The sequence of glucagon-like peptide-1 (7-36) amide (GLP-1) is completely conserved in all mammalian species studied, implying that it plays a critical physiological role. We have shown that GLP-1 and its specific receptors are present in the hypothalamus. No physiological role for central GLP-1 has been established. We report here that intracerebroventricular (ICV) GLP-1 powerfully inhibits feeding in fasted rats. ICV injection of the specific GLP-1-receptor antagonist, exendin (9-39), blocked the inhibitory effect of GLP-1 on food intake. Exendin (9-39) alone had no influence on fast-induced feeding but more than doubled food intake in satiated rats, and augmented the feeding response to the appetite stimulant, neuropeptide Y. Induction of c-fos is a marker of neuronal activation. Following ICV GLP-1 injection, c-fos appeared exclusively in the paraventricular nucleus of the hypothalamus and central nucleus of the amygdala, and this was inhibited by prior administration of exendin (9-39). Both of these regions of the brain are of primary importance in the regulation of feeding. These findings suggest that central GLP-1 is a new physiological mediator of satiety.

The melanocortin-4 receptor (MC4R) in the hypothalamus is thought to be important in physiological regulation of food intake. We investigated which hypothalamic areas known to express MC4R are involved in the regulation of feeding by using -m e l a n o c y t e -s t i m u l a ting hormone ( -MSH), an endogenous MC4R agonist, and agouti-related peptide (Agrp), an endogenous MC4R antagonist. Cannulae were inserted into the rat hypothalamic paraventricular (

1. Cold stimulus applied to the face causes bradycardia and peripheral vasoconstriction (i.e. the diving reflex), and has been suggested as a test of the autonomic pathways involved. The purpose of this study was to define standard procedures for conducting the test and analysing the responses to the cold face test, to evaluate variability in responses between subjects and within subjects when the same test is repeated, and to examine its usefulness in clinical autonomic assessment. 2. Sixteen (nine female, seven male) healthy adult (21-35 years old) subjects were used. Cold stimulus was applied with gel-filled compresses. Forehead temperature under the compress as an indication of stimulus magnitude, heart rate, blood flow in the finger, toe and calf by venous occlusion plethysmography, and systolic and diastolic blood pressure were monitored. Three protocols were carried out in which the temperature (0, 5, 10, 15 degrees C), placement (whole face, unilateral, forehead) and duration (20, 40, 60, 120 s) of the cold compress application were varied. 3. The data indicate that 0 degrees C compresses applied bilaterally for 40 s produced the maximum bradycardia and peripheral vasoconstriction. No subject found this test to be obnoxious, but a 120 s application was objectionable to some subjects. This cold face test resulted in 22%, 72%, 59% and 44% reductions in heart rate and blood flow to the finger, toe and calf, respectively. There was significant between-subject variability, but good consistency in responses to tests repeated in the same subject on different days, at different times of day and in different seasons.(ABSTRACT TRUNCATED AT 250 WORDS)

To examine the influence of the putative satiety factor (GLP-1) on the hypothalamo-pituitary-gonadal axis, we used GT1-7 cells as a model of neuronal luteinizing hormone- releasing hormone (LHRH) release. GLP-1 caused a concentration-dependent increase in LHRH release from GT1-7 cells. Specific, saturable GLP-1 binding sites were demonstrated on these cells. The binding of [125I]GLP-1 was time-dependent and consistent with a single binding site (Kd = 0.07+/-0.016 nM; binding capacity = 160+/-11 fmol/mg protein). The specific GLP-1 receptor agonists, exendin-3 and exendin-4, also showed high affinity (Ki = 0.3+/-0.05 and 0.32+/-0.06 nM, respectively) as did the antagonist exendin-(9-39) (Ki = 0.98+/-0.24 nM). At concentrations that increased LHRH release, GLP-1 (0.5-10 nM) also caused an increase in intracellular cAMP in GT1-7 cells (10 nM GLP-1: 7.66+/-0.4 vs. control: 0.23+/-0.02 nmol/mg protein; P < 0.001). Intracerebroventricular injection of GLP-1 at a single concentration (10 microg) produced a prompt increase in the plasma luteinizing hormone concentration in male rats (GLP-1: 1.09+/-0.11 vs. saline: 0.69+/-0.06 ng/ml; P < 0.005). GLP-1 levels in the hypothalami of 48-h-fasted male rats showed a decrease, indicating a possible association of the satiety factor with the low luteinizing hormone levels in animals with a negative energy balance.

The adipose tissue hormone, leptin, and the neuropeptide glucagon-like peptide-1 (7-36) amide (GLP-1) both reduce food intake and body weight in rodents. Using dual in situ hybridization, long isoform leptin receptor (OB-Rb) was localized to GLP-1 neurons originating in the nucleus of the solitary tract. ICV injection of the specific GLP-1 receptor antagonist, exendin(9-39), at the onset of dark phase, did not affect feeding in saline pre-treated controls, but blocked the reduction in food intake and body weight of leptin pro-treated rats. These findings suggest that GLP-1 neurons are a potential target for leptin in its control of feeding.