A spoonful of sugar: feedback signals of energy stores and corticosterone regulate responses to chronic stress Mary F. Dallman*, Susan F. Akana, Kevin D. Laugero, Francisca Gomez, Sotara Manalo, M.E. Bell, Seema Bhatnagar Department of Physiology, University of California San Francisco, Box 0444, San Francisco, CA 94143-0444, USA Received 3 February 2003; accepted 3 February 2003 Abstract To begin to understand the effects of chronic stress on food intake and energy stores, the effects of increased activity in the hypothalamo – pituitary –adrenal (HPA) axis and glucocorticoids (GCs) on the body and brain must first be understood. We propose two major systems that are both GC sensitive: a metabolic feedback that is inhibitory and a direct central GC drive. Under basal conditions, the metabolic feedback signal to brain is dominant, although infusion of GC into a lateral brain ventricle blocks the effects of the metabolic feedback. Chronic stress activates GC secretion and brain nuclear GC receptor occupancy, markedly changing the normal relationships between these two major corticosteroid-activated systems. The stressor-induced switch in the relative strengths of these signals determines subsequent brain regulation of stress responses (behavioral, neuroendocrine and autonomic outflows). The metabolic feedback effects of GCs are mimicked by voluntary sucrose ingestion in adrenalectomized rats, and experiments suggest that the metabolic feedback also inhibits the stressor-induced direct GC drive on brain. We speculate that the interaction between peripheral and central GC- sensitive signaling systems may be coupled through the inhibitory actions of endogenous opiatergic inputs on corticotropin-releasing factor (CRF) neurons. D 2003 Elsevier Science Inc. All rights reserved. Keywords: Corticosterone; Chronic stress; Food intake; Energy stores 1. Introduction This article deals with the effects of chronic stress on energy balance. However, in order to begin to understand the effects of chronic stress on food intake and energy stores, we must first take into account the effects of increased activity in the hypothalamo–pituitary–adrenal (HPA) axis and glucocorticoids (GC). Chronic stress acti- vates GC secretion and markedly changes the normal relationships between two major systems in the brain: negative feedback from metabolic stores (modulated by peripheral actions of GCs) and direct drive on brain by GCs. The stress-induced change in the relative strengths of these GC-mediated signals determines subsequent brain regulation of behavioral, neuroendocrine and autonomic outflows. In this review, we will first discuss our findings on the effects of corticosterone (B) treatment of adrenalec- tomized rats on ingestion of saccharin and sucrose. These studies revealed the marked postingestive effect of sucrose on regulation of function in the HPA axis of adrenalectom- ized rats and greatly clarified our understanding of the role of corticosteroid-sensitive metabolic feedback to brain. Next, we will discuss the effects of infusion of B into the brain and our conclusion that B drive in brain directly regulates behavioral, neuroendocrine and autonomic respon- sivity to chronic stress, but does not directly activate basal metabolic feedback. Finally, we will discuss the effects of chronic cold and restraint stress in the light of the foregoing. Many of the experiments described here used adrenalec- tomized rats provided with corticosterone pellets to clamp circulating corticosteroid concentrations at a desired level. In all studies using adrenalectomized rats, the animals had free access to a sodium chloride solution to drink to compensate for the adrenalectomy-induced loss of the salt- retaining hormone, aldosterone. 0031-9384/03/$ – see front matter D 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0031-9384(03)00100-8 * Corresponding author. Tel.: +1-415-476-4614; fax: +1-415-476- 4929. E-mail address: dallman@itsa.ucsf.edu (M.F. Dallman). Physiology & Behavior 79 (2003) 3 – 12