Neuropeptide-Y Concentration in Microdissected Hypothalamic Regions andin VitroRelease from the Medial Basal Hypothalamus-Preoptic Area of Streptozotocin-Diabetic Rats with and without Insulin Substitution Therapy*

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Abstract
Experimental diabetes adversely affects hypothalamic control of gonadotropin secretion and sex behavior and induces hyperphagia accompanied by severe body weight loss. Neuropeptide-Y (NPY) stimulates pituitary gonadotropin release, inhibits sexual behavior, and stimulates robust feeding in rats by acting at different sites in the hypothalamus. Therefore, we tested the hypothesis that altered hypothalamic NPY neurosecretion may mediate the constellation of effects observed in streptozotocin-induced diabetic (STZ-D) rats. Adult male rats were made diabetic by a single injection of STZ (50 mg/kg). Five months later, in vitro NPY release from the hypothalamic fragment encompassing the medial basal hypothalamus and preoptic area and NPY concentrations in seven hypothalamic sites were assessed. Basal NPY release was not significantly changed after STZ treatment. However, in response to a 30-min pulse of KC1 (45 HIM), NPY release from the medial basal hypothalamuspreoptic area of STZ-D rats was significantly increased compared to that in age-matched controls. In the STZ-D rats, NPY concentrations in six of the seven microdissected nuclei, including those mediating control of pituitary gonadotropin, sexual, and feeding behaviors, were increased compared to control values. In an additional study similar increments in NPY concentrations in the hypothalamic sites were observed 6 months after STZ treatment. The effects of insulin on NPY levels in microdissected hypothalamic sites in STZ-treated and BB diabetic rats was next assessed. One group of rats was treated with STZ, and the other group of rats was additionally treated with insulin (6 U/kg-day) for 3 months after development of diabetes with STZ. Again, STZ treatment alone, even for 3 months, increased NPY levels in all seven nuclei, including the suprachiasmatic nuclei. Insulin therapy completely prevented the STZ-induced increments in NPY levels in all hypothalamic sites, and the blood glucose level was 233 ± 22 mg/dl in insulin-treated STZD rats and 496 ± 6 mg/dl in untreated STZ-D rats. Similarly, NPY concentrations in five of the seven nuclei were unchanged in spontaneously diabetic BB rats (blood glucose, 435 ± 67 mg/ dl) maintained on insulin (5–8 U/kg-day). These results demonstrate that STZ-D rats have a widespread increase in NPY levels in hypothalamic sites, and there is an increase in the evoked release of NPY from the hypothalamus. These findings are in accord with the hypothesis that increased secretion of NPY in those hypothalamic sites, which have been implicated in the control of gonadotropin secretion, feeding, and sexual behaviors, may be responsible for the impaired neuroendocrine and behavioral effects reported in STZ-D rats. The observation that insulin therapy prevented the hypothalamic NPY response in conjunction with mild hyperglycemia further suggests that insulin may in part regulate the secretory activity in NPYergic neurons. (Endocrinology126: 192–198,1990)