Long-Lasting Effects of GSPE on Ileal GLP-1R Gene Expression Are Associated with a Hypomethylation of the GLP-1R Promoter in Female Wistar Rats

Abstract

Flavonoids have been shown to modulate GLP-1 in obesity. GLP-1 induces some of its effects through the intestinal GLP-1 receptor (GLP-1R), though no data exist on how flavonoids affect this receptor. Here, we examine how a dose of grape seed proanthocyanidin extract (GSPE) with anti-obesity activity affects intestinal GLP-1R and analyze whether epigenetics play a role in the long-lasting effects of GSPE. We found that 10-day GSPE administration prior to the cafeteria diet upregulated GLP-1R mRNA in the ileum 17 weeks after the GSPE treatment. This was associated with a hypomethylation of the GLP-1R promoter near the region where the SP1 transcription factor binds. In the colon, the cafeteria diet upregulated GLP-1R without showing any GSPE effect. In conclusion, we have identified long-lasting GSPE effects on GLP-1R gene expression in the ileum that are partly mediated by hypomethylation at the gene promoter and may affect the SP1 binding factor.

Glucagon Shows Higher Sensitivity than Insulin to Grapeseed Proanthocyanidin Extract (GSPE) Treatment in Cafeteria-Fed Rats

“…The cafeteria diet did not show differences in the total GLP-1 ratio ( Figure 2 ). The present results, together with previous data showing no effects of GLP-1 on the ileum or colon of cafeteria-fed rats [ 13 ], do not evidence higher intestinal GLP-1 production due to cafeteria treatment. At the pancreatic level, no significant changes were observed in GLP-1R, similar to what was observed in the ileum of the same animals [ 13 ] and in the hypothalamus of rats after 12 weeks of cafeteria diet [ 12 ].…”

“…The present results, together with previous data showing no effects of GLP-1 on the ileum or colon of cafeteria-fed rats [ 13 ], do not evidence higher intestinal GLP-1 production due to cafeteria treatment. At the pancreatic level, no significant changes were observed in GLP-1R, similar to what was observed in the ileum of the same animals [ 13 ] and in the hypothalamus of rats after 12 weeks of cafeteria diet [ 12 ]. However, we found a statistically significant increase in total GLP-1 time 15 compared to time zero after a glucose load in the animals that received the GSPE pre-treatment (PRE-17), compared to the cafeteria animals, suggesting a higher ability to secrete GLP-1 after stimulus ( Figure 2 ), although there were no effects on food intake after GSPE treatment at this time point ( Table S2 and [ 21 ]).…”

“…The grapeseed extracts enriched in proanthocyanidins (GSPE) were kindly provided by Les Dérivés Résiniques et Terpéniques (Dax, France). We used batch numbers 124,029 [ 13 ] and 174,860 (containing 21.6% flavan-3-ol monomers, 41.6% dimers+trimers) for the 17-week cafeteria study and the 12-week cafeteria study, respectively.…”

“…It has been shown that an acute dose of grapeseed-derived procyanidin extract (GSPE) can increase plasma GLP-1 [ 11 ] and prevent the decrease in GLP-1 associated with a cafeteria diet [ 12 ]. Furthermore, this effect is still maintained 17 weeks after GSPE is administered before a cafeteria diet [ 13 ]. Some of these effects could be related to the corrective effects of GSPE on β-cells that are disturbed by a cafeteria diet [ 14 ]; however, there is no information regarding the effects of GSPE on glucagon production.…”

Maternal dietary supplementation with grape seed extract in reproductive hens increases fertility in females but decreases semen quality in males of the F1 generation

“…Some studies, have screened libraries of natural compounds which possess an epigenetic modifiers activity [ 52 ]. In mice, a proanthocyanidin enriched diet decreased the DNMT activity leading to upregulation gene expression induced by hypomethylation of promoter [ 53 , 54 ]. Few study have investigated the transgenerational effects of maternal bioactive compounds supplementation.…”