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Leptin, a hormone secreted by adipose tissue in proportion to body adiposity, is proposed to be involved in the central nervous regulation of food intake and body weight. In addition, evidence is emerging that leptin regulates neuroendocrine and metabolic functions as well, presumably via its action in the central nervous system (CNS). To investigate this regulatory effect of leptin, we infused 3.5 microg of human leptin directly into the third cerebral ventricle (i3vt) of lean male Long-Evans rats, 90 min before the onset of their dark phase. Before and after infusion, blood samples were withdrawn through indwelling catheters for assessment of hormonal (plasma corticosterone, insulin, leptin), autonomic (plasma norepinephrine, epinephrine), and metabolic (plasma glucose) parameters. I3vt leptin caused an increase in plasma corticosterone and plasma leptin levels relative to the control condition. The effects of i3vt leptin on corticosterone secretion became particularly apparent after the onset of the dark phase. The results of the present study indicate that i3vt leptin stimulates the hypothalamo-pituitary-adrenal (HPA) axis, particularly when rats normally encounter their largest meals. These results are consistent with the possibility that high circulating leptin levels may underlie the increased activity of the HPA axis that is generally characteristic of human obesity and most animal models of obesity.

The present study was designed to investigate the mechanism leading to inhibition of insulin release during exercise. To investigate the influence of circulating epinephrine and norepinephrine, these catecholamines were infused intravenously in resting islet-transplanted and control rats. The role of neural influences on insulin release was investigated by a swimming exercise study in islet-transplanted and control rats, before and after adrenodemedullation. Streptozotocin-induced diabetic Albino Oxford rats received 5 microliters islet tissue into the portal vein, resulting in return of normal basal glucose and insulin levels. Transplanted and control animals were provided with two permanent heart catheters to sample blood and to give infusions. Infusion of epinephrine and norepinephrine did not result in inhibition of plasma insulin levels. Blood glucose levels, as well as nonesterified fatty acids and insulin levels in plasma, were similar in both groups. After the infusion study, the animals were subjected to strenuous swimming. During exercise, plasma insulin levels decreased not only in controls, but also in the islet-transplanted group. Blood glucose and plasma catecholamine responses were identical in both groups. After adrenodemedullation, epinephrine was not detectable and the exercise-induced decrease of insulin was not affected. These results indicate that circulating epinephrine and norepinephrine in physiological concentrations do not cause inhibition of insulin secretion. Since the exercise-induced inhibition of insulin secretion is still present in rats with islet grafts, it seems reasonable to suggest that sympathetic neural influences are responsible for the inhibition of insulin release during exercise and that transplanted islets are sympathetically reinnervated.

The effects of physiological doses of sulfated cholecystokinin-8 (CCK-8) on insulin secretion were investigated in unrestrained unanesthetized rats. The routes of administration were intravenous or intraportal infusion. Intravenous infusion (0.33-5.0 micrograms CCK-8.kg-1.20 min-1) resulted in a biphasic response pattern consisting of a fast 1st-min rise in plasma insulin concentration and a slower second phase that lasted throughout the infusion. The first phase showed the same amplitude with all amounts of CCK-8 administered in this study, whereas the second phase exhibited dose dependency. Blood glucose levels were lowered during all infusions of CCK-8, although the second phase of insulin release was absent with the lowest dose. These results suggest a strong stimulatory effect of CCK-8 on the pancreatic beta-cells, probably by changing the set point for glucose. The described effects of intravenous administration of CCK-8 cannot be produced when the infusion is given into the portal vein. Only very high concentrations of CCK-8 (15 micrograms.kg-1.20 min-1) produced a small increase in plasma insulin levels, indicating a strong CCK-8-eliminating mechanism in the liver. These results indicate that 1) CCK-8 evokes biphasic insulin release and a concomitant drop in glucose levels, and 2) CCK-8 acting on the beta-cell in vivo is not of intestinal origin but is probably released by the pancreatic vagal branch.