Differential effects of a restricted feeding schedule on clock-gene expression in the hypothalamus of the rat.

Restricted feeding schedules (RFS) entrain digestive, hormonal, and metabolic functions as well as oscillations of clock genes, such as Per1 and Per2, in peripheral organs. In the brain, in particular the hypothalamus, RFS induce and shift daily rhythms of Per1 and Per2 expression. To determine whether RFS affect clock genes in extra-SCN oscillators in a uniform manner, the present study investigated daily rhythms of Per1, Per2, and Bmal1 expression in various hypothalamic regions. Wistar rats were entrained to daily RFS (2 h food access starting at ZT6, RFS) or fed ad libitum (C) for three weeks. Brains were sampled every 3 h starting at ZT0, and were processed with in situ hybridization. In response to RFS, Per1 expression showed a 3 h phase advance in the suprachiasmatic nucleus (SCN), while Per2 and Bmal1 remained unaffected. Per1 was triggered at ZT6, anticipating food access in both arcuate (ARC) and dorsomedial nuclei (DMH), and was unaffected in the ventromedial (VMH) and paraventricular (PVN) nuclei. In contrast, Per2 expression during RFS showed a marked postprandial peak in the PVN, was unchanged in the ARC, and was down-regulated in the DMH and VMH. The temporal patterns of Bmal1 expression were not significantly modified in RFS rats. RFS differentially affected clock-gene expression (phase change, up- or downregulation) depending on the combination of hypothalamic nuclei and targeted genes. Present data highlight that metabolic or temporal cues elicited by feeding modify the temporal organization in the hypothalamus and are not exclusive for a food-entrained oscillator.