|Budget Amount *help
¥5,300,000 (Direct Cost : ¥5,300,000)
Fiscal Year 1996 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1995 : ¥4,400,000 (Direct Cost : ¥4,400,000)
Aims of the Research : There have been no systematic investigations into distorted higher brain functions in diabetes mellitus, while brain damages due to neuropathy and/or ischemic changes in the brain vessels were abundantly reported as the complications of the disease. Our present study aimed to examine the mechanisms as to how metabolic dysfunctions of diabetic patients may affect their higher brain functions. To address the present investigaton, dynamic changes in hypothalamic neuronal histamine were assessed as a main parameter because of its essential regulatory functions in energy homeostasis.
Results : 1) Both steptozotocin-induced diabetic rats, an insulin deficient animal model, and Zucker obese rats, a genetically hyperinsulinemic model, showed deficiency in hypothalamic neuronal histamine. The results indicate that there must be some factor (s) oter than insulin which regulate activity of histamine neuron systems in the hypothalamus. 2) Peripheral administration of leptin,
an ob gene product, increased histamine turnover in the hypothalamus, concomitantly with suppression of food intake. 3) Depletion of hypothalamic neuronal histamine by alpha-fluoromethylhistidine (FMH) attenuated the leptin-induced feeding suppression by almost 50%. These findings indicate that a half of the leptin-induced feeding suppression is controlled by hypothalamic-neuronal histamine. 4) In ob/ob and db/db mice with the genetic abnormalities in ob gene and leptin receptor, respectively, concentrations of hypothalamic neuronal histamine were predominantly lower than those in their lean littermates. Thus, the defect in leptin action in the brain produces insufficient activity of central histamine neuron systems. 5) In diet-induced obese rats, however, both concentrations of plasma leptin and neuronal histamine in the hypothalamus increased along with development of the obesity. Taken together, changes in neuronal histamine in the hypothalamus of these obese animal models are resulted from leptin action, but not from obesity per se. 6) Corticotropin releasing hormone (CRH), a neuropeptide to induce feeding suppression, elevated histamine turnover in the hypothalamus. In contrast, both neuropeptide-Y (NPY), a peptide to increase food intake, and tumor necrosis factor-alpha (TNF-alpha), a cytokine to induce insulin resistance, did not affect the activity of hypothalamic histamine neurons. 7) The neuronal histamine enhanced mRNA expression of glucose transporter 4 (GLUT4) in the brain. Together with those findings, neuronal histamine has been shown to play crucial roles in homeostatic regulation of energy metabolism in the central nervous system. 8) Hypothalamic neuronal histamine decreased insulin secretion and increased lipolytic action in the adipose tissues through activaton of sympathetic nervous system. 9) L-Histidine and fatty acids affected brain histamine functions. 10) Histamine neuron systems in the brain potently regulated higher brain functions including learning and memory in health and the disease so that the functions could be maintained within the physiological state. In particular, activation of the systems was expected to potentiate memory consolidation in the physiological state and improve the impaired higher brain functions in the disease.
Summary : The activity and then the functions of histamine neuron systems have been found to be regulated by a variety of humoral factors including brain neuropeptides, blood-born metabolites such as glucose etc, and adipocyte-borm leptin. Changes in those humoral signals under diabetic condition may be integrated by the histamine neuron systems to affect not only higher brain functions but also peripheral metabolisms as a feedback circle.