Shigeo Nakaishi

Chronic effects of interleukin-1 on hypothalamus, pituitary and adrenal glands in rat.

To assess the chronic effects of interleukin-1 (IL-1) and IL-2 on the hypothalamo-pituitary-adrenal axis in vivo, we administered recombinant human (rh) IL-1 alpha, rhIL-1 beta or rhIL-2 (2.0 micrograms/day) repetitively to adult male rats for 10 days. In rhIL-1 beta-treated rats, adrenocorticotropic hormone-like immunoreactivity (ACTH-LI) of the anterior pituitary appeared to increase first on day 3 followed by an increase of corticotropin-releasing hormone (CRH)-LI both in the hypothalamus and in the adrenal gland after day 7. At the end of the 10-day treatment, wet weights of the adrenal glands of rhIL-1 beta-treated rats increased significantly compared with those of control rats. Plasma ACTH levels in rhIL-1 beta-treated rats at the sampling time continued to be elevated throughout the experimental period. Under the same experimental design, rhIL-1 alpha increased plasma ACTH levels at the sampling time without changes in adrenal weight or in the peptide contents investigated. The same amount of rhIL-2 had no effect on these measured variables during the 10-day treatment. These data indicate that the repetitive administration of IL-1 beta resulted in chronic effects in the hypothalamo pituitary-adrenal axis to increase the activities in these organs during the treatment and, moreover, IL-1 possibly has a positive direct effect on the CRH-containing cells in the adrenal glands.

Monoamine metabolism and its responses to food deprivation in the brain of Zucker rats

Monoamines and their metabolites levels were simultaneously measured by high-performance liquid chromatography in brain regions of lean and fatty Zucker rats when fed ad lib and deprived of food for 72 hr to evaluate each monoamine metabolism. Metabolite/monoamine ratios were shown for brevity to represent its metabolism. 3-Methoxy-4-hydroxyphenylethyleneglycol/noradrenaline ratios were not affected by the phenotype factor but increased in the cortex of fatty rats and reduced in the midbrain of both phenotypes after fasting; the interaction between phenotype and feeding factors was observed in the cortex and hippocampus. 3,4-Dihydroxyphenylacetic acid/dopamine ratios were increased in the cortex of deprived fatty rats and in the medulla-pons of ad lib-fed fatties compared with lean counterparts and also increased in the striatum of lean rats after food deprivation; the interaction was observed in the cortex, midbrain and medulla-pons. Homovanillic acid/dopamine ratios were decreased in the striatum of deprived fatty rats and in the midbrain and medulla-pons of fatty rats whether deprived or not, but the ratios were not significantly changed by fasting; the interaction was observed in the striatum. 5-Hydroxyindoleacetic acid/5-hydroxytryptamine ratios were reduced in the cortex, striatum and medulla-pons of fatty rats in both feeding states and in the midbrain of deprived fatties, and after food deprivation increased in the cortex and midbrain of lean rats and in the hippocampus of both phenotypes; the interaction was observed in the midbrain.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of gemfibrozil administration on very low density lipoprotein receptor mRNA levels in rabbits

To elucidate the regulation of very low density lipoprotein (VLDL) receptor gene expression, we administered to rabbits for 14 days gemfibrozil, a fabric acid derivative and a lipid lowering drug that is also included among peroxisome proliferators. VLDL receptor mRNA levels were examined by Northern blot analysis. The VLDL receptor mRNA levels in retroperitoneal adipose tissue and in gastrocnemius muscle were increased 6.9-fold and 3.7-fold, respectively, with gemfibrozil treatment, but no marked changes were observed in the heart, the organ in which VLDL receptor is most highly expressed. In the liver, VLDL receptor mRNA was not detected either before or after gemfibrozil administration. Lipoprotein lipase (LPL) and long-chain acyl coenzyme A synthetase (ACS) mRNA levels were also increased in parallel in adipose tissue. The enhanced expression of VLDL receptor mRNA may contribute to the increase of triglyceride-rich lipoprotein catabolism in peripheral tissues such as adipose tissue and muscles.

Immunoreactive corticotropin-releasing hormone levels in discrete hypothalamic nuclei of genetically obese Zucker rats

The levels of immunoreactive corticotropin-releasing hormone (ir-CRH) were measured in discrete hypothalamic nuclei and the median eminence of obese Zucker rats and their lean littermates. More than 90% of total hypothalamic ir-CRH was detected in the median eminence in both obese and lean rats. Though ir-CRH levels in the paraventricular nucleus of obese rats tended to be lower than those of their lean littermates, no significant difference of ir-CRH levels was observed in any hypothalamic nuclei studied between obese and lean rats. However, ir-CRH levels in the median eminence of obese rats were significantly lower than those of their lean littermates (5263 +/- 438 pg/tissue vs. 7050 +/- 473 pg/tissue, P < 0.05). These results suggest that the hypoactive hypothalamic CRH tonus would play some role in the phenotypic expression of obesity in the genetically obese Zucker rats.

Effects of food deprivation and high fat diet on immunoreactive dynorphin A(1–8) levels in brain regions of Zucker rats

The levels of immunoreactive dynorphin A(1-8) (ir-DYN8) were measured in discrete brain regions of lean Zucker rats subjected to food deprivation for 72 hr and to a high fat diet, and in fatty Zucker rats after food deprivation for 72 hr. Fatty rats showed higher concentrations of ir-DYN8 in the cortex and midbrain, when compared to lean rats fed a stock diet ad lib. Food deprivation increased ir-DYN8 levels in the cortex of lean rats and fatty rats and in the hippocampus of fatty rats, but decreased its content in the striatum of lean rats and in the midbrain of fatty rats. The high fat diet increased ir-DYN8 levels in the cortex and midbrain of lean rats. These results suggest that ir-DYN8 levels in extrahypothalamic structures of Zucker rats could be differentially modified under conditions of hereditary obesity and dietary manipulations.

Immunoreactive corticotropin-releasing hormone levels in the hypothalamus of female Wistar fatty rats.

We have studied immunoreactive corticotropin-releasing hormone (CRH) levels in the hypothalamus of female Wistar fatty rats, a strain with the fa gene transferred from the Zucker rat to the Wistar Kyoto rat, in an attempt to understand the role of CRH in the development of obesity. A study was conducted with 5-week- and 12-week-old female Wistar fatty rats and lean littermates. There was no significant difference in hypothalamic CRH levels between lean and obese rats at the age of 5 weeks (1887 +/- 99.6 vs. 1767 +/- 124 pg/tissue; mean +/- S.E.M.). Hypothalamic CRH immunoreactivities, however, were significantly lower in 12-week-old obese rats (2361 +/- 132 pg/tissue) than those in lean littermates (2992 +/- 118 pg/tissue; P less than 0.05). The difference of CRH contents between the lean and obese group becomes apparent as they grow up and develop obesity.

Drug delivery system. Therapeutic application of hypothalamic hypophysiotropic hormones.

Therapeutic applications of hypothalamic hypophysiotropic hormones were discussed. Pulsatile administration of gonadotropin-releasing hormone (Gn RH) is effective to maintain menstrual cycles and ovulation in female patients with hypothalamic gonadal dysfunction and testicular function in male patients. On the other hand, continuous administration of Gn-RH or its analog is able to suppress gonadal function and thereby gonadal hormonedependent activities effectively. Application of this medical gonadectomy includes treatments for excessive menstrual bleeding, endometriosis, prostatic cancer and benign prostatic hypertrophy. Thyrotropin-releasing hormone has been applied in patients with spinocerebellar degeneration or some kinds of consciousness disturbance and somatostatin analog has benn tried to treat acromegaly. Corticotropin-releasing hormone and growth hormone-releasing hormone have also therapeutic potentials. We believe that many-sided research trials, which include development of new potent analogs, new effective drug delivery systems and further elucidation of physiology and pathophysiology about the functions of the hypothalamic hormones, are inevitable to materialize therapeutic potentials of these hormones.