Obese mice (C57BL/6J ob/ob) and their lean littermates were studied at various ages from immediately post weaning until 62 weeks of age, at which mortality increased markedly. Several age-related changes were noted. 1) Plasma glucose levels were elevated in obese mice 5-20 weeks and 62 weeks of age, but were similar to those in the lean mice at 20-60 weeks of age. Plasma insulin levels were elevated in obese mice, and there were no age-related differences. 2) Brain serotonin was elevated in obese mice at all ages and increased with age in both obese and lean animals. 3) Pituitary contents of ACTH and beta-endorphin were elevated in young obese mice and increased further as these mice approached their life expectancy. 4) The ratios of ACTH to beta-endorphin immunoreactivities were similar in obese and lean mice, except in obese mice over 50 weeks of age where this ratio was increased. We conclude that: 1) the obese mouse is characterized by hyperinsulinemia and hyperadrenocorticism throughout its life; 2) the insulin resistance of the obese mouse improves at 20 weeks of age, yet deteriorates as its life expectancy is approached; 3) the obese mouse has an elevated brain serotonin content similar to previously described elevations of the putative neurotransmitters dopamine and norepinephrine in these mice; and 4) as the obese mouse approaches its life expectancy, abnormalities may occur in the synthesis, processing, or secretion of ACTH and/or beta-endorphine.

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Plasma glucose and insulin concentrations were measured during oral glucose and iv tolbutamide tolerance tests in nine women with hyperprolactinemia and the amenorrheagalactorrhea syndrome (AGS). Glucose tolerance curves, basal insulin levels, and postchallenge plasma insulin responses were significantly higher in AGS women compared to those in an age- and weight-matched control group. Fasting plasma glucagon concentrations were unaltered in AGS, but suppression of the hormone after oral glucose was greater and more prolonged relative to the control response. Oral glucose tolerance tests were performed on nine normal women during late pregnancy who had physiological hyperprolactinemia comparable to that in the AGS group. Glucose tolerance curves, exaggerated plasma insulin responses, and glucagon suppression resembled those observed in the AGS women. These results suggest that elevated plasma PRL concentrations may contribute to the development of hyperinsulinemia and accentuated glucagon suppression in response to glucose that is characteristic of late human pregnancy.

Vasoactive intestinal polypeptide (VIP) has been identified in hypothalamic tissue, is secreted into hypophysial portal blood, and stimulates prolactin (PRL) release in vivo and in vitro. It has been proposed, therefore, that VIP is a physiologic PRL-releasing factor. In this study, we confirm that VIP stimulates PRL release from rat pituitary cells in vitro, and demonstrate that an anti-VIP antiserum blocks VIP-induced PRL secretion. Surprisingly, the anti-VIP antiserum inhibited basal PRL secretion from rat pituitary cells in 3 separate experiments. Data from these experiments were pooled, as the responses were similar, revealing basal PRL release of 10.7 + 1.3 ng rPRL/10⁵ cells (X ± SE), while anti-VIP antisera significantly inhibited release to 4.4 ±0.6 ng rPRL/10⁵ cells (p < 0.001). PRL release in incubates containing control non-immune sera did not differ from basal release, 8.1 ng rPRL/10⁵ cells. A further control experiment was conducted wherein cells were incubated with an anti-ACTH antiserum, representing another hyperimmune serum, which had no effect on PRL secretion. These data suggest that VIP, in addition to its possible role as a hypothalamic-derived PRL-releasing factor, may play a role within the pituitary as a regulator of basal PRL secretion.

Previous studies have suggested that vasoactive intestinal polypeptide (VIP) is involved in regulation of PRL secretion within the pituitary gland. In order to determine whether VIP is synthesized in anterior pituitary tissue, we performed three experiments. In all experiments, anterior pituitaries were obtained from male rats. The tissue was then labeled by incubation in leucine-free minimum essential medium containing [3H]leucine, 14 microCi/ml. In Exp I, the labeled tissue was homogenized, centrifuged, and the supernatant was chromatographed on Sephadex G-50F. The fractions indicated a large peak of counts near the void volume and another peak coeluting with VIP. These latter fractions were pooled and subjected to reverse phase HPLC. Fractions from the HPLC indicated: a protein peak, VIP immunoreactivity, and maximum counts immunoprecipitated by anti-VIP serum at the retention time of synthetic porcine VIP. Exp II consisted of perifusion of labeled pituitary quarters over a 120-min period followed by an additional 60 min in the presence of 56 mM KCl. During this latter period of KCl depolarization, a large amount of 3H-labeled material was secreted. These fractions were then chromatographed on Sephadex G-50F, and the fractions coeluting with [125I]porcine VIP were subjected to immunoprecipitation with anti-VIP serum. In addition, all fractions from the Sephadex column were assayed for VIP, and the only activity was at the elution volume of [125I]porcine VIP. In Exp III, the pituitary labeling procedure included 3.6 X 10(-5) M cycloheximide. Subsequently, the tissue was perifused and the perifusate collected during the 60-min 56 mM KCl perifusion phase was pooled and immunoprecipitated with anti-VIP serum. No immunoprecipitable counts were obtained. These experiments indicate that anterior pituitary tissue synthesizes VIP on the basis of the HPLC profile and immunoprecipitation with specific anti-VIP antiserum. These results, in addition to other studies by our laboratory and others, suggest that intrapituitary VIP may be an important regulator of anterior pituitary hormone secretion, particularly PRL.

Aging is associated with alterations in mood, thermoregulation, pain threshold, and stress response. Because these functions may be modulated by endogenous opiates, we measured immunoreactive ACTH and β-endorphin in discrete brain areas and pituitary glands from rats aged 6 weeks (young), 6 months (mature), and 20–24 months (senescent). β-Endorphin and ACTH declined significantly with aging in the hypothalamus and corpus striatum. β-Endorphin and ACTH increased in the frontal lobe during early life; however, no change was noted after maturity. A discordant response with age was noted in the pituitary in that ACTH did not change, while β-endorphin increased early in life without change after maturity. Cerebellar tissue exhibited no immunoreactive ACTH or β-endorphin. Age-related changes in brain and pituitary β-endorphin and ACTH must be considered in the evaluation of the physiological aging process and when comparing studies of these neuropeptides.

Twenty minutes of submaximal treadmill running was associated with an elevation in plasma levels of p-endorphin immunoreactivity (P < 0.02). This increase was greater in men (14.9 * 3.4 fmole/ml) than women (2.6 k 1.2 fmole/ml) (P < 0.05). Plasma levels of ACTH and growth hormone also increased after running. ACTH increased more in men (7.8 k 1 . 1 fmole/ml) than in women (1.1 ? 0.44 fmole/ml) (P < 0.02). There was a 1 0037-9727/8 1/09OO 1-04$0 1 .OO/O

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