Details

Autor(en) / Beteiligte

• Thennati, Rajamannar
• Burade, Vinod
• Rutter, Guy
• Vilsbøll, Tina
• Thorens, Bernard

Titel

A GLP-1 Receptor Agonist, GL0034, Improves Liver Function in Diet Induced-Obesity Mouse Model

Ist Teil von

• Obesity (Silver Spring, Md.), 2022-11, Vol.30, p.56-57

Ort / Verlag

Silver Spring: Blackwell Publishing Ltd

Erscheinungsjahr

2022

Quelle

Wiley Blackwell Single Titles

Beschreibungen/Notizen

• Background: The potent and long-acting novel human glucagon-like peptide 1 receptor (GLP-1R) agonist (GLP-1RA); GL0034, selectively activates GLP-1R. Based on the anti-obesogenic and metabolic benefits of GLP-1RAs, we evaluated the efficacy of GL0034 in diet induced-obesity (DIO) mouse model. Methods: C57BL6/J mice (age 7 weeks) were fed with high fat pelleted diet for 12 weeks to induce obesity and glucose intolerance. DIO mice were administered placebo or GL0034 (6.25 pg/kg or 25 pg/kg) or semaglutide (50pg/kg) every alternate day (q2d) for 4 weeks. On day 29, biochemical parameters, liver lipid and histology were evaluated. NAS-score was calculated as the sum of the scores for steatosis (0-3), lobular inflammation (0-3), and ballooning (0-2), with a total range of 0 to 8. Statistical evaluation was performed using Prism 5 software, where ·p<0.05, ··p<0.01 and ···p<0.001 vs. placebo and #p<0.05, ##p<0.01 and ###p<0.001 vs. semaglutide. Semaglutide was synthesized in-house. Results: DIO mice treated with GL0034 (6.25 pg/kg and 25 pg/kg) and semaglutide (50 pg/kg) demonstrated reduction in body weight of 0.4%, 10.4%··· and 14.9%··· and concomitant fat mass 11.0%, 29.8%··· and 39.1%··· respectively. Insulin levels were decreased from 10.7 (±2.0) ng/mL to 10.4 (±1.3), 6.0··· (±0.6), and 5.7··· (±1.0) ng/mL. Triglycerides levels were reduced from 40.9(±3.5) mmol/kg to 31.1··· (±3.3), 20.1··· (±1.3), and 18.0··· (±1.8) mmol/ kg respectively and low-density lipoprotein cholesterol were reduced from 1.34(±0.27) mmol/kg to 0.91·· (±0.17), 0.64··· (±0.05), and 0.57··· (±0.06) mmol/kg, respectively. The circulating levels of alanine aminotransferase (ALT) were significantly more reduced with GL0034 than with semaglutide treatment: 56%···#, 54%···# and 34% ···, respectively, for the three treatment groups vs. the placebo group. Further steatosis score was 1.0···, 0.3··· and 0.1··· as against 1.9 of placebo. Lobular inflammation grade of 0.7#, 0.4···### and 1.3 was observed vs. 0.9 of placebo. The observed NAS total score of 1.7···, 0.7···# and 1.4··· respectively vs. 2.7 of placebo. Conclusions: Our study demonstrates that, GL0034, even at lower doses, improves plasma and liver biochemical markers and histopathological changes. The efficacy of GL0034 was similar or superior to semaglutide at 2-8-fold lower doses in ameliorating the steatohepatic condition.