Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Circulating levels of insulin and glucagon were monitored daily in weanling rats bearing bilateral radiofrequency lesions of the hypothalamic region comprising the ventral pole of the dorsomedial nucleus and at least one third of the dorsal pole of the ventromedial nucleus (V-DMH). Plasma insulin levels in the animals with lesions were significantly elevated by the eighth post-lesion day while plasma glucagon levels were significantly reduced by the 13th day. An intravenous glucose bolus administered to conscious unrestrained animals with lesions had no significant effect on circulating insulin levels but resulted in a dramatic increase in circulating glucagon levels. The IV glucose injections had no significant effect on circulating glucagon levels in the sham-lesioned and unoperated controls while the plasma insulin levels in both control groups were significantly elevated. After a glucose challenge in vitro (300 mg%), insulin release by islets from the lesioned animals showed only a slight increase whereas glucagon release was paradoxically increased. These results provide evidence for an abnormal glucose-sensing function of the pancreatic islet after hypothalamic lesions.
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PMID:Hypothalamic lesions in the weanling rat alter pancreatic response to glucose. 639 2

Leptin has profound effects on food intake, body weight, and neuroendocrine status. The lack of leptin results in hormonal and metabolic alterations and a dramatic increase in body weight. Leptin acts in the brain, especially in the hypothalamus; however, the central nervous system sites that respond to leptin have not been examined comprehensively. In this study, we explored systematically the distribution of leptin-activated neurons throughout the rat brain. Furthermore, we investigated the chemical identity of subsets of these leptin-activated cells. Fos-like immunoreactivity (Fos-IR) was investigated in the rat brain after two different doses of leptin (1.0 mg/kg and 5.0 mg/kg) at 2 hours and 6 hours after injections. The induction of Fos-IR was observed in hypothalamic nuclei, including the paraventricular nucleus (PVH), the retrochiasmatic area (RCA), the ventromedial nucleus (VMH), the dorsomedial nucleus (DMH), the arcuate nucleus (Arc), and the ventral premammillary nucleus (PMV). In addition, leptin-induced Fos-IR was found in several nuclei of the brainstem, including the superior lateral and external lateral subdivisions of the parabrachial nucleus (slPB and elPB, respectively), the supragenual nucleus, and the nucleus of the solitary tract (NTS). By using double-labeling immunohistochemistry or immunohistochemistry coupled with in situ hybridization, leptin-activated neurons were found that contained cocaine- and amphetamine-regulated transcript mRNA in several hypothalamic nuclei, including the RCA, Arc, DMH, and PMV. In the Arc and DMH, leptin-induced Fos-IR was observed in neurons that expressed neurotensin mRNA. Dynorphin neurons in the VMH and in the Arc also expressed Fos-IR. In the brainstem, we found that cholecystokinin neurons in the slPB and glucagon-like peptide-1 neurons in the NTS were activated by leptin. We also investigated the coexpression of Fos-IR and the long form of the leptin receptor (OBRb) mRNA. We found double-labeled neurons surrounding the median eminence and in the RCA, Arc, VMH, DMH, and PMV. However, in brainstem sites, very little OBRb mRNA was found; thus, there were very few double-labeled cells. These results suggest that leptin stimulates brain pathways containing neuropeptides that are involved in the regulation of energy balance, autonomic homeostasis, and neuroendocrine status.
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PMID:Chemical characterization of leptin-activated neurons in the rat brain. 1086 58

The mechanism(s) underlying hypoglycemia-associated autonomic failure (HAAF) are unknown. To test the hypothesis that the activation of brain regions involved in the counterregulatory response to hypoglycemia is blunted with HAAF, rats were studied in a 2-day protocol. Neuroendocrine responses and brain activation (c-Fos immunoreactivity) were measured during day 2 insulin-induced hypoglycemia (0.5 U insulin x 100 g body x wt(-1) x h(-1) iv for 2 h) after day 1 hypoglycemia (Hypo-Hypo) or vehicle. Hypo-Hypo animals demonstrated HAAF with blunted epinephrine, glucagon, and corticosterone (Cort) responses and decreased activation of the medial hypothalamus [the paraventricular (PVN), dorsomedial (DMH), and arcuate (Arc) nuclei]. To evaluate whether increases in day 1 Cort were responsible for the decreased hypothalamic activation, Cort was infused intracerebroventricularly (72 microg) on day 1 and the response to day 2 hypoglycemia was measured. Intracerebroventricular Cort infusion failed to alter the neuroendocrine response to day 2 hypoglycemia, despite elevating both central nervous system and peripheral Cort levels. However, day 1 Cort blunted responses in two of the same hypothalamic regions as Hypo-Hypo (the DMH and Arc) but not in the PVN. These results suggest that decreased activation of the PVN may be important in the development of HAAF and that antecedent exposure to elevated levels of Cort is not always sufficient to produce HAAF.
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PMID:PVN activation is suppressed by repeated hypoglycemia but not antecedent corticosterone in the rat. 1164 Nov 12

The pre-proglucagon derived peptides, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are both involved in a wide variety of peripheral functions, such as glucose homeostasis, gastric emptying, intestinal growth, insulin secretion as well as the regulation of food intake. Pre-proglucagon is also found in the brainstem in a small population of nerve cells in the nucleus of the solitary tract (NTS) that process the pre-propeptide as in the gut to yield GLP-1 and GLP-2. GLP-1 containing nerve fibres and the GLP-1 receptor are found predominantly in hypothalamic midline nuclei. GLP-1 given centrally to naive rats results in a marked induction of c-Fos protein in the supraoptic nucleus, paraventricular nucleus of the hypothalamus (PVN) and central nucleus of the amygdala, but only a moderate increase in the arcuate nucleus. The pattern of c-Fos activation is compatible with the appetite suppressing effects of GLP-1. This anorectic effect of GLP-1 appears to be mediated by the PVN, as direct injections of GLP-1 into this nucleus cause anorexia without concomitant taste aversion, suggesting a specific action upon neuronal circuits involved in the regulation of feeding. Recent experiments have also shown that GLP-1 is implicated in mediating signals from the gastrointestinal tract pertaining to discomfort and malaise. The distribution of the co-localised peptide, GLP-2, displays a perfect overlap with GLP-1 in the CNS with the highest concentration in the diffuse ventral part of the dorsomedial nucleus (DMHv). In contrast to the widely distributed GLP-1 receptor mRNA, GLP-2 receptor mRNA is exclusively expressed in the compact part of the DMH (DMHc). Interestingly, the DMHc is also the only nucleus responding to central administration of GLP-2 with a significant increase in the number of c-Fos positive cells. When injected into the lateral ventricle, GLP-2 has a marked inhibitory effect on feeding. The effect of GLP-2 on feeding is both behaviourally and pharmacologically specific. Future experiments will elucidate whether or not GLP-1 and GLP-2 are involved in the long-term or short-term regulation of feeding behaviour and hence have an impact on bodyweight.
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PMID:Glucagon-like peptide containing pathways in the regulation of feeding behaviour. 1184 Feb 14

Glucagon-like peptide 1-(7-36) amide (GLP-1) potently inhibits rat feeding behavior after central administration. Because third ventricular injection of GLP-1 appeared to be less effective than lateral ventricular injection, we have reexamined this issue. In addition, we attempted to identify brain regions other than the paraventricular nucleus of the hypothalamus that are sensitive toward GLP-1-induced feeding suppression. Finally, we examined the local role of endogenous GLP-1 by specific GLP-1 receptor blockade. After lateral ventricular injection, GLP-1 significantly inhibited food intake of 24-h-fasted rats in a dose-dependent fashion with a minimal effective dose of 1 microg. After third ventricular injection, GLP-1 (1 microg) was similarly effective in suppressing food intake, which extends previous findings. Intracerebral microinjections of GLP-1 significantly suppressed food intake in the lateral (LH), dorsomedial (DMH), and ventromedial hypothalamus (VMH), but not in the medial nucleus of the amygdala. The minimal effective dose of GLP-1 was 0.3 microg at LH sites and 1 microg at DMH or VMH sites. LH microinjections of exendin-(9-39) amide, a GLP-1 receptor antagonist, at 1 or 2.5 microg did not alter feeding behavior in 24-h-fasted rats. In satiated animals, however, a single LH injection of 1 microg exendin-(9-39) amide significantly augmented food intake, but only during the first 20 min (0.6 vs. 0.1 g). With three repeated injections of 2.5 microg exendin-(9-39) amide every 20 min, 1-h food intake was significantly increased by 300%. These data strongly support and extend the concept of GLP-1 as a physiological regulator of food intake in the hypothalamus.
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PMID:Peptides that regulate food intake: glucagon-like peptide 1-(7-36) amide acts at lateral and medial hypothalamic sites to suppress feeding in rats. 1277 26

The metabolic stressor, hypoglycemia, elicits integrated counterregulatory responses, including activation of the hypothalamic-pituitary-adrenal axis. Type II glucocorticoid receptors (GR) occur in multiple components of the central autonomic circuitry that regulates glucostasis, and antecedent GR stimulation is implicated in impaired glucagon and counterregulatory dysfunction during recurrent insulin-induced hypoglycemia (RIIH). To examine the hypothesis that this chronic stress may alter basal and/or hypoglycemic patterns of GR gene expression in a site-specific manner, real-time RT-PCR techniques were utilized to evaluate tissue GR mRNA levels in the microdissected lateral hypothalamic area (LHA) and paraventricular (PVH), dorsomedial (DMH), ventromedial (VMH), and arcuate (ARH) hypothalamic nuclei, before and after one or four injections, on as many days, of the intermediate-acting insulin formulation, Humulin NPH (NPH), while controls were treated with diluent alone. Rats injected with four doses of NPH were pretreated by intracerebroventricular (icv) administration of the selective nonsteroidal GR antagonist, CP-472555, or vehicle alone prior to insulin injections on days 1-3. The results show that acute hypoglycemia had no impact on GR mRNA levels in each structure evaluated. Basal GR gene expression was not altered by antecedent hypoglycemia, but tissue transcript levels were elevated in the DMH, PVH, VMH, and ARH during RIIH. Icv CP-472555 administration prior to antecedent hypoglycemia prevented RIIH-associated increases in GR mRNA in each of these sites. These data show that GR gene transcripts are increased in discrete CNS metabolic loci during RIIH, and that these local responses are attenuated by pharmacological blockade of central GR activation. The present studies demonstrate that hypoglycemic hypercorticosteronemia causes upregulated GR gene expression during RIIH, and implicate GR in mechanisms underlying this action.
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PMID:Effects of acute and chronic insulin-induced hypoglycemia on type II glucocorticoid receptor (GR) gene expression in characterized CNS metabolic loci. 1686 Nov 9

In the brain preproglucagon expression is limited to a cluster of neurons in the caudal part of the nucleus of the solitary tract (NTS) as well as a smaller number of neurons that extend laterally from the NTS through the dorsal reticular area into the A1 area. These neurons process preproglucagon to glucagon-like peptide-1 (GLP-1), GLP-2, oxyntomodulin and glicentin. The neurons project mainly to the hypothalamus, where especially two nuclei involved in appetite regulation--the paraventricular (PVN) and dorsomedial (DMH) hypothalamic nuclei--are heavily endowed with GLP-immunoreactive nerve fibres. To gain further insight into this neurocircuitry, we injected the retrograde tracers cholera toxin, subunit B (ChB) and Fluorogold (FG) into the PVN and the DMH, respectively. Of thirty-five injected rats, six had successful injections that predominantly restricted within the boundaries of the PVN and DMH. Hindbrain sections from these rats were triple labelled for ChB, FG and GLP-2. A total of 24+/-1% of the PVN-projecting NTS-neurons contained GLP-2-ir whereas 67+/-4% of the DMH-projecting neurons were also stained for GLP-2, suggesting that the NTS-projections to the DMH arise mainly from preproglucagon neurons. Approximately 20% of backfilled cells in the NTS contained both retrograde tracers, therefore presumably representing neurons projecting to both the PVN and the DMH. The results of the present study demonstrate that the majority of the preproglucagon-expressing neurons in the NTS project in a target-specific manner to the hypothalamus. It is therefore possible that individual subgroups of GLP-containing neurons can mediate different physiological responses.
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PMID:Characterization of brainstem preproglucagon projections to the paraventricular and dorsomedial hypothalamic nuclei. 1743 66

A high number of neurons express c-fos in response to unlimited food intake in fasted rats in the ventral subdivision of the hypothalamic dorsomedial nucleus (DMHv). We report here, that in same conditions, limited food consumption failed to induce Fos expression in DMHv neurons suggesting that satiation should be one of the important signals that activate these neurons. The possible origin of fibers conducting satiation signals to the DMHv could be in the lower brainstem, especially glucagon-like peptide-1 (GLP-1)-containing neurons in the nucleus of the solitary tract (NTS). We demonstrate that GLP-1-immunoreactive fibers and fiber terminals topographically overlap with activated Fos-positive neurons in the DMHv in refed rats. Using immunocytochemistry and in situ hybridization histochemistry, we demonstrated GLP-1 receptors in Fos-expressing neurons of the DMH. Unilateral transections of ascending GLP-1-containing fibers from the NTS inside the pons in refed rats (unlimited food consumption) resulted in a dramatic decrease in the density of GLP-1 fibers and in the number of Fos-immunoreactive neurons in the DMHv, but only on the side of the transection. Contralateral to the transection, neither the GLP-1 fiber density nor the number of Fos-positive cells changed significantly. Meanwhile, the density of GLP-1 immunoreactivity was markedly accumulated in transected nerve fibers caudal to the cuts, as a consequence of the interruption of the ascending GLP-1 transport route. These findings suggest that the solitary-hypothalamic projections may represent the neuronal route through GLP-1 neurons of the NTS activate DMHv neurons via GLP-1 receptors by conveying information on satiety.
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PMID:Glucagon-like peptide-1 of brainstem origin activates dorsomedial hypothalamic neurons in satiated rats. 2240 7

Glucagon-like peptide 2 (GLP-2), a member of Glucagon peptide family involved in regulating energy metabolism, can be produced and secreted by preproglucagonergic (PPG) neurons in the brain. GLP-2 reduces food intake but at which brain sites GLP-2 exerts its feeding-suppress effects are still unclear. In this study, we used the stereological microinjection technique and behavioral test to examine the functions of locally delivered GLP-2 into DMH on feeding behavior. We compared effects of different concentration of GLP-2 on the food intake behavior in free-feeding rats and fasted-refeeding rats. We found that GLP-2 inhibited food intake in fasted rats after a short-term intervention in a dose-dependent manner. Importantly, the effects of locally delivered GLP-2 can be blocked by specific GLP-1 receptor antagonist Exendin(9-39), but not the melanocortin-4 receptor antagonist SHU9119, indicating the involvement of specificity of GLP-2 signaling in regulating the feeding behavior. Taken together, our data revealed that GLP-2 peptide pharmacologically inhibited food intake in DMH and this effect could be blocked functionally by Exendin(9-39).
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PMID:GLP-2 decreases food intake in the dorsomedial hypothalamic nucleus (DMH) through Exendin (9-39) in male Sprague-Dawley (SD) rats. 3322 Mar 30