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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prevalence of obesity is increasing rapidly and the associated morbidity and mortality has led to an urgent need for potential therapeutic targets to reduce appetite and food intake. Gut hormones released after eating that coordinate digestive activity and promote satiety are novel potential treatments for obesity. Oxyntomodulin is a gut hormone that is produced by the L cells in the small intestine and reduces food intake. It is timely to review some of the original literature on oxyntomodulin, to evaluate what is already known about the peptide, and also to set the recent findings on its effects on food intake and bodyweight into context.Recent studies have shown that long-term peripheral administration of oxyntomodulin to rats leads to reduced food intake and reduced weight gain. Studies in humans have demonstrated that acute administration reduces food intake by 19%. When given preprandially by subcutaneous injection three times daily, oxyntomodulin resulted in a reduction in food intake and mean weight loss of 2.8kg over 4 weeks. Oxyntomodulin thus represents a potential therapy for obesity.The mechanism of action of oxyntomodulin is not known. Current evidence suggests that it acts via the glucagon-like peptide 1 (GLP-1) receptor. There may be an additional receptor in the gastric mucosa mediating its effects on gastric acid secretion. Although oxyntomodulin probably acts via the GLP-1 receptor, the two peptides differentially regulate food intake and energy expenditure in the mouse.Oxyntomodulin represents a potential therapy for obesity. Further work will help to clarify its mechanisms of action.
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PMID:Oxyntomodulin : a novel potential treatment for obesity. 1700 86

Oxyntomodulin (OXM), a postprandially released intestinal hormone, inhibits food intake via the glucagon-like peptide-1 receptor (GLP-1R). Although OXM may have clinical value in treating obesity, the cardiovascular effects of OXM are not well understood. Using telemetry to measure heart rate (HR), body temperature (Tb), and activity in conscious and freely moving mice, we tested 1) whether OXM affects HR and 2) whether this effect is mediated by the GLP-1R. We found that peripherally administered OXM significantly increased HR in wild-type mice, raising HR by >200 beats/min to a maximum of 728 +/- 11 beats/min. To determine the extent to which the sympathetic nervous system mediates the tachycardia of OXM, we delivered this hormone to mice deficient in dopamine-beta-hydroxylase [Dbh(-/-) mice], littermate controls [Dbh(+/-) mice], and autonomically blocked C57Bl mice. OXM increased HR equally in all groups (192 +/- 13, 197 +/- 21, and 216 +/- 11 beats/min, respectively), indicating that OXM elevated intrinsic HR. Intrinsic HR was also vigorously elevated by OXM in Glp-1R(-/-) mice (200 +/- 28 beats/min). In addition, peripherally administered OXM inhibited food intake and activity levels in wild-type mice and lowered Tb in autonomically blocked mice. None of these effects were observed in Glp-1R(-/-) mice. These data suggest multiple modes of action of OXM: 1) it directly elevates murine intrinsic HR through a GLP-1R-independent mechanism, perhaps via the glucagon receptor or an unidentified OXM receptor, and 2) it lowers food intake, activity, and Tb in a GLP-1R-dependent fashion.
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PMID:Oxyntomodulin increases intrinsic heart rate in mice independent of the glucagon-like peptide-1 receptor. 1703 40

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) control glucose homeostasis through well-defined actions on the islet beta cell via stimulation of insulin secretion and preservation and expansion of beta cell mass. We examined the importance of endogenous incretin receptors for control of glucose homeostasis through analysis of Glp1r(-/-), Gipr(-/-), and double incretin receptor knockout (DIRKO) mice fed a high-fat (HF) diet. DIRKO mice failed to upregulate levels of plasma insulin, pancreatic insulin mRNA transcripts, and insulin content following several months of HF feeding. Both single incretin receptor knockout and DIRKO mice exhibited resistance to diet-induced obesity, preservation of insulin sensitivity, and increased energy expenditure associated with increased locomotor activity. Moreover, plasma levels of plasminogen activator inhibitor-1 and resistin failed to increase significantly in DIRKO mice after HF feeding, and the GIP receptor agonist [D-Ala(2)]GIP, but not the GLP-1 receptor agonist exendin-4, increased the levels of plasma resistin in studies of both acute and chronic administration. These findings extend our understanding of how endogenous incretin circuits regulate glucose homeostasis independent of the beta cell via control of adipokine secretion and energy expenditure.
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PMID:Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. 1718 81

Peptidic mimics of the gut hormone glucagon-like peptide (GLP) 1, exemplified by the recently approved drug exenatide, show promise as therapies for type 2 diabetes. Such "incretin mimetics" regulate glucose appearance in the plasma and can restore glucose-stimulated insulin secretion without excess risk of hypoglycemia. The need for injection, which may limit the use of peptidic GLP-1 receptor (GLP-1R) agonists, has driven largely unsuccessful efforts to find smaller molecules. The failure to identify orally effective agonists has instead promoted the indirect approach of inhibiting the GLP-1-degrading enzyme dipeptidyl peptidase IV. Here we report a nonpeptidic GLP-1R agonist with sufficient activity to evoke effects in whole animals, including antidiabetic efficacy in db/db mice. Two substituted cyclobutanes (S4P and Boc5) were developed after screening a compound library against a cell line stably cotransfected with GLP-1R and a cAMP-responsive reporter. Each bound to GLP-1R and increased intracellular cAMP. Agonist effects were blocked by the GLP-1R antagonist exendin(9-39). Boc5 amplified glucose-stimulated insulin secretion in isolated rat islets. Both i.p. and oral administration of Boc5 dose-dependently inhibited food intake in mice, an effect that could be blocked by pretreatment with exendin(9-39). Daily injections of Boc5 into db/db mice reduced HbA1c to nondiabetic values, an effect not observed in ad libitum-fed or pair-fed diabetic controls. Thus, Boc5 behaved as a full GLP-1 mimetic in vitro and in vivo. The chemical genus represented by Boc5 may prompt the exploration of orally available GLP-1R agonists with potential utility in diabetes and obesity.
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PMID:A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice. 1721 6

The glucagon-like peptide (GLP)-1 receptor is a promising target for the treatment of type 2 diabetes and obesity, and there is great interest in characterizing the pharmacology of the GLP-1 receptor and its ligands. In the present report, we have applied bioluminescence resonance energy transfer assays to measure agonist-induced recruitment of betaarrestins and G-protein-coupled receptor kinase (GRK) 2 to the GLP-1 receptor in addition to traditional measurements of second messenger generation. The peptide hormone oxyntomodulin is described in the literature as a full agonist on the glucagon and GLP-1 receptors. Surprisingly, despite being full agonists in GLP-1 receptor-mediated cAMP accumulation, oxyntomodulin and glucagon were observed to be partial agonists in recruiting betaarrestins and GRK2 to the GLP-1 receptor. We suggest that oxyntomodulin and glucagon are biased ligands on the GLP-1 receptor.
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PMID:Oxyntomodulin differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment and signaling through Galpha(s). 1739 66

Glucagon-like peptide 1 (GLP-1) is a potent inhibitor of food intake. GLP-1 receptor mRNA is densely expressed in hypothalamic arcuate nucleus (ARC) and precisely overlaps the area occupied by proopiomelanocortin (POMC) neurons. Activation of POMC neurons suppresses appetite, and lack of POMC-derived peptides or inhibition of POMC neuronal firing causes obesity. Here, we identify living POMC cells in mouse ARC brain slices by targeted expression of green fluorescent protein. Using whole-cell patch-clamp recordings, we show that GLP-1 increases the spontaneous action-potential firing of POMC neurons. The stimulatory effect of GLP-1 was mimicked by GLP-1 receptor agonist exendin-4 and abolished by the receptor antagonist exendin 9-39. The effect of GLP-1 was unchanged in the presence of the synaptic blockers DAP5 (D(-)-2-amino-5-phosphonopentanoic acid)/CNQX (6-cyano-7-nitroquinoxaline-2,3-dione disodium salt) and picrotoxin. These results suggest that GLP-1 excites POMC neurons postsynaptically, via interaction with GLP-1 receptors on POMC cells. Whole-cell Ca2+ currents increased approximately 70% in the presence of GLP-1, and this effect was abolished by L-type Ca2+ channel antagonist nifedipine. Forskolin (which activates cAMP) mimicked the effects of GLP-1 and the PKA inhibitor Rp-8-Bromo-cAMPS (8-bromoadenosine-3',5'-cyclic monophosphorothioate, Rp-isomer) blocked GLP-1 action. These data indicate that GLP-1 stimulates the electrical activity of hypothalamic POMC neurons by activation of PKA and a subsequent increase in L-type Ca2+ current. This effect may contribute to the anorectic action of GLP-1, because excitation of POMC cells is well established to reduce food intake.
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PMID:Glucagon-like peptide 1 stimulates hypothalamic proopiomelanocortin neurons. 2165 75

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.
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PMID:The physiology of glucagon-like peptide 1. 1792 88

Inulin-type fructans have been tested for their capacity to modulate lipid and glucose metabolism in several animal models. Oligofructose (OFS) decreases food intake, fat mass development, and hepatic steatosis in normal and in obese rats; moreover, it exerts an antidiabetic effect in streptozotocin-treated rats and high-fat-fed mice. In most cases, the beneficial effects of OFS are linked to an increase of glucagon-like peptide-1 (GLP-1) level in the portal vein and of GLP-1 and proglucagon mRNA, its precursor, in the proximal colon. In this organ, OFS increases the number of GLP-1-positive L cells by promoting factors (Neurogenin 3 and NeuroD) involved in the differentiation of stem cells into L cells. The chronic administration of GLP-1 receptor antagonist exendin 9-39 totally prevents the beneficial effects of OFS (improved glucose tolerance, fasting blood glucose, glucose-stimulated insulin secretion, insulin-sensitive hepatic glucose production, and reduced body weight gain). Furthermore GLP-1 receptor knockout mice are completely insensitive to the antidiabetic actions of OFS. These findings highlight the potential interest of enhancing endogenous GLP-1 secretion by inulin-type fructans for the prevention/treatment of obesity and type 2 diabetes. Moreover, OFS is also able to modulate other gastrointestinal peptides (such as PYY and ghrelin) that could be involved in the control of food intake. Several studies in humans already support interest in OFS in the control of satiety, triglyceridemia, or steatohepatitis. The link with gut peptides production in humans remains to be proven.
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PMID:Modulation of glucagon-like peptide 1 and energy metabolism by inulin and oligofructose: experimental data. 1795

The prevalence of obesity has been increasing dramatically in the last decades; the major metabolic complication of obesity is insulin resistance and type-2 diabetes because there are pathogenetic mechanisms linking obesity and type-2 diabetes. Diabetes is also rapidly increasing worldwide; such a description of the key stages in the evolution of type-2 diabetes may be of great interest for implementing antidiabetes treatment. In recent times, type-2 diabetes therapy has been based on drugs, which improve insulin sensibility or stimulate insulin secretion or slow down glucose absorption. Recently, an ADA and EASD consensus has been released to develop a common approach for the management of hyperglycaemia in adults. The development of new classes of blood-glucose-lowering medications to supplement the older therapies, such as lifestyle-directed interventions, insulin, sulfonylureas, and metformin, has increased the different possible options for the treatment of type-2 diabetes. Therapeutic approaches aiming to potentiate the biological effects of incretins include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-IV (DPP-IV) activity (incretin enhancers) will be very useful to slow down type-2 diabetes progression. Weight-loss interventions, such as a hypocaloric diet and physical exercise, in addition to agents such as orlistat, sibutramine and cannabinoid receptor antagonists, may have favourable effects upon fat storage, nutrient metabolism and ultimately glucose tolerance or type-2 diabetes. When the therapeutic target is not achieved, insulin with metformin could be suggested, but is this approach the ideal one for all patients? Perhaps it is possible to delay the initiation of insulin therapy, therefore, the actual and future therapeutical options are considered in the present review.
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PMID:Time to insulin in type-2 diabetes: high hurdles or Santiago way? 1840 82

The obesity epidemic in the developed and developing world is being followed by an epidemic of type 2 diabetes. In type 2 diabetes, subjects cannot manage glucose properly because they do not produce enough insulin, and the peripheral tissues have become resistant to insulin. Glucagon-like peptide 1 (GLP-1) is an intestinal peptide hormone that is secreted in response to food to regulate the postprandial blood glucose concentration. One of the actions of GLP-1 is to stimulate insulin secretion. In subjects with type 2 diabetes, intravenous or subcutaneous GLP-1 stimulated insulin production and decreased blood glucose levels. However, as GLP-1 is rapidly metabolised, it is not suitable for use in most subjects with type 2 diabetes. Exendin-4 is a 39-amino acid peptide that acts as an agonist at the GLP-1 receptor. After subcutaneous administration, synthetic exendin-4 (exenatide) decreased postprandial concentrations of glucose and insulin, and fasting glucose levels in subjects with type 2 diabetes, and the effects lasted several hours. Subsequently, exenatide was been trialled in subjects taking metformin only, a sulfonylurea only, or metformin and a sulfonylurea, and shown to improve glycemic control with few adverse events, initially over 30 weeks, and then extended to 82 weeks. Exenatide may also be as effective as insulin glargine in subjects with type 2 diabetes not adequately controlled with the oral agents. In conclusion, exenatide represents a new and beneficial addition to the medicines used to treat type 2 diabetes.
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PMID:Is exenatide improving the treatment of type 2 diabetes? Analysis of the individual clinical trials with exenatide. 1847 91


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