Early morning rise in hypothalamic—pituitary— adrenal activity: A role for maintaining the brain’s energy balance Christian Benedict a, * , Werner Kern b , Sebastian M. Schmid b , Bernd Schultes b,c , Jan Born a , Manfred Hallschmid a a Department of Neuroendocrinology, University of Lu ¨beck, Ratzeburger Allee 160, 23538 Lu ¨beck, Germany b Department of Internal Medicine I, University of Lu ¨beck, Lu ¨beck, Germany c Interdisciplinary Obesity Center, Kantonsspital St. Gallen, Switzerland Received 10 September 2008; received in revised form 10 October 2008; accepted 13 October 2008 1. Introduction Secretory activity of the hypothalamic—pituitary—adrenal (HPA) axis follows a distinct 24-h pattern, which, after a nadir during the early night, is characterized by a most prominent rise in activity in the late night, reaching a Psychoneuroendocrinology (2009) 34, 455—462 KEYWORDS Central nervous system; Adrenocorticotropin; Cortisol; Circadian rhythm; Energy metabolism; Food intake Summary A profound rise in secretory activity in the early morning hours hallmarks the circadian regulation of the hypothalamic—pituitary—adrenal (HPA) stress axis. Functions and mechanisms underlying this regulation are barely understood. We tested the hypothesis that the early morning rise in HPA axis activity originates in part from a negative energy balance due to nocturnal fasting and concomitant increases in cerebral glucose demands. According to a 2  2 design, healthy men were infused with glucose (4.5 mg/kg min, 2300—0700 h) 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 rapid eye movement (REM) sleep at the expense of sleep stage 2 (each P < 0.05). Glucose infusion increased leptin levels in both groups (P < 0.005) and reduced morning food intake in the Wake (P < 0.02) but not in the Sleep group (P > 0.46). Our 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 may reduce the brain’s sensitivity to the anorexigenic effect of enhanced glucose supply. # 2008 Elsevier Ltd. All rights reserved. * Corresponding author. Tel.: +49 451 5004602; fax: +49 451 5003640. E-mail address: benedict@kfg.uni-luebeck.de (C. Benedict). available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/psyneuen 0306-4530/$ — see front matter # 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2008.10.010