Daily rhythms in physiology and behaviour are orchestrated by theautonomously rhythmic cells of the suprachiasmatic nucleus (SCN).Restricting food intake to the rest phase of nocturnal rodents, leads to thedevelopment of meal anticipatory behaviour, corticosterone and bodytemperature. Given that lesions to the SCN fail to abolish meal anticipation, asecond oscillator of unknown location, referred to as the food-entrainableoscillator (FEO) is thought to exist. Although the site of the FEO is unknown,several hypothalamus nuclei, including the dorsomedial hypothalamus(DMH) are thought to play a role in meal anticipation. Given thatadrenalectomy is reported to abolish meal anticipation, an intact HPA axis isalso thought to contribute to the functioning of the FEO. Some forms ofobesity are characterised by high basal levels of circulating corticosterone. Inaddition, limited access to high fat diet, fails to induce the development ofrobust meal anticipation in rats. During our initial studies, the effect of a standard and 45% high fat diet onthe development of meal anticipatory behaviour and hypothalamic c-Fosexpression were investigated. Restricted access to high fat diet led toattenuation of meal anticipation compared to those fed standard diet. Thiswas concurrent with a failure to develop an anticipatory rise in DMH c-Fosexpression. A meal anticipatory rise in corticosterone is thought to benecessary for the presence of meal anticipation as well as adaptation ofmetabolism to daily restricted feeding. In the next set of studies, weconfirmed that restricted access to standard diet leads to the development ofa meal anticipatory rise in plasma corticosterone. In contrast we observed adramatic post-anticipatory rise in plasma corticosterone in rats givenrestricted access to the 45% high fat diet. We hypothesised that the highcorticosterone levels resulting from high fat diet were a contributing factor tothe lack of meal anticipation in high fat fed rats. With the aid of apharmacokinetic study, a suitable experiment was designed for daily dosingof a potent glucocorticoid receptor antagonist, RU486, with the aim ofrescuing meal anticipation in high fat fed rats. Interestingly, treatment withRU486 successfully rescued meal anticipation in high fat fed rats, butattenuated meal anticipation in standard diet restricted fed rats. In the finalseries of studies the effect of diet and feeding regime on glucose toleranceand metabolism were investigated. High fat feeding was found to reduceglucose tolerance in both ad lib and restricted fed rats, with RU486 treatmentimproving glucose tolerance in a time dependant manner. Restricted accessto food was found to induce post satiation lipogenesis in both standard dietfed and to a lesser extent in high fat fed rats, an effect which may bebeneficial in reducing obesity. Overall the results provide further insight intothe complex role of corticosterone in promoting or preventing mealanticipatory behaviour. An anticipatory rise in plasma corticosterone isrequired for meal anticipation, as repeated daily dosing of RU486 inhibit mealanticipation. The high basal levels of corticosterone in high fat fed rats mayprevent meal anticipation, insulin secretion and post-satiation lipogenesiswhich may in fact be a homeostatic mechanism to prevent obesity. Nonetheless, treatment with RU486 rescues behavioural meal anticipationand glucose tolerance.

La première partie de mon travail de thèse a été de définir le rôle joué par le récepteur nucléaire Rev-erb alpha dans les mécanismes de synchronisation par la nourriture d’une horloge circadienne putative, non encore localisée, appelée « horloge alimentaire ». La seconde partie de mon travail a consisté à étudier la participation de Rev-erb alpha dans les régulations des métabolismes glucidique et lipidique. L’ensemble de nos données indique que le répresseur transcriptionnel Rev-erb alpha joue un rôle charnière dans les fonctions circadiennes ainsi que dans le métabolisme. En effet, d’un point de vue circadien, l’absence de Rev-erb alpha altère la synchronisation à l’heure des repas – démontré par une réduction des sorties comportementales et physiologiques de l’horloge alimentaire, ainsi que par l’absence d’ajustement du rythme de la protéine d’horloge PER2 dans l’oscillateur cérébelleux. Sur le plan métabolique, la délétion de ce gène modifie notamment le métabolisme des lipides – démontré par une accumulation excessive de tissu adipeux, une utilisation préférentielle des acides gras, ainsi qu’une perte de contrôle de l’expression de la Lipoprotéine lipase. / The work performed during this PhD thesis aimed at investigating the role of the transcriptional silencer Rev-erbα in both the circadian clockwork of the food-entrainable oscillator and metabolic regulations. Firstly, by evaluating food-anticipatory components in animals fed once a day at the same time, we showed that mice lacking Rev-erbα display a reduction in locomotor activity prior to food access compared to littermate controls. Accordingly, the rises in body temperature and corticosterone that anticipate mealtime are also diminished. Interestingly, daily p-ERK expression in hypothalamic regions and daily PER2 expression in the cerebellum of Rev-erbα KO mice are not phase-adjusted to feeding time. These results indicate that Rev-erbα participates in the integration of feeding signals and in food-seeking behaviors. Secondly, by investigating energy balance in fasted, normal chow or high-fat fed animals, we revealed that Rev-erbα KO mice exhibit greater reliance on lipid fuels as energy substrates, contributing to a mild hyperglycemic state. We also found that Lipoprotein lipase (Lpl) expression, is strongly up-regulated in peripheral tissues of Rev-erbα KO mice, predisposing mice to obesity. In this regard, we uncovered a new molecular pathway that ties clock-driven Lpl expression to energy homeostasis. These findings highlight the significance of daily Rev-erbα oscillations to prevent the appearance of the metabolic syndrome.In conclusion, we provide evidence that REV-ERBα may be a part of the food-entrainable oscillator clockwork that triggers food-anticipatory components, and represents a pivotal player to link the core clock machinery to metabolic pathways.