Recurrent hypoglycemia alters hypothalamic expression of the regulatory proteins FosB and synaptophysin

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2008-11, Vol.295 (5), p.R1446-R1454
• Main Authors: Al-Noori, Salwa, Sanders, Nicole M, Taborsky, Gerald J., Jr, Wilkinson, Charles W, Zavosh, Aryana, West, Connie, Sanders, Colleen M, Figlewicz, Dianne P
• Format: Article
• Language: English
• Subjects: Adrenocorticotropic Hormone - metabolism; Animals; Biochemistry; Blood Glucose - metabolism; Blotting, Western; Brain; Endocrine Physiology and Metabolism; Endocrine system; Epinephrine - metabolism; Fluorescent Antibody Technique; gamma-Aminobutyric Acid - metabolism; Genes; Glucagon - metabolism; Hydrocortisone - metabolism; Hypoglycemia; Hypoglycemia - metabolism; Hypothalamus - metabolism; Hypothalamus, Middle - metabolism; Hypotheses; Immunohistochemistry; Male; Neurons - physiology; Oxytocin - metabolism; Paraventricular Hypothalamic Nucleus - metabolism; Proteins; Proto-Oncogene Proteins c-fos - biosynthesis; Rats; Rats, Wistar; Recurrence; Synaptophysin - biosynthesis; Thyrotropin-Releasing Hormone - metabolism; Vasopressins - metabolism
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.90511.2008

Departments of 1 Psychiatry and Behavioral Science and 2 Medicine, University of Washington, Seattle; 3 Division of Endocrinology/Metabolism and 4 Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington Submitted 17 June 2008 ; accepted in final form 22 August 2008 A limiting factor to the clinical management of diabetes is iatrogenic hypoglycemia. With multiple hypoglycemic episodes, the collective neuroendocrine response that restores euglycemia is impaired. In our animal model of recurrent hypoglycemia (RH), neuroendocrine deficits are accompanied by a decrease in medial hypothalamic activation. Here we tested the hypothesis that the medial hypothalamus may exhibit unique changes in the expression of regulatory proteins in response to RH. We report that expression of the immediate early gene FosB is increased in medial hypothalamic nuclei, anterior hypothalamus, and posterior paraventricular nucleus of the thalamus (THPVN) of the thalamus following RH. We identified the hypothalamic PVN, a key autonomic output site, among the regions expressing FosB. To identify the subtype(s) of neuronal populations that express FosB, we screened candidate neuropeptides of the PVN for coexpression using dual fluorescence immunohistochemistry. Among the neuropeptides analyzed [including oxytocin, vasopressin, thyrotropin-releasing hormone, and corticotropin-releasing factor (CRF)], FosB was only identified in CRF-positive neurons. Inhibitory -aminobutyric acid-positive processes appear to impinge on these FosB-expressing neurons. Finally, we observed a significant decrease in the presynaptic marker synaptophysin within the PVN of RH-treated vs. saline-treated rats, suggesting that rapid alterations of synaptic morphology may occur in association with RH. Collectively, these data suggest that RH stress triggers cellular changes that support synaptic plasticity, in specific neuroanatomical sites, which may contribute to the development of hypoglycemia-associated autonomic failure. FosB; recurrent hypoglycemia; paraventricular nucleus; corticotropin-releasing factor; synaptophysin Address for reprint requests and other correspondence: S. Al-Noori, Metabolism/Endocrinology (151), VA Puget Sound Health Care System, 1660 So. Columbian Way, Seattle, WA 98108 (e-mail: saan{at}u.washington.edu )