To identify the sequences of changes in putative signals, reception of these and responses to starvation, we sampled fed and starved rats at 2- to 6-h intervals after removal of food 2 h before dark. Metabolites, hormones, hypothalamic neuropeptide expression, fat depots, and leptin expression were measured. At 2 h, insulin decreased, and FFA and corticosterone (B) increased; by 4 h, leptin and glucose levels decreased. Neuropeptide Y messenger RNA (mRNA) increased 6 h after food removal and thereafter. Adrenal and plasma B did not follow ACTH and were elevated throughout, with a nadir at the dark-light transition. Leptin correlated inversely with adrenal B. Fat stores decreased during the last 12 h. Leptin mRNA in perirenal and sc fat peaked during the dark period, resembling plasma leptin in fed rats. We conclude that 1) within the first 4 h, hormonal and metabolic signals relay starvation-induced information to the hypothalamus; 2) hypothalamic neuropeptide synthesis responds rapidly to the altered metabolic signals; 3) catabolic activity quickly predominates, reinforced by elevated B, not driven by ACTH, but possibly to a minor extent by leptin, and more by adrenal neural activity; and 4) leptin secretion decreases before leptin mRNA or fat depot weight, showing synthesis-independent regulation.