Potential Model of the Metabolic Syndrome in Mouse Endocrine and Physiological Changes in Response to Chronic Corticosterone: A

Laboratories of Neuroendocrinology (I.N.K., S.M.B., N.P.B., Z.M.W., B.S.M.) and Neurobiology andBehavior (Z.M.W., D.W.P.), The Rockefeller University, New York, New York 10065Numerousclinicalandexperimentalstudieshavelinkedstresstochangesinriskfactorsassociatedwith the development of physiological syndromes, including metabolic disorders. How differentmediators of the stress response, such as corticosterone (CORT), influence these changes in riskremains unclear. Although CORT has beneficial short-term effects, long-term CORT exposure canresult in damage to the physiological systems it protects acutely. Disruption of this importantphysiologic signal is observed in numerous disparate disorders, ranging from depression to Cush-ing’s syndrome. Thus, understanding the effects of chronic high CORT on metabolism and phys-iology is of key importance. We explored the effects of 4-wk exposure to CORT dissolved in thedrinking water on the physiology and behavior of male mice. We used this approach as a nonin-vasive way of altering plasma CORT levels while retaining some integrity in the diurnal rhythmpresent in normal animals. This approach has advantages over methods involving constant CORTpellets, CORT injections, or adrenalectomy. We found that high doses of CORT (100 g/ml) resultinrapidanddramaticincreasesinweightgain,increasedadiposity,elevatedplasmaleptin,insulinandtriglyceridelevels,hyperphagia,anddecreasedhome-cagelocomotion.AlowerdoseofCORT(25 g/ml)resultedinanintermediatephenotypeinsomeofthesemeasuresbuthadnoeffectonothers. We propose that the physiological changes observed in the high-CORT animals approxi-mate changes observed in individuals suffering from the metabolic syndrome, and that they po-tentially serve as a model for hypercortisolemia and stress-related obesity.