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)

The discovery of leptin, the product of the ob gene, has led to major developments in understanding the regulation of energy balance. It is now recognised that leptin is produced in several organs additional to white adipose tissue, including brown fat, the placenta and fetal tissues (such as heart and bone/cartilage). The hormone has multiple functions-in inhibiting food intake, in the stimulation/maintenance of energy expenditure, as a signal to the reproductive system and as a 'metabolic' hormone influencing a range of processes (for example, insulin secretion, lipolysis, sugar transport). The production of leptin by white fat is subject to a number of regulatory influences, including insulin and glucocorticoids (which are stimulatory), and fasting and beta-adrenoceptor agonists (which are inhibitory). A key role in the regulation of leptin production by white fat is envisaged for the sympathetic system, operating through beta3-adrenoceptors. The leptin receptor gene is widely expressed, with the several splice variants exhibiting different patterns of expression. The long form variant (Ob-Rb) is expressed particularly in the hypothalamus, although it is being increasingly identified in other tissues. Leptin exerts its central effects through several neuroendocrine systems, including neuropeptide Y, glucagon-like peptide-1, melanocortins, corticotrophin releasing hormone (CRH) and cocaine- and amphetamine-regulated transcript (CART). In essence, the leptin system now appears highly complex, the hormone being involved in a range of physiological processes in a manner far transcending the initial lipostatic concept. This complexity may reduce the potential of the leptin system as a target for anti-obesity therapy.
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PMID:Leptin: fundamental aspects. 1019 58

Recent advances in the molecular basis of body fat regulation have identified several genes in which genetic variation may influence obesity and related measures in human populations. Genes that have been shown to have a regulatory function in the control of body fat utilization, eating behavior, and/or metabolic rate in rodent models of obesity include leptin (LEP), leptin receptor (LEPR), neuropeptide Y (NPY), NPY Y1 receptor (NPYY1), glucagon-like peptide-1 (GLP-1), GLP-1 receptor (GLP1R), and uncoupling protein 1 (UCP1). We have typed microsatellite markers located within or near these seven candidate obesity genes in 302 non-diabetic individuals from 59 Mexican-American families from Starr County, Texas. Sib pair linkage analysis was used to examine linkage between these genes and obesity status (obese siblings only; n = 170 pairs) and several obesity-related quantitative variables (all siblings; n = 545 total sibling pairs). Significant linkage (P = 0.042) was found between obesity and NPY within the obese sibling pairs. No other candidate gene was linked to obesity status in this subsample. Consistent with the obese sib pair linkage results, NPY showed evidence of linkage to body weight (P = 0.020), abdominal circumference (P = 0.031), hip circumference (P = 0.012), diastolic blood pressure (P = 0.005), and a composite measure of body mass and size (P = 0.048) in the entire sibling sample. Other significant linkages observed were between LEP and waist/hip ratio (P = 0.010), total cholesterol (P = 0.030), and HDL cholesterol (P = 0.026) and between LEPR and fasting blood glucose (P = 0.018) and diastolic blood pressure (P = 0.003). These results support further investigation of NPY, LEP, and LEPR to identify genetic variation that may influence obesity status, glucose and lipid metabolism, and blood pressure in Mexican Americans.
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PMID:Linkage analysis of candidate obesity genes among the Mexican-American population of Starr County, Texas. 1020 20

Hepatocyte nuclear factors 3 (HNF-3) belong to an evolutionarily conserved family of transcription factors that are critical for diverse biological processes such as development, differentiation, and metabolism. To study the physiological role of HNF-3alpha, we generated mice that lack HNF-3alpha by homologous recombination in embryonic stem cells. Mice homozygous for a null mutation in the HNF-3alpha gene develop a complex phenotype that is characterized by abnormal feeding behavior, progressive starvation, persistent hypoglycemia, hypotriglyceridemia, wasting, and neonatal mortality between days 2 and 14. Hypoglycemia in HNF-3alpha-null mice leads to physiological counter-regulatory responses in glucocorticoid and growth hormone production and an inhibition of insulin secretion but fails to stimulate glucagon secretion. Glucagon-producing pancreatic alpha cells develop normally in HNF-3alpha-/- mice, but proglucagon mRNA levels are reduced 50%. Furthermore, the transcriptional levels of neuropeptide Y are also significantly reduced shortly after birth, implying a direct role of HNF-3alpha in the expression of these genes. In contrast, mRNA levels were increased in HNF-3 target genes phosphofructo-2-kinase/fructose-2,6-bisphophatase, insulin growth factor binding protein-1, and hexokinase I of HNF-3alpha-null mice. Mice lacking one or both HNF-3alpha alleles also show impaired insulin secretion and glucose intolerance after an intraperitoneal glucose challenge, indicating that pancreatic beta-cell function is also compromised. Our results indicate that HNF-3alpha plays a critical role in the regulation of glucose homeostasis and in pancreatic islet function.
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PMID:Impaired glucose homeostasis and neonatal mortality in hepatocyte nuclear factor 3alpha-deficient mice. 1046 78

Dipeptidyl-peptidase IV (DPP IV/CD26) has a dual function as a regulatory protease and as a binding protein. Its role in the inactivation of bioactive peptides was recognized 20 years ago due to its unique ability to liberate Xaa-Pro or Xaa-Ala dipeptides from the N-terminus of regulatory peptides, but further examples are now emerging from in vitro and vivo experiments. Despite the minimal N-terminal truncation by DPP IV, many mammalian regulatory peptides are inactivated--either totally or only differentially--for certain receptor subtypes. Important DPP IV substrates include neuropeptides like neuropeptide Y or endomorphin, circulating peptide hormones like peptide YY, growth hormone-releasing hormone, glucagon-like peptides(GLP)-1 and -2, gastric inhibitory polypeptide as well as paracrine chemokines like RANTES (regulated on activation normal T cell expressed and secreted), stromal cell-derived factor, eotaxin and macrophage-derived chemokine. Based on these findings the potential clinical uses of selective DPP IV inhibitors or DPP IV-resistant analogues, especially for the insulinotropic hormone GLP-1, have been tested to enhance insulin secretion and to improve glucose tolerance in diabetic animals. Thus, DPP IV appears to be a major physiological regulator for some regulatory peptides, neuropeptides, circulating hormones and chemokines.
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PMID:Dipeptidyl-peptidase IV (CD26)--role in the inactivation of regulatory peptides. 1058 46

Palatable cephalic stimuli induce a simultaneous activation of gastrointestinal motility, gastric acid and pancreatic enzyme secretion, as well as, release of the gastrointestinal hormones gastrin and pancreatic polypeptide. Cholinergic neural input is the dominant mediator of these responses with cholecystokinin and gastrin acting as additional stimulatory modulators. Central cholinergic circuits, neuropeptide Y, and thyrotropin releasing hormone are candidate central stimulators of the cephalic phase. There are good arguments for glucagon-like peptide-1 and peptide YY to be physiological inhibitors of cephalic-phase responses with these peptides being released in the intestinal phase of digestion and putatively contributing to termination of the cephalically stimulated pattern. Cephalic-phase responses are used clinically as diagnostic tests to assess completeness of selective proximal vagotomy and to explore autonomic neuropathy. Pancreatic polypeptide secretion with sham feeding is an appropriate test of abdominal vagal function. Cephalically stimulated motor and secretory activity contribute greater than 50% of overall postprandial responses. Pharmacological inhibition of cephalic-vagal stimulation, resulting in reduced food intake, may be a novel approach to obesity management. Glucagon-like peptide-1 is a particular candidate because it inhibits the cephalic phase of digestion, diminishes food intake, and reduces the glycemic excursion after a meal by retarding gastric emptying, stimulating insulin and lowering glucagon release.
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PMID:Nutritional implications of cephalic phase gastrointestinal responses. 1074 9

In the literature, neuropeptide Y (NPY) has been described in the brain and peripheral nerves. More recently, it has also been detected in endocrine cells of hamster, embryonic mouse, and rat pancreas. However, the presence of NPY in avian embryos and the possible colocalization of this peptide with the other pancreatic hormones have not been reported previously. In this study, NPY presence was studied by immunocytochemical methods in the endocrine pancreas of domestic duck during pre- and postnatal development. NPY immunoreactivity (IR) was detected in embryos and adult animals. Around hatching the intensity of IR in endocrine cells decreased. Double immunohistochemical staining revealed that: 1) NPY-IR is extensively colocalized in small and mixed islets with insulin-IR both in embryos and in adults; and 2) in early embryos NPY-IR occasionally colocalized with glucagon and somatostatin. In early embryos, the colocalization of NPY-IR with several pancreatic hormones could be related to the presence of multi-hormonal progenitor cells. The close relation between insulin and NPY, both in embryos and adults, led us to hypothesize a key role for NPY on insulin cells of duck pancreas.
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PMID:NPY immunoreactivity in endocrine cells of duck pancreas: an ontogenetic study. 1076 Jul 41

The pathophysiology of obesity is complex with many different pathways involved. A better understanding of these weight-regulating mechanisms has lead to the identification of new targets for anti-obesity agents. Most attention has been given to the centrally acting neuropeptides regulating food intake. Leptin, playing a key-role, exerts its action through several neuropeptides such as neuropeptide Y, alpha-melanocyte stimulating hormone and agouti related protein. Cocaine- and amphetamine-regulated transcript peptide and the orexins are the latest discovered peptides acting at the level of the hypothalamus. Targets for new drugs acting on peptides secreted from the periphery are cholecystokinin and glucagon-like peptide 1. Another potential target in the treatment of obesity is increasing energy expenditure via beta3 adrenoceptors or uncoupling proteins. These new pharmacological agents in development could be valuable adjuncts to more traditional treatment strategies such as dietary treatment, behavioural/psychological counselling and physical activity.
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PMID:Promising new approaches to the management of obesity. 1092 26

Obesity is rapidly becoming a worldwide epidemic, with significant consequences in terms of clinical burden and economic costs in treating its complications, so effective new approaches are urgently needed. Development of new drugs in this therapeutic area requires a detailed understanding of the physiology underlying body weight regulation. Recently several significant advances have been made in this area, including the identification of the appetite regulating hormone, leptin, and a detailed understanding of its targets in the central nervous system (CNS), such as neuropeptide Y (NPY) and the melanocortin-4 receptor. The observation that some humans with severe childhood-onset obesity have defects in these regulatory systems has confirmed their relevance in humans as well as in animal models, and the search is now on to produce drugs which act on these and other CNS targets such as glucagon-like peptide I and the orexins to help reduce body weight. Other recently identified targets outside the central nervous system include agents acting to inhibit digestive enzymes, specifically pancreatic lipase in the form of orlistat (which has recently been licensed for obesity treatment), and looking to the future, the possibility of altering energy expenditure by modulating the newly identified uncoupling proteins is being considered. It should be remembered however, that pharmacotherapy for obesity is unlikely to provide a 'magic bullet', and that diet and lifestyle changes are likely to remain the cornerstone of treatment for the foreseeable future.
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PMID:The future of obesity treatment. 1099 89

There is increasing evidence that body weight is homeostatically regulated and that in obesity this regulation maintains weight at a high level. Weight loss activates mechanisms that are designed to return individuals to their pre-existing weight. This explains the universally poor results of current strategies to maintain weight loss. On this basis, life-long drug therapy may be justified for those with significant obesity. Currently available drugs include selective serotonin re-uptake inhibitors (e.g., fluoxetine), noradrenergic re-uptake inhibitors (e.g., phentermine), a serotonin and noradrenergic re-uptake inhibitor (sibutramine) and an intestinal lipase inhibitor (orlistat). An active research program is underway to develop new agents based on the rapidly expanding knowledge of the complex mechanisms regulating body weight. Leptin, a hormone produced by adipocytes that inhibits food intake, has undergone clinical trials and analogues are currently being developed. Other agents include amylin, melanocortin-4 receptor agonists, neuropeptide Y antagonists, beta(3) adrenergic agonists and glucagon-like peptide-1 agonists. As some redundancy exists in the central regulatory system controlling body weight, some agents might need to be used in combination to be effective.
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PMID:Novel anti-obesity drugs. 1106 Jul 45

Membrane peptidases are a group of ectoenzymes with a broad functional repertoire. In protein metabolism, their importance is well known, especially in peptide degradation and amino acid scavenging at the intestinal and renal brush border. However, they also perform more subtle tasks; not only do they provide or extinguish signals by cleaving exterior peptide mediators, but they also may function as receptors or participate in signal transduction or in adhesion. Dipeptidyl peptidase IV (DPPIV), which is identical to the lymphocyte surface glycoprotein CD26, is unique among these peptidases because of its ability to liberate Xaa-Pro and less efficiently Xaa-Ala dipeptides from the N-terminus of regulatory peptides. It occurs in the plasma membrane as a homodimer with a total molecular mass of 22-240 KdA and the C-terminal domain probably forms on alpha/beta hydrolase fold. In addition to, but independent of its serine type catalytic activity, DPPIV binds closely to the soluble extracellular enzyme adenosine deaminase. The in vivo expression on epithelial, endothelial and lymphoid cells of DPPIV is compatible with a role as physiological regulator of a number of peptides that serve as biochemical reporters between and within the immune and neuroendocrine system. Surprisingly, not cytokines with a N-terminal Xaa-Pro motif, but a number of chemokines have recently been identified as substrates. Despite DPPIV mediates only a minimal N-terminal truncation, important alterations in chemokine activities and receptor specificitIes were observed in vitro together with modified inflammatory and antiviral responses. Most probably the great flexibility of the N-terminus of a number of chemokines facilitates the accessibIlity to the catalytic site of DPPIV. Other known substrates which are subject in vitro to receptor-specific changes induced by DPPIV truncation include neuropeptides such as substance P, peptidE YY and neuropeptide Y. On the other hand, DPPIV mediated cleavage of the N-terminal His-Ala or Tyr-Ala dipeptides from circulating incretin hormones like, glucagon-like peptides (GLP)-1 and -2, gastric inhibitory polypeptide (GIP), all members of the enteroglucagon/GRF superfamily, results in their biological inactivation in vitro and in vivo. Administration of specific DPPIV inhibitors closes this pathway of incretin degradation and greatly enhances insulin secretion. The improved glucose tolerance in several animal models for type II diabetes points to specific DPPIV inhibition as a pharmaceutical approach for type 2 diabetes drug development.
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PMID:Peptide truncation by dipeptidyl peptidase IV: a new pathway for drug discovery? 1128 88


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