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The flavonoid apigenin improves glucose tolerance through inhibition of microRNA maturation in miRNA103 transgenic mice.

Ohno M, Shibata C, Kishikawa T, Yoshikawa T, Takata A, Kojima K, Akanuma M, Kang YJ, Yoshida H, Otsuka M, Koike K - Sci Rep (2013)

Bottom Line: Polyphenols are representative bioactive substances with diverse biological effects.Here, we show that apigenin, a flavonoid, has suppressive effects on microRNA (miRNA) function.These results suggest that apigenin may have favorable effects on the pathogenic status induced by overexpression of miRNA103, whose maturation is mediated by phosphorylated TRBP.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. otsukamo-tky@umin.ac.jp

ABSTRACT
Polyphenols are representative bioactive substances with diverse biological effects. Here, we show that apigenin, a flavonoid, has suppressive effects on microRNA (miRNA) function. The effects were mediated by impaired maturation of a subset of miRNAs, probably through inhibition of the phosphorylation of TRBP, a component of miRNA-generating complexes via impaired mitogen-activated protein kinase (MAPK) Erk activation. While glucose intolerance was observed in miRNA103 (miR103)-overexpressing transgenic mice, administration of apigenin improved this pathogenic status likely through suppression of matured miR103 expression levels. These results suggest that apigenin may have favorable effects on the pathogenic status induced by overexpression of miRNA103, whose maturation is mediated by phosphorylated TRBP.

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Apigenin improves glucose tolerance in miR103 transgenic mice.(a), Expression levels of mature miR103, miR122, and miR185 in liver tissues of miR103 transgenic mice (miR103 Tg) were determined by Northern blotting. (b), Expression levels of mature miR103 and its precursor in liver tissues of miR10-transgenic mice treated with apigenin were determined by Northern blotting. Control (DMSO) or apigenin (40 mg/kg) was injected intraperitoneally daily for 14 days. Representative results from three independent mouse sets are shown. (c), Liver tissue homogenates from miR103 transgenic mice were separated using a phos-tag gel to determine the phosphorylation status of TRBP. Representative results from three independent mouse sets are shown. Full-length blot image is available in Supplementary Figure 5g. (d), Blood glucose levels were determined at random times or after 12 h fasting in control and miR103 transgenic (miR103 Tg) mice (n = 8 in each group). Data represent the means ± s.d. *, p < 0.05 (t-test). (e), (f), Glucose and pyruvate tolerance tests in control, miR103 transgenic (miR103 Tg), and miR103 transgenic with apigenin treatment (miR103 Tg + apigenin) mice (n = 6 in each group). Data represent the means ± s.d. *, p < 0.05 (t-test).
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f4: Apigenin improves glucose tolerance in miR103 transgenic mice.(a), Expression levels of mature miR103, miR122, and miR185 in liver tissues of miR103 transgenic mice (miR103 Tg) were determined by Northern blotting. (b), Expression levels of mature miR103 and its precursor in liver tissues of miR10-transgenic mice treated with apigenin were determined by Northern blotting. Control (DMSO) or apigenin (40 mg/kg) was injected intraperitoneally daily for 14 days. Representative results from three independent mouse sets are shown. (c), Liver tissue homogenates from miR103 transgenic mice were separated using a phos-tag gel to determine the phosphorylation status of TRBP. Representative results from three independent mouse sets are shown. Full-length blot image is available in Supplementary Figure 5g. (d), Blood glucose levels were determined at random times or after 12 h fasting in control and miR103 transgenic (miR103 Tg) mice (n = 8 in each group). Data represent the means ± s.d. *, p < 0.05 (t-test). (e), (f), Glucose and pyruvate tolerance tests in control, miR103 transgenic (miR103 Tg), and miR103 transgenic with apigenin treatment (miR103 Tg + apigenin) mice (n = 6 in each group). Data represent the means ± s.d. *, p < 0.05 (t-test).

Mentions: To apply the above results in a clinical setting, we focused on recent findings demonstrating that a gain of miR103/107 expression induces impaired glucose homeostasis in vivo10. To utilize this, we generated transgenic mice expressing a miR103 precursor under control of the CMV promoter (Supplementary Figure 3a). Overexpression of miR103 in these mice was confirmed by Northern blotting against mature miR103 in liver tissues (Figure 4a and Supplementary Figure 3b). No significant over-saturation of RISC complexes due to overexpressing miR103 in these mice was confirmed by a lack of significant changes in the expression levels of other mature miRNAs, such as miR122 and miR185 (Figure 4a). As expected from a previous report10, these miR103 transgenic mice showed an increase in both random and fasting blood-glucose levels and insulin levels (Supplementary Figure 3c and d). The mean size of adipocytes in visceral fat was larger in normal chow fed miR103 transgenic mice than in control mice, and their size became larger nearly in parallel in both control and miR103 transgenic mice under a high-fat diet (Supplementary Figure 3e).


The flavonoid apigenin improves glucose tolerance through inhibition of microRNA maturation in miRNA103 transgenic mice.

Ohno M, Shibata C, Kishikawa T, Yoshikawa T, Takata A, Kojima K, Akanuma M, Kang YJ, Yoshida H, Otsuka M, Koike K - Sci Rep (2013)

Apigenin improves glucose tolerance in miR103 transgenic mice.(a), Expression levels of mature miR103, miR122, and miR185 in liver tissues of miR103 transgenic mice (miR103 Tg) were determined by Northern blotting. (b), Expression levels of mature miR103 and its precursor in liver tissues of miR10-transgenic mice treated with apigenin were determined by Northern blotting. Control (DMSO) or apigenin (40 mg/kg) was injected intraperitoneally daily for 14 days. Representative results from three independent mouse sets are shown. (c), Liver tissue homogenates from miR103 transgenic mice were separated using a phos-tag gel to determine the phosphorylation status of TRBP. Representative results from three independent mouse sets are shown. Full-length blot image is available in Supplementary Figure 5g. (d), Blood glucose levels were determined at random times or after 12 h fasting in control and miR103 transgenic (miR103 Tg) mice (n = 8 in each group). Data represent the means ± s.d. *, p < 0.05 (t-test). (e), (f), Glucose and pyruvate tolerance tests in control, miR103 transgenic (miR103 Tg), and miR103 transgenic with apigenin treatment (miR103 Tg + apigenin) mice (n = 6 in each group). Data represent the means ± s.d. *, p < 0.05 (t-test).
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f4: Apigenin improves glucose tolerance in miR103 transgenic mice.(a), Expression levels of mature miR103, miR122, and miR185 in liver tissues of miR103 transgenic mice (miR103 Tg) were determined by Northern blotting. (b), Expression levels of mature miR103 and its precursor in liver tissues of miR10-transgenic mice treated with apigenin were determined by Northern blotting. Control (DMSO) or apigenin (40 mg/kg) was injected intraperitoneally daily for 14 days. Representative results from three independent mouse sets are shown. (c), Liver tissue homogenates from miR103 transgenic mice were separated using a phos-tag gel to determine the phosphorylation status of TRBP. Representative results from three independent mouse sets are shown. Full-length blot image is available in Supplementary Figure 5g. (d), Blood glucose levels were determined at random times or after 12 h fasting in control and miR103 transgenic (miR103 Tg) mice (n = 8 in each group). Data represent the means ± s.d. *, p < 0.05 (t-test). (e), (f), Glucose and pyruvate tolerance tests in control, miR103 transgenic (miR103 Tg), and miR103 transgenic with apigenin treatment (miR103 Tg + apigenin) mice (n = 6 in each group). Data represent the means ± s.d. *, p < 0.05 (t-test).
Mentions: To apply the above results in a clinical setting, we focused on recent findings demonstrating that a gain of miR103/107 expression induces impaired glucose homeostasis in vivo10. To utilize this, we generated transgenic mice expressing a miR103 precursor under control of the CMV promoter (Supplementary Figure 3a). Overexpression of miR103 in these mice was confirmed by Northern blotting against mature miR103 in liver tissues (Figure 4a and Supplementary Figure 3b). No significant over-saturation of RISC complexes due to overexpressing miR103 in these mice was confirmed by a lack of significant changes in the expression levels of other mature miRNAs, such as miR122 and miR185 (Figure 4a). As expected from a previous report10, these miR103 transgenic mice showed an increase in both random and fasting blood-glucose levels and insulin levels (Supplementary Figure 3c and d). The mean size of adipocytes in visceral fat was larger in normal chow fed miR103 transgenic mice than in control mice, and their size became larger nearly in parallel in both control and miR103 transgenic mice under a high-fat diet (Supplementary Figure 3e).

Bottom Line: Polyphenols are representative bioactive substances with diverse biological effects.Here, we show that apigenin, a flavonoid, has suppressive effects on microRNA (miRNA) function.These results suggest that apigenin may have favorable effects on the pathogenic status induced by overexpression of miRNA103, whose maturation is mediated by phosphorylated TRBP.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. otsukamo-tky@umin.ac.jp

ABSTRACT
Polyphenols are representative bioactive substances with diverse biological effects. Here, we show that apigenin, a flavonoid, has suppressive effects on microRNA (miRNA) function. The effects were mediated by impaired maturation of a subset of miRNAs, probably through inhibition of the phosphorylation of TRBP, a component of miRNA-generating complexes via impaired mitogen-activated protein kinase (MAPK) Erk activation. While glucose intolerance was observed in miRNA103 (miR103)-overexpressing transgenic mice, administration of apigenin improved this pathogenic status likely through suppression of matured miR103 expression levels. These results suggest that apigenin may have favorable effects on the pathogenic status induced by overexpression of miRNA103, whose maturation is mediated by phosphorylated TRBP.

Show MeSH
Related in: MedlinePlus