The ability of an organism to respond lo challenges to its physiological homeostasis by increasing the activity of the brain- pituitary-adrenocortical hormonal axis is critical to survival in all mammals, including rats and man. In the absence of a functional adrenal cortex such challenges, or """"""""stresses,"""""""" are usually fatal. One of the most potent and reliable stimuli to secretion of adrenocorticotropic hormone (ACTH) from the pituitary is hypoglycemia, lypically induced experimentally by injections of insulin. The effect of hypoglycemia is now known to be mediated at least in part via glucose sensors in the hypothelomas. resulting in secretion of corticotropin-releasing factor (CRF) into the hypophysial-portal circulating. Conversely, in isolated rat hypothalami, hyperglycemia inhibits secretion of CRF and also of oxytocin, another hypothalamic peptide known to stimulate ACTH secretion. Failure to adequately regulate circulating products of metabolism (glucose, fatty acids) within normal limits is one of the most widespread endocrine associated disorders in human beings, and can result from numerous pathologies (diabetes, fasting). This 'rises the question of the capacity of individuals to respond to different physiological stresses, such as hemorrhage, during periods of abnormal metabolic status (hyperglycemia, hyperlipidemia). Fatty acids have been shown lo inhibit secretion of growth hormone in rats and man, at both the hypothalamic and pilutuary level. Since one of the major functions of adrenal glucoconlcoids is to catabolize triglycerides in order to provide usable energy substrates for the brain, it may well be that fatty acids, like glucose, inhibit the secretion of CRF and AGTH. Therefore, the long term goals of these projects will be to characterize in detail the effects of glucose and fatty acids on secretion of CRF and ACTH at the tissue or cellular level, and to relate these effects to the ability of rats to respond to stress in vivo under periods of experimentally altered intermediary metabolism. The role of other substances that themselves influence intermediary metabolism, such as catecholamines, in activating CRF release will also be examined. These studies will also determine the ontogeny of the ACTH and corticosterone secretory responses to insulin-induced hypoglycemia, since young rats typically show reduced sensitivity to certain stimuli that produce robust secretory responses in adults. Similarly, human newborns also undergo a period of abnormal responsivity to some, but not all, types of stress. Finally, the effects of hyperglycemia on suckling-induced secretion of oxytocin in rats will be examined, since glucose decreases oxytocin secretion in vitro, and since a relatively high proportion of pregnant women develop gestational deabetes in the last trimester of pregnancy, resulting in chronic hyperglycemia.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Endocrinology Study Section (END)
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Boston University
Schools of Arts and Sciences
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Brake, P B; Arai, M; As-Sanie, S et al. (1999) Developmental expression and regulation of adrenocortical cytochrome P4501B1 in the rat. Endocrinology 140:1672-80
Widmaier, E P; Margenthaler, J; Sarel, I (1995) Regulation of pituitary-adrenocortical activity by free fatty acids in vivo and in vitro. Prostaglandins Leukot Essent Fatty Acids 52:179-83
Sarel, I; Widmaier, E P (1995) Stimulation of steroidogenesis in cultured rat adrenocortical cells by unsaturated fatty acids. Am J Physiol 268:R1484-90
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Widmaier, E P; Kunz, T H (1993) Basal, diurnal, and stress-induced levels of glucose and glucocorticoids in captive bats. J Exp Zool 265:533-40
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Arai, M; Widmaier, E P (1993) Steroidogenesis in isolated adrenocortical cells during development in rats. Mol Cell Endocrinol 92:91-7
Widmaier, E P; Rosen, K; Abbott, B (1992) Free fatty acids activate the hypothalamic-pituitary-adrenocortical axis in rats. Endocrinology 131:2313-8
Arai, M; Widmaier, E P (1991) Activation of the pituitary-adrenocortical axis in day-old rats by insulin-induced hypoglycemia. Endocrinology 129:1505-12
Widmaier, E P (1991) Endocrine control of glucose homeostasis in mammals: food for thought. Mol Cell Endocrinol 75:C1-6

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