Early morning rise in hypothalamic-pituitary-adrenal activity: a role for maintaining the brain's energy balance

We hypothesized that the circadian rise in hypothalamic-pituitary-adrenal (HPA) axis activity in the morning hours originates in part from a negative energy balance due to nocturnal fasting and concomitant increases in cerebral glucose demands. To test this hypothesis, we examined the effects of nocturnal glucose infusion on HPA axis activity and food intake. According to a 2×2 design, healthy men were infused with glucose (4.5mg/kg*min, 2300 to 0700h) and saline, respectively, during nocturnal sleep (n=9) or wakefulness (n=11). Circulating concentrations of ACTH, cortisol, glucose, insulin, and leptin were measured and food consumption in the next morning was assessed. Independent of sleep, glucose infusion reduced levels of ACTH (P<0.01) and cortisol (P<0.02) during the second night half. In the Sleep group, glucose infusion enhanced REM sleep while reducing time spent in sleep stage 2 (each P<0.05). While leptin levels were slightly reduced in the Wake as compared to the Sleep group (P<0.06), they were distinctly increased by glucose infusion in both treatment groups (P<0.005). Nocturnal glucose infusion reduced morning food intake in the Wake (P<0.02) but not in the Sleep group (P>0.46). These findings support the view that increasing energy demands of the brain towards the end of the night essentially contribute to the early morning rise in HPA axis activity. Sleep is not critically involved in this glucose-glucocorticoid feedback loop but reduces the brain's sensitivity to the anorexigenic effect of enhanced glucose supply.