The projection from the arcuate nucleus during fetal and neonatal development

Abstract

Obesity is an increase in adiposity and affects a large proportion of the population. Maternal overnutrition and undernutrition during pregnancy and/or lactation have been shown to induce offspring obesity.

The arcuate nucleus (ARC) contains neuropeptide Y (NPY)/ agouti-related protein (AgRP)-expressing neurons and proopiomelanocortin (POMC)-expressing neurons: the main cellular mediators of energy homeostasis. Both NPY/AgRP and POMC-expressing neurons in the ARC form neural connections to brain regions such as the paraventricular nucleus of the hypothalamus (PVH), which regulates food intake. Both neurons also receive and integrate peripheral signals such as leptin, which is critical for the regulation of energy homeostasis.

The studies in this thesis are divided into two parts, where the first part has characterised the development of the ARC neurons and projections from the ARC to the PVH during the fetal period. The differentiation of NPY/AgRP and POMC-expressing neurons are initiated in the fetal period, and both neurons have been shown to increase numbers between early and late gestation. AgRP-immunoreactive fibres have been observed in the PVH at mid-gestation with an increased number of fibres at late-gestation, which shows that the development of nerve fibre circuitry of the ARC begins in the fetal period. In addition, this thesis has shown expression of receptors for axon guidance or growth molecules, such as brain-derived neurotrophic factor (BDNF), sonic hedgehog (Shh) and netrin-1 in the ARC during mid-late gestation. The expression of axon guidance or growth receptors in the ARC indicates potential candidate molecules to interact with projection of the nerve fibres from the ARC neurons. The second part of the thesis has observed the effect of maternal undernutrition on the nerve fibre projection from the ARC to the PVH, as the offspring raised by food-restricted dams during lactation have decreased nerve fibre projection to the PVH in comparison to the offspring raised by standard-diet fed dams. Moreover, this study has highlighted the effect of leptin on the nerve fibre projection from the ARC to the PVH during lactation, as the administration of leptin to the offspring of food-restricted dams has restored the decreased nerve fibre projection from the ARC to the PVH.

In conclusion, this project has characterised the development of the ARC neurons during the fetal period, and is the first study to verify the presence of the nerve fibre projections from the ARC neurons during the fetal period in mice. Further studies can be continued based on this information, to study the mechanisms that drive the formation of these neural connections, and how dysregulated maternal diet can alter the mechanisms, and thus predispose offspring to obesity. This project has also elaborated the importance of maternal diet during lactation and the effect of leptin on the neuroanatomy of the ARC.