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

We report the efficacy of a new peptide with agonism at the glucagon and GLP-1 receptors that has potent, sustained satiation-inducing and lipolytic effects. Selective chemical modification to glucagon resulted in a loss of specificity, with minimal change to inherent activity. The structural basis for the co-agonism appears to be a combination of local positional interactions and a change in secondary structure. Two co-agonist peptides differing from each other only in their level of glucagon receptor agonism were studied in rodent obesity models. Administration of PEGylated peptides once per week normalized adiposity and glucose tolerance in diet-induced obese mice. Reduction of body weight was achieved by a loss of body fat resulting from decreased food intake and increased energy expenditure. These preclinical studies indicate that when full GLP-1 agonism is augmented with an appropriate degree of glucagon receptor activation, body fat reduction can be substantially enhanced without any overt adverse effects.
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PMID:A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. 1959 7

Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.
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PMID:Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents. 1983 46

GLP-1 (9-36)amide is the cleavage product of GLP-1(7-36) amide, formed by the action of diaminopeptidyl peptidase-4 (Dpp4), and is the major circulating form in plasma. Whereas GLP-1(7-36)amide stimulates glucose-dependent insulin secretion, GLP-1(9-36)amide has only weak partial insulinotropic agonist activities on the GLP-1 receptor, but suppresses hepatic glucose production, exerts antioxidant cardioprotective actions and reduces oxidative stress in vasculature tissues. These insulin-like activities suggest a role for GLP-1 (9-36)amide in the modulation of mitochondrial functions by mechanisms independent of the GLP-1 receptor. In this paper, we discuss the current literature suggesting that GLP-1(9-36)amide is an active peptide with important insulin-like actions. These findings have implications in nutrient assimilation, energy homeostasis, obesity, and the use of Dpp4 inhibitors for the treatment of diabetes.
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PMID:Insulin-like actions of glucagon-like peptide-1: a dual receptor hypothesis. 2001 25

Type 2 diabetes (T2DM) is a heterogeneous syndrome, characterized by beta-cell failure in the setting of obesity-related insulin resistance. T2DM has a progressive course and is associated with a high cardiovascular disease (CVD) risk, regardless of the treatment used. The incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are secreted in the gut upon meal ingestion and lower blood glucose by glucose-dependent stimulation of insulin secretion and production. Exogenously administered GLP-1 lowers postprandial glucose excursions by inhibiting glucagon secretion and delaying gastric emptying, improves beta-cell function, and promotes satiety and weight loss. Native GLP-1 is degraded rapidly by the ubiquitous enzyme dipeptidyl-peptidase (DPP)-4. Thus, injectable DPP-4-resistant GLP-1 receptor agonists (GLP-1RA) and oral DPP-4 inhibitors have been developed. Exenatide is the first GLP-1RA that became available for the treatment of T2DM patients. Exenatide has unique characteristics, as to date it is the only agent that addresses the multiple defects of the T2DM phenotype, including hyperglycaemia, islet-cell dysfunction, alimentary obesity, insulin resistance, hypertension and dyslipidaemia. In animals, exenatide also increased beta-cell mass. Long-term prospective studies in high-risk populations should address the potentially disease modifying effect of exenatide and its effect on CVD risk, in addition to its safety and tolerability.
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PMID:Does glucagon-like peptide-1 receptor agonist therapy add value in the treatment of type 2 diabetes? Focus on exenatide. 2011 29

Bariatric surgery is indicated in cases of severe obesity. However, malabsorption-based techniques (gastric bypass and biliopancreatic diversion, both of which exclude the duodenum and jejunum from the alimentary circuit), but not restrictive techniques, can abolish type 2 diabetes within days of surgery, even before any significant weight loss has occurred. This means that calorie restriction alone cannot entirely account for this effect. In Goto-Kakizaki rats, a type 2 diabetes model, glycaemic equilibrium is improved by surgical exclusion of the proximal intestine, but deteriorates again when the proximal intestine is reconnected to the circuit in the same animals. This effect is independent of weight, suggesting that the intestine is itself involved in the immediate regulation of carbohydrate homoeostasis. In humans, the rapid improvement in carbohydrate homoeostasis observed after bypass surgery is secondary to an increase in insulin sensitivity rather than an increase in insulin secretion, which occurs later. Several mechanisms are involved--disappearance of hypertriglyceridaemia and decrease in levels of circulating fatty acids, disappearance of the mechanisms of lipotoxicity in the liver and skeletal muscle, and increases in secretion of GLP-1 and PYY--and may be intricately linked. In the medium term and in parallel with weight loss, a decrease in fatty tissue inflammation (which is also seen with restrictive techniques) may also be involved in metabolic improvement. Other mechanisms specific to malabsorption-based techniques (due to the required exclusion of part of the intestine), such as changes in the activity of digestive vagal afferents, changes in intestinal flora and stimulation of intestinal neoglucogenesis, also need to be studied in greater detail. The intestine is, thus, a key organ in the regulation of glycaemic equilibrium and may even be involved in the pathophysiology of type 2 diabetes.
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PMID:What can bariatric surgery teach us about the pathophysiology of type 2 diabetes? 2015 34

Liraglutide, a GLP-1 mimetic has recently been approved for clinical use in obesity-diabetes. The purpose of this study was to assess if acylation of Liraglutide via its gamma-glutamyl linker contributes to DPP-IV inhibition and efficacy of the molecule, given that such an approach could be useful in prolonging bioactivity of related peptides. Liraglutide lacking the gamma-glutamyl linker (Lira-gammaGlu) and Liraglutide exhibited enhanced DPP-IV resistance with extension of t(1/2) plus effective cAMP production (EC(50): 0.15+/-0.11 and 0.16+/-0.11nM, respectively) compared to GLP-1 (EC(50) 3.81+/-0.80nM). GLP-1, Lira-gammaGlu and Liraglutide increased insulin secretion compared to glucose (1.5-3.0-fold; p<0.05 to p<0.001). In vivo, Lira-gammaGlu and Liraglutide significantly lowered plasma glucose when administered 4 and 8h prior to a glucose load (1.3-1.9-fold; p<0.05 to p<0.001). Twice-daily administration of Lira-gammaGlu and Liraglutide for 14 days significantly decreased food intake (1.2-fold; p<0.05) and plasma glucose (1.1-1.6-fold; p<0.05 to p<0.01) whilst increasing plasma insulin (1.4-1.6-fold; p<0.05). At 14 days, Lira-gammaGlu and Liraglutide markedly improved glucose tolerance (1.4-3.4-fold; p<0.05 to p<0.001), insulin response to glucose (1.4-1.5-fold; p<0.05), insulin sensitivity (1.3-1.4-fold; p<0.05 to p<0.01), as well as increasing pancreatic insulin content (1.4-fold; p<0.05). Functional characteristics of Lira-gammaGlu and Liraglutide are almost indistinguishable, questioning necessity of gamma-glutamyl linker in acylation for generation of long-acting incretin mimetics.
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PMID:Effects of gamma-glutamyl linker on DPP-IV resistance, duration of action and biological efficacy of acylated glucagon-like peptide-1. 2041 87

Because obesity is a risk factor for many serious illnesses such as diabetes, better understandings of obesity and eating disorders have been attracting attention in neurobiology, psychiatry, and neuroeconomics. This paper presents future study directions by unifying (i) economic theory of addiction and obesity [4-6], and (ii) recent empirical findings in neuroeconomics and neurobiology of obesity and addiction. It is suggested that neurobiological substrates such as adiponectin, dopamine (D2 receptors), endocannabinoids, ghrelin, leptin, nesfatin-1, norepinephrine, orexin, oxytocin, serotonin, vasopressin, CCK, GLP-1, MCH, PYY, and stress hormones (e.g., CRF) in the brain (e.g., OFC, VTA, NAcc, and the hypothalamus) may determine parameters in the economic theory of obesity. Also, the importance of introducing time-inconsistent and gain/loss-asymmetrical temporal discounting (intertemporal choice) models based on Tsallis' statistics and incorporating time-perception parameters into the neuroeconomic theory is emphasized. Future directions in the application of the theory to studies in neuroeconomics and neuropsychiatry of obesity at the molecular level, which may help medical/psychopharmacological treatments of obesity (e.g., with sibutramine), are discussed.
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PMID:Toward molecular neuroeconomics of obesity. 2046 3

The availability of useful animal models reflecting the human obesity syndrome is crucial in the search for novel compounds for the pharmacological treatment of obesity. In the current study, we have performed an extensive characterization of the obesity syndrome in a polygenetic animal model, namely the selectively bred diet-induced obese (DIO) and diet-resistant (DR) rat strains. We show that they constitute useful models of the human obesity syndrome. DIO and DR rats were fed either a high-energy (HE) or a standard chow (Chow) diet from weaning to 9 months of age. Metabolic characterization including blood biochemistry and glucose homeostasis was examined at 2, 3, 6, and 9 months of age. Furthermore, in 6-month-old HE-fed DIO rats, the anti-obesity effects of liraglutide and sibutramine were examined in a 28-day study. Only HE-fed DIO rats developed visceral obesity, hyperleptinemia, hyperinsulinemia, and dyslipidemia, and showed a worsening of glucose tolerance over time. In line with the hyperlipidemic profile, a severe hepatic fat infiltration was observed in DIO rats at 6 months of age. The effects of liraglutide and sibutramine were tested in 6-month-old DIO rats. Both compounds effectively reduced food intake and body weight in DIO rats. Liraglutide furthermore improved glucose tolerance when compared with sibutramine. Our data highlights the usefulness of a polygenetic animal model for screening of compounds affecting food intake, body weight, and glucose homeostasis. Furthermore, the results underscore the effectiveness of GLP-1 mimetics both as anti-diabetes and anti-obesity agents.
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PMID:Long-term characterization of the diet-induced obese and diet-resistant rat model: a polygenetic rat model mimicking the human obesity syndrome. 2050 79

Nowadays, the literature provides evidence that obesity, type 2 diabetes and insulin resistance are characterized by a low grade inflammation. Among the environmental factors involved in such diseases, the gut microbiota has been proposed as a key player. This neglected "organ" has been found to be different between healthy and or obese and type 2 diabetic patients. For example, recent data have proposed that dysbiosis of gut microbiota (at phyla, genus, or species level) affects host metabolism and energy storage. Among the mechanisms, metabolic endotoxemia (higher plasma LPS levels), gut permeability and the modulation of gut peptides (GLP-1 and GLP-2) have been proposed as putative targets. Here we discuss 1 degrees the specific modulation of the gut microbiota composition by using prebiotics and 2 degrees the novel findings that may explain how gut microbiota can be involved in the development or in the control of obesity and associated low-grade inflammation.
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PMID:Involvement of the gut microbiota in the development of low grade inflammation associated with obesity: focus on this neglected partner. 2069 May 67

Obesity prevalence has risen dramatically over the past decades, which poses a great number of patients at risk of metabolic and cardiovascular complications. Long-term efficacy of lifestyle modification isolated has shown to be modest which, therefore, urges the need of more aggressive interventions such as adjuvant pharmacotherapy or the more radical surgical approach. Bariatric surgery has proven to date to be the most effective treatment, although it may be associated with nutritional and metabolic complications not yet completely recognized. By contrast, there is limited availability of antiobesity agents currently in the market, as well as historical facts involving the suspension of previously existing medications due to safety concerns. This article aims to present recent data on clinical trials of novel weight-loss drugs with short perspective to enter the market, if approved by the regulatory agencies. This review will discuss the efficacy and safety of these compounds, which include lorcaserin (selective serotonin 5-HT2c agonist), tesofensine (triple monoamine reuptake inhibitor), liraglutide (GLP-1 analogue) and cetilistat (gastrointestinal lipase inhibitor), as well as the combination therapies of bupropion/naltrexone, bupropion/zonisamide, phentermine/topiramate and pramlintide/metreleptin.
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PMID:[Recent progress and novel perspectives on obesity pharmacotherapy]. 2085 56


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