Central regulation of food intake and reproduction

Abstract

The work described in this thesis investigates the actions of hypothalamic neuropeptides involved in the control of energy homeostasis and reproduction. Cerebellin 1 (Cbln1) is a 16-amino acid peptide abundantly expressed in the cerebellum and the hypothalamus. I have shown that Cbln1 increases food intake when administered centrally to rats, and that this effect may be partly mediated by neuropeptide Y. I have also demonstrated that Cbln1 mRNA expression within the ventromedial nucleus of the hypothalamus is up-regulated following a 48-hour fast, suggesting that Cbln1 may have a physiological role in the control of food intake. In addition to hypothalamic centres, the reward system has an important role in the control of feeding. The melanocortin system has a well characterised role in the homeostatic control of food intake. My work suggests that the melanocortin system may also have a previously unknown role within the ventral tegmental area (VTA) in the hedonic control of feeding. Intra- VTA administration of a melanocortin agonist reduced, whereas an antagonist increased, food intake in rats. My work suggests that the VTA melanocortin system may act upstream of dopamine signalling to influence feeding. Kisspeptin is a hypothalamic neuropeptide with a crucial role in reproduction. The hypothalamus contains two populations of kisspeptin neurones, located in the arcuate nucleus (Arc) and in the anteroventral periventricular nucleus. The physiological role of these two populations is unknown. I used recombinant adeno-associated virus (rAAV) to suppress kisspeptin expression within the Arc in female rats. Animals injected bilaterally into the Arc with rAAV-kisspeptin antisense had significantly fewer oestrous cycles, and an increase in oestrous cycle length, compared to controls. In summary, these studies have identified novel roles for Cbln1 and the melanocortin system in the control of food intake, and have demonstrated the importance of Arc kisspeptin signalling in the regulation of reproduction.