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【Nobiletin】Main Citrus Flavonoids with Antidiabetic Effects

Nobiletin, chemically known as 5,6,7,8,3′,4′-hexamethoxyflavone, is a dietary flavone with the empirical formula C21H22O8 and the molecular weight 402.39. It is found in the peel of various citrus fruits, such as oranges and tangerines. Like other bioflavonoids, nobiletin has shown potential medicinal properties in several pathologies and their associated causes, such as preventing type 2 diabetes, protecting against bone mineral density loss, treating cancer, and lowering blood cholesterol. Studies have suggested that this flavone may be an effective therapeutic molecule for the treatment of metabolic syndromes, such as cardiovascular disease, abdominal obesity, and increased blood pressure.

To elucidate the antidiabetic mechanism of nobiletin in adipocytes, Kanda et al. conducted a study using 3T3-L1 preadipocyte cells in which nobiletin suppressed lipid accumulation in 3T3-L1 adipocytes, suggesting that nobiletin inhibited adipogenesis in 3T3-L1 cells when the adipocyte differentiation was induced by insulin, 3-isobutyl-1-methylxanthine (IBMX), and dexamethasone (DEX). Regarding the mechanism of action involved in this response, nobiletin did not affect the protein expression of peroxisome proliferator-activated receptor gamma (PPARγ)1 in 3T3-L1 cells; however, it significantly suppressed PPARγ2 protein expression, an important marker in adipogenesis. The transcripts of PPARγ2 and adipocyte protein 2 (aP2), two target genes of PPARγ, were significantly down-regulated by nobiletin treatment. In addition, it suppressed CCAAT-enhancer-binding protein beta (C/EBPβ) expression, suggesting that nobiletin may inhibit adipocyte differentiation by down-regulating PPARγ2 gene expression via decreasing C/EBPβ expression. Finally, nobiletin reduced the phosphorylation of the cAMP-response element-binding protein (CREB) and strongly improved the phosphorylation of the signal transducer and activator of transcription 5 (STAT5), suggesting that a suppressive effect of nobiletin on adipocyte differentiation was involved due to the enhanced activation of STAT5 by the regulation of PPARγ activity.

A recent study tested the hypothesis that nobiletin provides metabolic protection against the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in three different mouse models; mice deficient in hepatic AMPK (Ampkβ1-/-), mice incapable of the inhibitory phosphorylation of ACC (AccDKI), and mice with adipocyte-specific AMPK deficiency (iβ1β2AKO) [46]. Nobiletin was able to activate (increase the phosphorylation of) AMPK in human hepatocarcinoma HepG2 cells in the presence of high glucose. Additionally, ACC phosphorylation, which was suppressed by hyperglycemia, was reversed through nobiletin treatment. In vitro nobiletin-treated cells had reduced lipogenesis and increased fatty acid oxidation independent of AMPK. In summary, the results of this study showed that nobiletin treatment attenuated obesity, hepatic steatosis, dyslipidemia, and insulin resistance, and protected metabolism in three mouse models independently of AMPK activation. The authors also emphasized the potential therapeutic convenience of this citrus flavonoid nobiletin, specifically in the management of metabolic syndromes such as diabetes and obesity, and further in-depth studies are warranted to investigate the primary mechanism of action that influences insulin sensitivity.

Nobiletin has, therefore, been shown to have potent antidiabetic, anti-obesity, and hypolipidemic effects by modulating several physiological pathways. In addition, it acted as an immunomodulatory molecule, attenuating inflammatory and oxidative stress markers, which are linked to the various diabetic complications. This evidence reinforces the therapeutic potential of nobiletin for diabetes in in vitro experimental systems and animal models, which should be further verified in humans.

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