Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats

Fonseca, Fernando Rodriquez de; Navarro, Miguel; Álvarez, Elvira; Roncero, Isabel; Chowen, Julie A.; Maestre, Olivia; Gómez, R.; Muñoz, Riansares; Eng, John; Blázquez, Enrique

doi:10.1053/meta.2000.6251

Cited by 140 publications

(84 citation statements)

References 40 publications

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“…administration is also within the range of those reported previously. 25,27 Consistent with a plasma half-life of 150 min in rats (i.p. ), 5 the effect of exenatide, at the ED 50 dose, was sustained for 5 h post-injection.…”

Section: Discussionmentioning

confidence: 66%

“…Although dose dependent, this effect has shown to be durable in normal mice for 24 h. 31 Sustained exenatide exposure produced a persistent reduction in body weight in both mice and rats, with a maximal weight loss at 4 weeks of 16 and 11%, respectively. The demonstrated action of peripheral exenatide to reduce weight in monogenic models of obesity 6,18,27,28 can now be Exenatide reduces body weight in high-fat-fed rats CM Mack et al extended to normal rats consuming an HF diet. Comparing our findings with those from leptin-receptor-deficient models, both ZDF 6 and fa/fa rats 18,27,28 show weight reductions of similar magnitude, suggesting that exenatide effects are mediated via a leptin-independent pathway.…”

Section: Discussionmentioning

confidence: 99%

“…22,23 Agents with actions similar to GLP-1, particularly those resistant to degradation by DPPIV, may be potential therapeutic agents in the treatment of obesity. 24 Exenatide reduces food intake in rodents following either central [25][26][27] or peripheral 18,27-31 administration, and repeated or chronic exposure reduces body weight. 6,18,[26][27][28] Recent data from clinical trials have also revealed sustainable weight loss in exenatide-treated type 2 diabetic subjects.…”

Section: Introductionmentioning

confidence: 99%

“…24 Exenatide reduces food intake in rodents following either central [25][26][27] or peripheral 18,27-31 administration, and repeated or chronic exposure reduces body weight. 6,18,[26][27][28] Recent data from clinical trials have also revealed sustainable weight loss in exenatide-treated type 2 diabetic subjects. [10][11][12] In preclinical models, body weight reductions with systemic exenatide treatment have been demonstrated in leptinreceptor-deficient rodents under low-fat dietary conditions, 6,18,27,28 and most report single-dose effects.…”

Section: Introductionmentioning

confidence: 99%

“…6,18,[26][27][28] Recent data from clinical trials have also revealed sustainable weight loss in exenatide-treated type 2 diabetic subjects. [10][11][12] In preclinical models, body weight reductions with systemic exenatide treatment have been demonstrated in leptinreceptor-deficient rodents under low-fat dietary conditions, 6,18,27,28 and most report single-dose effects. One can readily postulate that polygenic models of obesity that mimic human consumption patterns may return a more physiologic picture of potential clinical utility.…”

Section: Introductionmentioning

confidence: 99%

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Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Mack¹,

Moore²,

Jodka³

et al. 2006

Int J Obes

129

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Background: Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents. Objective: To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity. Methods and results: High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 mg/kg/ day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 mg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 mg/kg/day (Po0.05). Decreased body weight gain was associated with a significant decrease in fat mass (Po0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (Po0.05). Exenatide at 10 mg/kg significantly reduced food intake (Po0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity. Conclusion: Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Mack¹,

Moore²,

Jodka³

et al. 2006

Int J Obes

129

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Glucagon‐Like Peptide‐1 Receptor Activators

Wagner¹,

Evers²,

Bossart³

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Type 2 diabetes (T2D) and obesity have reached pandemic levels and represent a major health burden to modern society. Peptidic GLP‐1 receptor agonists (GLP‐1RAs) have been established as an effective therapy with respect to glycemic control and provide moderate body weight reduction. Marketed first‐generation GLP‐1RAs are suitable for once‐ or twice‐daily subcutaneous dosing. Their substantial benefit on glucose control led to the discovery and development of longer lasting therapeutic options to improve patient convenience and compliance. Recently reported positive cardiovascular outcome studies for some GLP‐1RAs further underscore their therapeutic value. Besides long‐lasting action, alternative delivery formats for injectable GLP‐1RAs have been explored, for example oral formulations. One such oral formulation of a GLP‐1 analog has completed Phase 3 studies and is now approved for the treatment of T2D. In contrast, the discovery of orally available small molecule agonists of the GLP‐1R has been historically challenging, and only recently a few compounds have reached early clinical development. To further improve the efficacy of GLP‐1RAs, so‐called GLP‐1R dual or triple agonists have been developed. These peptides show promising results in early clinical trials but are awaiting confirmation of their therapeutic benefit in late‐stage development.

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Drugs Used Clinically to Reduce Body Weight

Bray

2009

Clinical Obesity in Adults and Children

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Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats

Cited by 140 publications

References 40 publications

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Glucagon‐Like Peptide‐1 Receptor Activators

Drugs Used Clinically to Reduce Body Weight

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