Comparative Effects of the Long-Acting GLP-1 Receptor Ligands, Liraglutide and Exendin-4, on Food Intake and Body Weight Suppression in Rats

Department of Psychology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Obesity (Impact Factor: 3.73). 03/2011; 19(7):1342-9. DOI: 10.1038/oby.2011.50
Source: PubMed


The glucagon-like-peptide-1 receptor (GLP-1R) agonists, liraglutide (Victoza) and the synthetic product of exendin-4 (Byetta), are approved for type II diabetes mellitus (T2DM) treatment and may be efficacious in obesity treatment as well, in part, due to the drugs' resistance to enzymatic degradation and prolonged half-life relative to endogenous GLP-1. To address the need to directly compare the food intake- and body weight-suppressive effects of these two GLP-1R ligands, acute and chronic dosing experiments were performed. Once-daily (q.d.) exendin-4 (0, 0.33, 1.5, and 3.0 µg/kg) and liraglutide (0, 50, 100, and 300 µg/kg, q.d.) both reduced the chow intake in nonobese rats in a dose-dependent fashion following either intraperitoneal (IP) or subcutaneous (SC) administration, whereas only liraglutide reduced 24 and 48 h body weight in nonobese, chow-maintained rats. Chow intake and body weight suppression by liraglutide were of greater magnitude and shorter latency following IP compared to SC delivery, whereas for exendin-4, the magnitude of intake-suppression was similar for IP and SC administration. The effects of chronic delivery (7 consecutive days; IP) of liraglutide (25 and 50 µg/kg; q.d.) and exendin-4 (3 µg/kg; q.d. and twice-daily (b.i.d.)) on food intake and body weight were also examined in diet-induced obese (DIO) rats. Liraglutide (50 µg/kg q.d.) and exendin-4 (3 µg/kg b.i.d.) were comparable in suppressing overall high fat/sucrose diet (HFS; 60% kcal from fat) intake. Both drugs regimens yielded marked weight loss over the 7-day period. The weight loss effect of liraglutide was achieved in the first 2 days and remained stable for the duration of the experiment; weight loss with exendin-4 appeared more linear over the 7-day period. In conclusion, administration of the GLP-1R ligands, exendin-4 (b.i.d.) and liraglutide (q.d.), lead to comparable and pronounced suppression of food intake and body weight in DIO rats, suggesting a potential role for these drugs as a clinical tool for obesity treatment.

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    • "Lowering of energy intake has been shown with liraglutide as well as native GLP-1 both in animals [30,31] and human subjects [10]. In rats, intracerebroventricular administration of GLP-1 has been shown to induce a marked reduction in food intake, presumably by interacting with GLP-1 receptors, which are present in several areas in the central nervous system [32,33]. In pharmacological doses, exogenous administration of GLP-1 has been shown to slow gastric emptying substantially [9]. "
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    ABSTRACT: Background and aims: Liraglutide treatment can improve glycemic control with a concomitant weight loss, but the underlying mechanism on weight loss is not completely understood. Cardiac natriuretic peptides (NPs) can resist body fat accumulation through increasing adipocytes lypolysis. In this study, we tested the hypothesis that liraglutide-induced weight loss was associated with increased plasma NPs concentrations. Thirty-one outpatients with type 2 diabetes (T2D) treated with metformin and other oral antidiabetic drugs except for thiazolidinediones (TZDs) were subcutaneously administered with liraglutide for 12 weeks. Body composition, abdominal visceral adipose tissue areas (VAT) and subcutaneous adipose tissue areas (SAT) were assessed at pre- and post-treatment by dual-energy X-ray absorptiometry (DXA) scanning and abdominal computerized tomography (CT). Plasma atrial natriuretic peptides (ANP) and B-type ventricular natriuretic peptides (BNP) concentrations were tested by commercial ELISA Kit quantitatively. Following 12-week liraglutide treatment, body weight, waist circumference, total fat and lean mass, fat percentage, SAT and VAT areas were significantly reduced from baseline. Concurrently, plasma ANP and BNP levels were significantly increased following 12-week liraglutide treatment. There were significant correlations between the reductions in body compositions and the increases in both plasma ANP and BNP levels. There were significant correlations between increases in both plasma ANP and BNP levels and changes in liraglutide-induced body composition. Our data implied that increases in plasma NPs may add a novel dimension to explain how liraglutide induces weight loss.
    Cardiovascular Diabetology 02/2014; 13(1):36. DOI:10.1186/1475-2840-13-36 · 4.02 Impact Factor
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    • "Because Ex-4 has a much longer half-life than endogenous GLP-1 (21) and can cross the blood–brain barrier (22), the long-term reduction of food intake after Ex-4 is likely mediated by central GLP-1R populations, possibly in the nucleus tractus solitarius (NTS) or paraventricular hypothalamus (13). This long-term sensitivity to Ex-4 during obesity is consistent with previous reports (23,24). "
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    ABSTRACT: Gastrointestinal mechanisms involved in the suppression of appetite are compromised in obesity. Glucagon-like peptide-1 (GLP-1) is released in response to nutrients, suppresses food intake, and has been shown to play a role in regulation of energy balance. It is not known whether obese-prone (OP) rats exhibit dysfunctional GLP-1 signaling that could contribute to decreased nutrient induced satiation and hyperphagia. Therefore, we examined the effects of exogenous IP administration of GLP-1R agonist, exendin-4 (Ex-4) on food intake in OP and obese-resistant (OR) rats during chow or high-energy/high-fat (HE/HF) feeding. All doses of Ex-4 effectively suppressed intake in both OP and OR rats on chow, however, during HE/HF-feeding, OP rats suppressed intake significantly less than OR rats at all Ex-4 doses tested. This was associated with downregulation of GLP-1R mRNA expression in the vagal nodose ganglia of OP rats. Furthermore, HE/HF-fed OP rats had significantly less plasma GLP-1 levels, decreased protein levels of GLP-1 in the intestinal epithelium, and reduced number of L-cells in the distal ileum. These results demonstrate that HE/HF-feeding coupled with OP phenotype results in reduced endogenous GLP-1 and GLP-1R activation, indicating that impaired GLP-1 signaling during obesity may exacerbate hyperphagia and weight gain.
    Diabetes 02/2013; 62(7). DOI:10.2337/db12-1204 · 8.10 Impact Factor
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    • "This reduction was accompanied by a reduction in body fat2. A similar effect with a reduction in food intake and body weight for the GLP1 receptor agonists liraglutide and exendin-4 has also been established in DIO rats fed the 60% HF diet from Research Diet68. Also, in DIO mice fed a diet containing 45% calories from fat, liraglutide reduces energy intake and body fat69. "
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    ABSTRACT: Obesity and obesity-related metabolic diseases represent a growing socioeconomic problem throughout the world. Great emphasis has been put on establishing treatments for this condition, including pharmacological intervention. However, there are many obstacles and pitfalls in the development process from pre-clinical research to the pharmacy counter, and there is no certainty that what has been observed pre-clinically will translate into an improvement in human health. Hence, it is important to test potential new drugs in a valid translational model early in their development. In the current mini-review, a number of monogenetic and polygenic models of obesity will be discussed in view of their translational character.
    Acta Pharmacologica Sinica 02/2012; 33(2):173-81. DOI:10.1038/aps.2011.203 · 2.91 Impact Factor
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