1229u91 and Hyperphagia

Neuropeptide Y (NPY) Y1 receptors are implicated in CNS regulation of food intake, but their role in hypoglycemic hyperphagia remains unclear. The present studies utilized a pharmacological approach to investigate the hypothesis that NPY acts via Y1 receptor-dependent mechanisms to regulate feeding and blood glucose profiles during intermediate insulin-induced hypoglycemia. Groups of ovariectomized, estradiol benzoate-treated female rats were injected subcutaneously with one or four doses of neutral protamine Hagedorn insulin (NPH), on as many days, or with diluent alone. Before final treatments on day four, the animals were pretreated by intracerebroventricular (icv) delivery of the NPY Y1 receptor antagonist, 1229U91, or the vehicle, artificial cerebrospinal fluid (acsf). Food intake during acute hypoglycemia was significantly diminished between t(o) and +2 h in animals pretreated with the Y1 receptor antagonist versus vehicle. Administration of 1229U91 prior to the fourth of four NPH doses suppressed hypoglycemic hyperphagia over a relatively longer interval, e.g. 4 h, after t(o) relative to the acute insulin group. Blood glucose levels after a single NPH injection were similar in acsf- and antagonist-pretreated rats at +2, +4, and +6 h, but were lower at +9 h in the latter group. Pretreatment with 1229U91 did not modify glucose profiles between +2 and +9 h after multiple dosing with NPH, but prevented recovery from hypoglycemia at +12 h. The present results show that central NPY Y1 receptor antagonism inhibits hypoglycemic hyperphagia, and that this suppressive effect on feeding was of greater duration during recurring hypoglycemia. The data also show that Y1 receptor blockade decreases glycemic responses to both single and serial NPH dosing, albeit at different post-injection time points. The current studies support the view that NPY Y1 receptors function within central neural pathways that govern feeding and glycemic responses to intermediate-acting insulin, and that Y1 receptor-mediated stimulation of food intake may habituate in a positive manner to repetitive insulin-induced hypoglycemia. Further research is needed to evaluate the impact of chronic insulin-induced hypoglycemia on neuropeptide Y neurotransmission and Y1 receptor expression within regulatory circuitries that control food intake and glucostasis.

Topics: Animals; Blood Glucose; Feeding Behavior; Female; Hyperphagia; Hypoglycemia; Hypoglycemic Agents; Insulin; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Time Factors

The present study aimed to examine whether hyperphagia, which is frequently observed in type 1 diabetic patients and model animals, also occurs in type 2 diabetic Goto-Kakizaki (GK) rats and, if so, to explore underlying abnormalities in the hypothalamus. GK rats at postnatal weeks 6-12, compared to control Wistar rats, exhibited hyperphagia, hyperglycaemia, hyperleptinemia and increased visceral fat accumulation, whereas body weight was unaltered. The ability of leptin to suppress feeding was reduced in GK rats compared to Wistar rats of these ages. In GK rats, leptin-induced phosphorylation of signal transducer and activator of transcription 3 was significantly reduced in the cells of the hypothalamic arcuate nucleus (ARC), but not of the ventromedial hypothalamus, whereas the mRNA level of functional leptin receptor was unaltered. By real-time polymerase chain reaction and in situ hybridisation, mRNA levels of neuropeptide Y, but not pro-opiomelanocortin and galanin-like peptide, were significantly increased in the ARC of GK rats at 11 weeks, but not 26 weeks. Following i.c.v. injection of a NPY Y1 antagonist, 1229U91, the amount of food intake in GK rats was indistinguishable from that in Wistar rats, thus eliminating the hyperphagia of GK rats. These results demonstrate that young adult GK rats display hyperphagia in association with leptin resistance and increased NPY mRNA level in the ARC.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Diabetes Mellitus; Eating; Hyperphagia; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Injections, Intraventricular; Leptin; Neuropeptide Y; Peptides, Cyclic; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; STAT3 Transcription Factor

Neuropeptide Y (NPY) has been implicated in the downstream mediation of ghrelin hyperphagia, with the site of action for both peptides considered to be intrinsic to the hypothalamus. Here, however, we observed robust hyperphagia with caudal brainstem (CBS) (fourth intracerebroventricular) ghrelin delivery and, moreover, that this response was reversed with coadministration of either of two NPY receptor antagonists (1229U91 and D-Tyr27,36, D-Thr32 NPY27-36) with contrasting NPY receptor subtype-binding properties. The same results were obtained after forebrain (third intracerebroventricular) administration, but the sites for both ghrelin and antagonist action were open to question, given the caudal flow of cerebrospinal fluid (CSF) through the ventricular system. To control for this, we occluded the cerebral aqueduct to restrict CSF flow between the forebrain and CBS ventricles and tested all combinations (same and cross ventricle) of ghrelin (150 pmol/1 microl) and NPY receptor antagonist delivery. With fourth intracerebroventricular ghrelin delivery after aqueduct occlusion, preadministration of either of the two antagonists through the same cannula reversed the hyperphagic response but neither was effective when delivered to the third ventricle. With third intracerebroventricular ghrelin administration, however, 1229U91 reversed the ingestive response only when delivered to the fourth ventricle, whereas D-Tyr27,36) D-Thr32 NPY27-36 was effective only when delivered to the forebrain. These results demonstrate distinct mediating pathways (due to location and subtypes of relevant NPY receptor) for the hyperphagic response driven separately by forebrain and CBS ghrelin administration.

Topics: Animals; Brain Stem; Cerebral Ventricles; Disease Models, Animal; Ghrelin; Hyperphagia; Injections, Intraventricular; Male; Neuropeptide Y; Peptide Hormones; Peptides, Cyclic; Prosencephalon; Rats; Rats, Sprague-Dawley; Time Factors

Disruption of neural signaling by microinjection of a neurotoxin, colchicine (COL), in the ventromedial hypothalamus (VMH) of rats results in rapid and transient hyperphagia and body weight gain. Since neuropeptide Y (NPY) is a potent hypothalamic orexigenic signal and continuous NPY receptor activation by intracerebroventricular (icv) NPY infusion results in hyperphagia and obesity, we tested the hypothesis that altered NPYergic signaling may underlie the transient hyperphagia in COL-injected rats. Immediately following COL (4 microg) microinjections in the ventromedial nucleus (VMN) rats displayed hyperphagia both during the lights-on and lights-off periods. Concomitant with hyperphagia, preproNPY mRNA levels in the arcuate nucleus and NPY levels in the paraventricular nucleus decreased in a time-dependent manner. However, food intake in response to intracerebroventricular injections of NPY (29, 117 and 470 pmole) was significantly higher in COL-injected rats and the latency to initiation of feeding was markedly reduced as compared to controls. The smallest dose of NPY which was virtually ineffective in control rats, evoked near maximal intake in COL-injected rats. This enhanced response lasted for only 4 days paralleling the transient hyperphagia. The NPY Y1 receptor antagonist 1229U91 (5 or 30 microg/rat, icv) significantly suppressed feeding in COL-treated rats thereby indicating that hyperphagia in these rats was dependent upon endogenous NPY. Overall, these studies demonstrate that not only high levels, but low levels of NPY may also result in hyperphagia and increased body weight and this hyperphagia may be attributed to the rapid development of NPY Y1 receptor hypersensitivity.

Topics: Animals; Appetite Stimulants; Behavior, Animal; Binding, Competitive; Colchicine; Darkness; Dose-Response Relationship, Drug; Eating; Hyperphagia; Hypothalamus; Injections, Intraventricular; Light; Male; Neuropeptide Y; Obesity; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; RNA, Messenger; Signal Transduction; Ventromedial Hypothalamic Nucleus; Weight Gain