Design of Xenopus GLP-1-Based Long-Acting Dual GLP-1/Y<sub>2</sub> Receptor Agonists

Yang, Qimeng; Tang, Weizhong; Sun, Lin; Yan, Zhiming; Tang, Chunli; Yuan, Yanggang; Zhou, Huan; Zhou, Feng; Zhou, Siyuan; Wu, Qingqing; Song, Peng; Fang, Ting; Xu, Ronglian; Han, Jing; Jiang, Neng

doi:10.1021/acs.jmedchem.2c01385

Cited by 9 publications

(1 citation statement)

References 50 publications

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“…We acknowledge that GEP44-and exendin-4 elicited effects on fasting blood glucose may also be due, in part, to GEP44-elicited weight loss and future studies will include weight-restricted controls. In addition, the effects of peripheral GEP44 and exendin-4 to reduce cholesterol in female GLP-1R +/+ and GLP-1R -/mice are also consistent with the potential GLP-1R and/or Y2-receptor mediated cholesterol lowering effects observed following the GLP-1R agonists, liraglutide [37] and exendin-4 (similar potency on Y2R as PYY3-36) [37], and dual GLP-1R/Y2 receptor agonists, 6q and peptide 19 [37], in DIO rodents.…”

Section: Discussionsupporting

confidence: 66%

The Novel Chimeric Multi-Agonist Peptide (GEP44) Reduces Energy Intake and Body Weight in Male and Female Diet-Induced Obese Mice in a Glucagon-Like Peptide-1 Receptor-Dependent Manner

Blevins,

Honeycutt,

Slattery

et al. 2024

Preprint

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We recently reported that a novel chimeric peptide (GEP44) targeting both the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2 receptor (Y1R and Y2R) reduced energy intake and body weight (BW) in diet-induced obese (DIO) rats. We hypothesized that GEP44 reduces energy intake and BW primarily through a GLP-1R dependent mechanism. To test this hypothesis, GLP-1R+/+ mice and GLP-1R null (GLP-1R-/-) mice were fed a high fat diet for 4 months to elicit diet-induced obesity prior to undergoing a sequential 3-day vehicle period, 3-day drug treatment (5, 10, 20 or 50 nmol/kg; GEP44 vs the selective GLP-1R agonist, exendin-4) and a 3-day washout. Energy intake, BW, core temperature and activity were measured daily. GEP44 (10, 20 and 50 nmol/kg) reduced BW after 3-day treatment in DIO male GLP-1R+/+ mice by -1.5 +/- 0.6, -1.3 +/- 0.4 and -1.9 +/- 0.4 grams, respectively (P<0.05), with similar effects being observed in female GLP-1R+/+ mice. These effects were absent in male and female DIO GLP-1R-/- mice suggesting that GLP-1R signaling contributes to GEP44-elicited reduction of BW. Further, GEP44 decreased energy intake in both male and female DIO GLP-1R+/+ mice, but GEP44 appeared to produce more consistent effects across multiple doses in males. In GLP-1R-/- mice, the effects of GEP44 on energy intake were only observed in males and not females, suggesting that GEP44 may reduce energy intake, in part, through a GLP-1R independent mechanism in males. In addition, GEP44 reduced core temperature and activity in both male and female GLP-1R+/+ mice suggesting that it may also reduce energy expenditure. Lastly, we show that GEP44 reduced fasting blood glucose in DIO male and female mice through GLP-1R. Together, these findings support the hypothesis that the chimeric peptide, GEP44, reduces energy intake, BW, core temperature, and glucose levels in male and female DIO mice primarily through a GLP-1R dependent mechanism.

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Section: Discussionsupporting

confidence: 66%

The Novel Chimeric Multi-Agonist Peptide (GEP44) Reduces Energy Intake and Body Weight in Male and Female Diet-Induced Obese Mice in a Glucagon-Like Peptide-1 Receptor-Dependent Manner

Blevins,

Honeycutt,

Slattery

et al. 2024

Preprint

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Novel enzyme‐resistant pancreatic polypeptide analogs evoke pancreatic beta‐cell rest, enhance islet cell turnover, and inhibit food intake in mice

Zhu,

Tanday,

Lafferty

et al. 2024

BioFactors

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Pancreatic polypeptide (PP) is a postprandial hormone secreted from pancreatic islets that activates neuropeptide Y4 receptors (NPY4Rs). PP is known to induce satiety but effects at the level of the endocrine pancreas are less well characterized. In addition, rapid metabolism of PP by dipeptidyl peptidase‐4 (DPP‐4) limits the investigation of the effects of the native peptide. Therefore, in the present study, five novel amino acid substituted and/or fatty acid derivatized PP analogs were synthesized, namely [P3]PP, [K13Pal]PP, [P3,K13Pal]PP, [N‐Pal]PP, and [N‐Pal,P3]PP, and their impact on pancreatic beta‐cell function, as well as appetite regulation and glucose homeostasis investigated. All PP analogs displayed increased resistance to DPP‐4 degradation. In addition, all peptides inhibited alanine‐induced insulin secretion from BRIN‐BD11 beta cells. Native PP and related analogs (10−8 and 10−6 M), and especially [P3]PP and [K13Pal]PP, significantly protected against cytokine‐induced beta‐cell apoptosis and promoted cellular proliferation, with effects dependent on the NPY4R for all peptides barring [N‐Pal,P3]PP. In mice, all peptides, except [N‐Pal]PP and [N‐Pal,P3]PP, evoked a dose‐dependent (25, 75, and 200 nmol/kg) suppression of appetite, with native PP and [P3]PP further augmenting glucagon‐like peptide‐1 (GLP‐1) and cholecystokinin (CCK) induced reductions of food intake. The PP peptides had no obvious detrimental effect on glucose tolerance and they did not noticeably impair the glucose‐regulatory actions of GLP‐1 or CCK. In conclusion, Pro3 amino acid substitution of PP, either alone or together with mid‐chain acylation, creates PP analogs with benefits on beta‐cell rest, islet cell turnover, and energy regulation that may be applicable to the treatment of diabetes and obesity.

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PYY (3-36) protects against high fat feeding induced changes of pancreatic islet and intestinal hormone content and morphometry

Sridhar¹,

Khan²,

Flatt³

et al. 2023

Biochimica et Biophysica Acta (BBA) - General Subjects

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Design of Xenopus GLP-1-Based Long-Acting Dual GLP-1/Y₂ Receptor Agonists

Cited by 9 publications

References 50 publications

The Novel Chimeric Multi-Agonist Peptide (GEP44) Reduces Energy Intake and Body Weight in Male and Female Diet-Induced Obese Mice in a Glucagon-Like Peptide-1 Receptor-Dependent Manner

The Novel Chimeric Multi-Agonist Peptide (GEP44) Reduces Energy Intake and Body Weight in Male and Female Diet-Induced Obese Mice in a Glucagon-Like Peptide-1 Receptor-Dependent Manner

Novel enzyme‐resistant pancreatic polypeptide analogs evoke pancreatic beta‐cell rest, enhance islet cell turnover, and inhibit food intake in mice

PYY (3-36) protects against high fat feeding induced changes of pancreatic islet and intestinal hormone content and morphometry

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Design of Xenopus GLP-1-Based Long-Acting Dual GLP-1/Y2 Receptor Agonists

Cited by 9 publications

References 50 publications

The Novel Chimeric Multi-Agonist Peptide (GEP44) Reduces Energy Intake and Body Weight in Male and Female Diet-Induced Obese Mice in a Glucagon-Like Peptide-1 Receptor-Dependent Manner

The Novel Chimeric Multi-Agonist Peptide (GEP44) Reduces Energy Intake and Body Weight in Male and Female Diet-Induced Obese Mice in a Glucagon-Like Peptide-1 Receptor-Dependent Manner

Novel enzyme‐resistant pancreatic polypeptide analogs evoke pancreatic beta‐cell rest, enhance islet cell turnover, and inhibit food intake in mice

PYY (3-36) protects against high fat feeding induced changes of pancreatic islet and intestinal hormone content and morphometry

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Design of Xenopus GLP-1-Based Long-Acting Dual GLP-1/Y₂ Receptor Agonists