Stimulation of NPY Y₂ receptors by PYY_3-36 reveals divergent cardiovascular effects of endogenous NPY in rats on different dietary regimens

Abstract

Nordheim, Ulrich, and Karl G. Hofbauer. Stimulation of NPY Y 2 receptors by PYY3-36 reveals divergent cardiovascular effects of endogenous NPY in rats on different dietary regimens. Am J Physiol Regul Integr Comp Physiol 286: R138-R142, 2004. First published October 9, 2003 10.1152/ajpregu.00374.2003In the present experiments the gut hormone peptide YY , which inhibits neuropeptide Y (NPY) release, was used as a tool to study the cardiovascular effects of endogenous NPY under different dietary regimens in rats instrumented with a telemetry transmitter. In a first experiment, rats were placed on a standard chow diet ad libitum and in a second experiment on a high-fat diet ad libitum. After 6 wk, PYY3-36 (300 g/kg) or vehicle was injected intraperitoneally. In a third experiment, PYY3-36 or vehicle was administered after 14 days of 50% restriction of a standard chow diet. In food-restricted rats, PYY3-36 increased mean arterial pressure (7 Ϯ 1 mmHg, mean Ϯ SE, P Ͻ 0.001 vs. saline, 1-way repeated-measures ANOVA with Bonferroni t-test) and heart rate (22 Ϯ 4 beats/min, P Ͻ 0.001) during 3 h after administration. Conversely, PYY3-36 did not influence mean arterial pressure (0 Ϯ 1 mmHg) and heart rate (Ϫ8 Ϯ 5 beats/min) significantly in rats on a high-fat diet. Rats fed standard chow diet ad libitum showed an intermediate response (mean arterial pressure 4 Ϯ 1 mmHg, P Ͻ 0.05, and heart rate 5 Ϯ 2 beats/min, not significant). Thus, in our studies, divergent cardiovascular responses to PYY3-36 were observed in rats on different dietary regimens. These findings suggest that the cardiovascular effects of PYY3-36 depend on the hypothalamic NPY release, which is increased after chronic food restriction and decreased during a high-fat diet. blood pressure; heart rate; sympathetic nerve activity; neuropeptide Y; peptide YY NEUROPEPTIDE Y (NPY) is one of the strongest endogenous stimulators of food intake (13) and is abundantly expressed in hypothalamic feeding centers such as the arcuate (ARC) and paraventricular nucleus (PVN; 6, 7). It has been demonstrated that the hypothalamic content of NPY varies with nutritional state probably due to different NPY release (25,28). In addition to its role in appetite control, NPY also decreases blood pressure, heart rate (HR), and plasma norepinephrine levels after injection into the PVN (10,26,27) or the nucleus of the solitary tract (NTS) (8). Consequently, NPY-containing neurons that project from hypothalamic feeding centers (e.g., ARC, PVN) to cardiovascular centers of the brain stem (e.g., NTS) might be involved in both the regulation of energy balance and the regulation of cardiovascular function.NPY and peptide YY (PYY) are closely related polypeptides, which are composed of 36 amino acids and share considerable homology (in rats: 67%) (19). While NPY acts as a neurotransmitter, the two endogenous forms of PYY (PYY and PYY 3-36 ) are gut-derived hormones secreted by intestinal endocrine cells (L cells) into the circulation after a meal (1, 22). PYY 1-36 binds and activates at ...

Impaired postprandial releases/syntheses of ghrelin and PYY3‐36 and blunted responses to exogenous ghrelin and PYY3‐36 in a rodent model of diet‐induced obesity

“…On the fifth and the following days, NW rats and DIO rats received i.p. injections (0.5 mL in volume) of 0.9% saline, ghrelin (25 µg/kg bodyweight), or PYY 3‐36 (300 µg/kg bodyweight) either following a 20‐h fast or in the fed state ( n = 10 per group) on three separate days with an interval of 3 days 22,23 . The rats were returned to their cages immediately after the injection.…”

PYY3‐36 as an anti‐obesity drug target

“…Moreover, the possibility that one must follow a strict injection habituation protocol in order to observe PYY3‐36‐induced hypophagia (31) is also challenged by the findings of Nordeim et al . (37). They detected slight 24 h reductions in intake with PYY3‐36 in rats that had only one week of acclimation to the environment (no mock saline injections) prior to extensive surgical procedures (abdominal incision, intestinal retraction, arterial re‐sectioning and telemetry transmitter transplantation) and introduction to unfamiliar dietary regimens (some that included restriction).…”

Weight Loss Drugs and Cardiovascular Risks

“…It was demonstrated that the gut hormone PYY 3-36 physiologically inhibits food intake [40]. Of note, PYY , which inhibits NPY release by activation of presynaptic NPY Y 2 receptors, was used as a tool to analyze the cardiovascular effects of endogenous NPY under different dietary regimens [41]. NPY Y 2 receptors are highly expressed on NPY neurons in the arcuate nucleus, which is a brain area directly accessible to circulating hormones.…”

“…For that reason, it was assumed that the peripheral administration of PYY 3-36 might influence cardiovascular regulation by an arcuate-paraventricular nucleus-brain stem neuronal projection and that the magnitude of the cardiovascular PYY 3-36 effects depends on the prevailing central NPY tone. Accordingly, it was shown that Y 2 receptor stimulation by PYY 3-36 exerted cardiovascular effects in conscious, unrestrained normotensive rats and that the magnitude of these cardiovascular effects differed depending on the dietary regimen [41]. In foodrestricted, standard chow diet-fed rats, PYY 3-36 increased mean arterial pressure and heart rate, whereas in ad libitum high-fat diet rats, PYY 3-36 did not affect mean arterial pressure and heart rate.…”