulation of hepatic glucose and lipid metabolisms in newborn mice.
