In male C57BL/6 mice, increasing levels of calorie restriction (10–40%) are associated with graded upregulation of hypothalamic Npy and Agrp and downregulation of Pomc and Cartpt, and these changes correlate negatively with circulating leptin, insulin, and IGF-1, indicating a coordinated hunger signaling response to reduced energy availability.

When less food is eaten, fat stores shrink and the liver produces less of a growth signal, causing blood levels of three key hormones to drop. These hormones normally keep hunger signals turned off and fullness signals turned on in the brain. When they fall, the brain flips a switch: hunger-promoting genes turn up and fullness-promoting genes turn down. At the same time, the brain's internal clock genes strengthen their rhythm, making the body more alert to meal times and lowering body temperature to save energy.