Identification of the global transcriptomic response of the hypothalamic arcuate nucleus to fasting and leptin.

Leptin plays a major role in coordinating the integrated response of the brain to changes in nutritional state. Leptin receptor expressing neurones within the arcuate nucleus (ARC) of the hypothalamus sense circulating leptin and densely innervate other regions of the hypothalamus, including the paraventricular nucleus (PVN). In the ARC, leptin is known to alter the expression of genes with important roles in the control of energy balance, and the aim of the present study was to obtain a more comprehensive picture of the action of leptin in these nuclei. Mice were ad libitum fed, or fasted for 48 h when receiving either sham or i.p. leptin treatment. We used laser capture microdissection and microarrays to identify leptin-regulated transcripts within the ARC. Expression of 639 genes are increased and 452 decreased within the fasted ARC. Leptin regulates 15% and 20% of these genes, respectively. In addition to expected changes in Pomc, Agrp, Npy and Cart, pathway analysis indicated that leptin regulated other genes concerned with energy homeostasis and endocrine function. As previously reported for the PVN, leptin also altered the expression of genes involved in nervous system development and synaptic function. However, aside from a small number of such genes (e.g. Gap43), leptin influenced the expression of different sets of neuronal developmental genes in the ARC and PVN. In conclusion, the present study identifies a set of genes that are regulated, at least in part, by leptin in the ARC, highlighting these as candidates for possible roles in leptin action and resistance.