FEAST AND FAMINE - CRITICAL ROLE OF GLUCOCORTICOIDS WITH INSULIN IN DAILY ENERGY-FLOW

The hypothesis proposed in this review is that normal diurnal rhythms in the hypothalamic-pituitary-adrenal (HPA) axis are highly regulated by activity in medial hypothalamic nuclei to effect an interaction bet ween corticosteroids and insulin such that optimal metabolism results in response to changes in the fed or fasted state of the animal. There are marked diurnal rhythms in function of the HPA axis under both bas al and stress conditions. The HPA axis controls corticosteroid output from the adrenal and, in turn, forward elements of this axis are inhib ited by feedback from circulating plasma corticosteroid levels. Basal activity in the HPA axis of mammals fed ad lib peaks about 2 h before the peak of the diurnal feeding rhythm, and is controlled by input fro m the suprachiasmatic nuclei. The rhythm in stress responsiveness is l owest at the time of the basal peak and highest at the time of the bas al trough in the HPA axis activity. There are also diurnal rhythms in corticosteroid feedback sensitivity of basal and stress-induced ACTH s ecretion which peak at the time of the basal trough. These rhythms are all overridden when feeding, and thus insulin secretion, is disrupted . Corticosteroids interact with insulin on food intake and body compos ition, and corticosteroids also increase insulin secretion. Corticoste roids stimulate feeding at low doses but inhibit it at high doses; how ever, it is the high levels of insulin, induced by high levels of cort icosteroids, that may inhibit feeding. The effects of corticosteroids on liver, fat, and muscle cell metabolism, with emphasis on their inte ractions with insulin, are briefly reviewed. Corticosteroids both syne rgize with and antagonize the effects of insulin. The effects of stres s hormones, and their interactions with insulin on lipid and protein m etabolism, followed by some of the metabolic effects of injury stress, with or without nutritional support, are evaluated. In the presence o f elevated insulin stimulated by glucocorticoids and nutrition, stress causes less severe catabolic effects. In the central nervous system, regulation of function in the HPA axis is clearly affected by the acti vity of medial hypothalamic nuclei that also alter feeding, metabolism , and obesity in rats. Lesions of the arcuate (ARC) and ventromedial ( VMN) paraventricular (PVN) nuclei result in obesity and hyperactivity in the HPA axis. Moreover, adrenalectomy inhibits or prevents developm ent of the lesion-induced obesity. There are interactions among these nuclei; one mode of communication is via inputs of neuropeptide Y (NPY ) cells in the ARC to the VMN, dorso-medial nuclei, and PVN. We sugges t that these NPY-ergic pathways, the activity of which is increased by fasting, and reduced by feeding, insulin, and lack of glucocorticoids , may mediate the fasting-induced override of diurnal rhythms in the H PA axis. Supporting data are drawn from studies of diabetic rats and r odents with genetic obesities. We conclude that (a) There are marked i nteractions between glucocorticoids and insulin on most aspects of met abolism; (b) The NPY-ergic pathway from arcuate to paraventricular nuc lei probably mediates fasting-induced alterations in hunger and the HP A axis activity; (c) modulation of NPY-ergic activity in the arcuate i s mediated by glucocorticoids through stimulation of insulin secretion ; insulin, in turn, inhibits NPY-ergic activity in the arcuate; (d) th e interaction between corticosteroids and insulin serves as a peripher al hormonal feedback loop that regulates this NPY-ergic feeding-fastin g system.