Long Term Exendin-4 Treatment Reduces Food Intake and Body Weight and Alters Expression of Brain Homeostatic and Reward Markers

Yang, Yan; Moghadam, Alexander A.; Cordner, Zachary A.; Liang, Nu-Chu; Moran, Timothy H.

doi:10.1210/en.2014-1052

Cited by 40 publications

(24 citation statements)

References 64 publications

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“…Secher et al used 100 µg/kg daily , while we have used 200 µg/kg twice a day in the current study, which may explain the different finding relative to POMC in neurons in the ARC. Similarly, previous studies have shown that exendin‐4 improved the gene expression of POMC , but little is known about the activities of neuropeptide CART relative to GLP‐1 administration.…”

Section: Discussionmentioning

confidence: 94%

Effects of liraglutide in hypothalamic arcuate nucleus of obese mice

Barreto-Vianna

Águila

Mandarim-de-Lacerda

2016

Obesity

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Objective: The neuroprotective effects of liraglutide (200 lg/kg, twice daily, subcutaneous administration) in the hypothalamic arcuate nucleus (ARC) of diet-induced obese mice were investigated. Methods: C57BL/6 mice were separated into groups: standard chow treated with vehicle or liraglutide and the respective liraglutide pair-fed group; high-fat diet treated with vehicle or liraglutide and the respective pair-fed group. Body mass (BM) evolution, carbohydrate metabolism, leptin resistance, proteins involved in energetic balance, apoptosis, and microglia in the ARC were studied. Results: Obese animals showed glucose intolerance, resistance to insulin and to anorexigenic effect of leptin, and microgliosis accompanied by elevated Bax/Bcl2 ratio in the ARC. Liraglutide improved the carbohydrate metabolism, BM loss, and the activation of pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) in the ARC. The liraglutide enhanced leptin sensitivity and diminished the microgliosis with decrease in Bax/Bcl2 ratio. Conclusions: Liraglutide activates central anorexigenic pathways, thereby diminishing the energy intake of obese mice and improving the metabolic parameters related to obesity. Liraglutide is a relevant neuroprotective agent, which can decrease the microgliosis and stimulate the anti-apoptotic pathway, a significant effect in the treatment of obesity and its comorbidities. Some benefits of liraglutide are independent of the BM loss, which usually accompanies the drug administration.

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Section: Discussionmentioning

confidence: 94%

Effects of liraglutide in hypothalamic arcuate nucleus of obese mice

Barreto-Vianna

Águila

Mandarim-de-Lacerda

2016

Obesity

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“…Theoretically, GLP-1 signaling could decrease the motivational value of food when the animal is sated. In support of this, recent studies have demonstrated that microinjections of EX4 into the VTA decrease food intake and body weight when animals are provided access to a variety of energy sources, including high fat, high sugar and standard rat chow diets (Yang et al 2014, Dickson et al 2012). Notably, it has been demonstrated that EX4 microinfusions into the VTA decreases responding for sucrose under a progressive ratio schedule of reinforcement and decreases conditioned place preference for chocolate pellets (Dickson et al, 2012).…”

Section: Introductionmentioning

confidence: 87%

The GLP-1 agonist exendin-4 attenuates self-administration of sweetened fat on fixed and progressive ratio schedules of reinforcement in rats

Bernosky-Smith

Stanger

Trujillo

et al. 2016

Pharmacology Biochemistry and Behavior

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GLP-1 agonists such as exendin-4 (EX4) are used in the treatment of type 2 diabetes and have the additional benefit of promoting weight loss. GLP-1 agonists decrease feeding through peripheral affects, but recent evidence suggests they may also influence sweet or high fat preference, as well as the motivation to obtain these tastants. Yet it remains unclear how GLP-1 induced alterations in food preference influences the decrease in overall feeding. The current study sought to determine if EX4 affects the reinforcing strength and consumption of a highly palatable sweet/fat reinforcer. Rats were trained to self-administer sweetened vegetable shortening (SVS) under fixed (FR) and progressive ratio (PR) schedules of reinforcement. EX4 (0.3 - 2.4 μg/kg, IP) administered one hour prior to operant sessions significantly reduced responding for SVS under both FR and PR schedules (e.g. total reinforcers and breakpoints, respectively), although the lowest active dose (0.6 μg/kg) significantly suppressed FR responding only. EX4 also dose dependently decreased locomotor activity (0.6-2.4 μg/kg doses), but did not enhance acute kaolin intake, indicating that EX4-induced nausea did not influence the self-administration results. Analysis of ED50 values show that EX4 is more effective at inhibiting FR responding versus PR, indicating that EX4 may have more potent effects on consummatory versus appetitive feeding behaviors. Although EX4 caused generalized behavioral suppression, these results cannot fully explain the decreases in operant responding. For example, the 0.6 μg/kg dose inhibited only FR responding, even though the rats were physically capable of responding at a higher rate during PR sessions. In addition, the rate of intake was constant at the beginning of the sessions in both PR and FR schedules, regardless of the dose. Together these data suggest that EX4 inhibits consumption of a palatable high sweet/high fat reinforcer potentially through altering satiety.

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“…The effect of exendin-4 on hepatic steatosis in ob/ob mice or HFD-induced obese mice is reported in literature (Lee et al 2012;Ding et al 2006). Exendin-4 reduces food intake by its action on ventromedial hypothalamus and arcuate nucleus (Yang et al 2014;Burmeister et al 2017).…”

Section: R a F Tmentioning

confidence: 99%

Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates nonalcoholic fatty liver disease

Patel

Joharapurkar

Kshirsagar

et al. 2018

Can. J. Physiol. Pharmacol.

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Nonalcoholic fatty liver disease (NAFLD) is often associated with obesity and type 2 diabetes. Coagonists of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) are under clinical investigation for the treatment of obesity and type 2 diabetes. In this study, we have demonstrated the effect of a balanced coagonist in the treatment of NAFLD using mouse models. GLP-1R agonist exendin-4, glucagon, and coagonist (Aib2 C24 chimera2) were administered to C57BL6/J mice, in which NAFLD was induced by carbon tetrachloride (CCl) treatment after high-fat diet (HFD) feeding, and choline-deficient, L-amino-acid-defined HFD (CDAHFD) feeding. Repeated dose administration of coagonist significantly attenuated liver inflammation and steatosis induced by acute and long-term treatment with CCl in HFD-fed mice. Coagonist markedly attenuated the CDAHFD-induced expression of TIMP-1, MMP-9, TNF-α, MCP-1, COL1A1, and α-SMA. It also inhibited progression of hepatic steatosis and fibrosis in mice. Exendin-4 was better than glucagon, but coagonist was most effective in reduction of hepatic inflammation as well as steatosis. Coagonist of GLP-1R and GCGR improved NAFLD in C57BL6/J mice. This effect is mediated by reduction in lipotoxicity and inflammation in liver.

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Long Term Exendin-4 Treatment Reduces Food Intake and Body Weight and Alters Expression of Brain Homeostatic and Reward Markers

Cited by 40 publications

References 64 publications

Effects of liraglutide in hypothalamic arcuate nucleus of obese mice

Effects of liraglutide in hypothalamic arcuate nucleus of obese mice

The GLP-1 agonist exendin-4 attenuates self-administration of sweetened fat on fixed and progressive ratio schedules of reinforcement in rats

Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates nonalcoholic fatty liver disease

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