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Ž. Ž . Ž . Glucagon-like-peptide-1 7-36 amide GLP-1 , when infused into the third ventricle IVT , reduces short-term food intake. In the present experiments, we assessed whether IVT administration of GLP-1 could influence long-term food intake and body weight of lean Ž . Long Evans rats and of fatty Zucker farfa rats. In Experiment 1, we replicated the observation that 10 mg GLP-1, given IVT, reduces one and 2 h food intake, and extended the observation to fatty Zucker rats. However, in both rat strains, 24 h food intake and body weight Ž . were unchanged by this acute treatment. In Experiment 2, GLP-1 30 mgrday was infused IVT continuously for 4 days via an osmotic mini-pump. This treatment also had no effect on food intake or body weight in either Long-Evans or fatty Zucker rats. A control experiment verified that the GLP-1 remained biologically active over the duration of the infusion period. In a final experiment, Long-Evans rats were restricted to two 2 h periods of access to food each day for 6 days. Prior to each of these access periods, rats received either 15 mg of GLP-1 IVT or a vehicle control injection. While GLP-1 significantly reduced food intake on the first day of treatment, this effect of GLP-1 rapidly disappeared such that it was reduced on the second day and absent on the third day; and there was no effect on body weight at any time. Collectively, the present experiments do not support the hypothesis that GLP-1, acting in the CNS, is an important regulator of long-term food intake and body weight. q 1998 Elsevier Science B.V.

Of the central 5-HT substrates that may mediate the anorexic actions of systemically administered d-fenfluramine (d-FEN), those in the forebrain have received the most attention. As a counterpoint to this forebrain focus, we evaluated the contribution of caudal brainstem substrates to the anorexic action of d-FEN. Two experimental protocols were employed. In one we compared the feeding response (intra-oral intake of 12.5% glucose) of intact and chronic supracollicular decerebrate (CD) rats to systemic administration of d-FEN. In the other, d-FEN was administered via fourth intracerebroventricular (ICV) injection to determine whether a dose-related suppression of intra-oral intake could be obtained. A dose-dependent suppression of intra-oral intake was obtained in the CD rat treated with d-FEN (0-8 mg/kg, delivered IP 20 min before testing). The threshold dose was two to three times higher in CD rats than in their intact controls, but the dynamic range of the dose-response curves of the two groups were overlapping with similar slopes of decline and with comparable maximal intake suppression. Fourth ICV administration of d-FEN in the intact rat yielded a dose-related suppression of intra-oral intake. Intake was also suppressed by fourth ICV d-FEN (30 mg) when rats drank 12.5% glucose solution from a spout. The reduced intra-oral intake following fourth ICV d-FEN treatment was partially attenuated by the systemic administration of the serotonin antagonist metergoline (0.4 mg/kg; IP). The CD results demonstrate the sufficiency of caudal brainstem receptors in mediating intake suppressive responses to systemic d-FEN. The fourth ICV results suggest further that 5-HT receptors in the caudal brainstem play a significant role in normal meal size control in the neurologically intact rat.

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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 ug 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. 13vt 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. Diabetes 46:1911-1914, 1997 L eptin (OB protein), the protein encoded by the obese gene, has rapidly emerged as a key substance in the regulation of metabolism, adiposity, and food intake (1). It is secreted from white adipose tissue in direct proportion to the amount of stored triglycerides (2), and it interacts with specific receptors in hypothalamic areas important in the control of food intake and metabolism (3). Because its local administration into the brain results in reduced food intake (4-6), increased energy expenditure (7), and, if prolonged over days, decreased adiposity (8), leptin has been suggested to be an important negative feedback signal in the control of these parameters (9).Consistent with this view, many species including primates and rodents secrete less leptin when they have been deprived of food (10) and have an increase in circulating leptin during states of positive energy balance (11). Because peripheral administration of leptin to fasting mice reverses fastinginduced changes of the adrenal, thyroid, and gonadal axes (12,13), it is reasonable to hypothesize that changes of leptin levels related to the nutritional state may normally regulate neuroendocrine activity. Related to this, leptin may modulate autonomic outflow, since leptin administration in ob/ob mice stimulates norepinephrine turnover in brown adipose tissue (BAT) (14).There is a diurnal pattern of leptin secretion, with plasma leptin levels roughly correlating with diurnal patterns of food intake. This rhythm has been proposed to modulate circadian rhythmicity of the hypothalamo-pituitary-adrenal (HPA) axis (12). To invest...