Table 2.
List of flavonoids and their underlying mechanisms of action in adipogenesis
| Flavonoids | Stages of adipogenesis | Effect | Pathways/target molecules | Experimental model and dose applied | Comments | References |
|---|---|---|---|---|---|---|
| Anthocyanidins | ||||||
| Cyanidin | Terminal differentiation | Anti-adipogenic | Upregulation of ChREBP and interfering with the extracellular matrix | Preadipocytes obtained from subcutaneous and visceral human adipose explant tissue | Reduces adipogenesis via interfering with extracellular matrix and decreasing ChREBP expression level | [93] |
| Cyanidin-3-O-glucoside | Terminal differentiation | Proadipogenic | Upregulation of Pparg and Cebpα | 3T3-L1 cells (20 and 100 µM)/db/db mice (black soy bean extract 30 mg/kg, orally) | Increases Pparg and Cebpα expression, adiponectin secretion and activates insulin signaling cascade | [95] |
| Determination | Anti-adipogenic | Activation of Wnt pathway | C3H10T1/2 cells (black rice extract 10, 20, 40, and 80 µg/ml)/HFD mice (black rice extract, 100 mg/kg, orally) | Inhibits differentiation of mesenchymal cells to preadipocytes and induces Wnt-specific target genes such as Axin2, Wisp2, and Cyclin d1 | [138] | |
| Terminal differentiation | Anti-adipogenic | Suppression of PPARG | 3T3-L1 cells (black soybean extract 12.5 and 50 µg/ml) | Reduces lipid accumulation and suppresses PPARG expression | [94] | |
| Delphinidin-3-O-glucoside | Terminal differentiation | Anti-adipogenic | Suppression of PPARG | 3T3-L1 cells (black soybean extract 12.5 and 50 µg/ml) | Reduces lipid accumulation and suppresses PPARG expression | [94] |
| Peonidin-3-O-glucoside | Determination | Anti-adipogenic | Activation of Wnt pathway | C3H10T1/2 cells (black rice extract 10, 20, 40, and 80 µg/ml)/HFD mice (black rice extract, 100 mg/kg, orally) | Inhibits differentiation of mesenchymal cells to preadipocytes and induces Wnt-specific target genes such as Axin2, Wisp2, and Cyclin D1 | [138] |
| Flavones | ||||||
| Apigenin | Clonal expansion | Anti-adipogenic | Inhibition of mitotic clonal expansion and cell-cycle arrest | 3T3-L1 cells (30 and 70 µM) | Inhibits clonal expansion, arrests cell cycle at the G0/G1 phase and decreases PPARG and C/EBPβ levels | [107] |
| Terminal differentiation | Anti-adipogenic | Activation of AMPK | 3T3-L1 cells (10, 50 µM) | Induces activation of AMPK and decreases expression of adipogenic and lipolytic genes | [97] | |
| Luteolin | Terminal differentiation | Anti-adipogenic | Inhibition of the transactivation of PPARG | 3T3-L1 cells | Attenuates PPARG and C/EBPα expression | [108] |
| Baicalein | Clonal expansion | Anti-adipogenic | Suppression of Akt-C/EBPα-GLUT4 signaling | 3T3-L1 cells (50 µM) | Decreases the intracellular lipid accumulation by downregulation of glucose uptake via repression of Akt-C/EBPα-GLUT4 signaling | [133] |
| Flavan-3-ols | ||||||
| Catechin | Terminal differentiation | Anti-adipogenic | Suppression of PPARG2, C/EBPα& GLUT4 | 3T3-L1 cells (50, 75, 100 µM) 3T3-L1 cells (30 µM) | Inhibits adipogenesis via suppression of PPARG2, C/EBPα, and GLUT4 | [111, 139] |
| (−)-Catechin | Determination | Proadipogenic | Upregulation of Pparg | hBM-MSCs (1 and 100 µM) | Upregulates the mRNA levels of adipogenic markers, such as Adipoq, Pparg, Fabp4, and Lpl in hBM-MSCs | [105] |
| (−)-Epigallocatechin gallate | Terminal differentiation | Proadipogenic | Upregulation of Pparg and Cebps | 3T3-L1 cells (0.5, 5, or 10 µM) | Increases expression of Pparg1, Pparg2, and Cebps | [104] |
| (−)Epigallocatechin gallate | Terminal differentiation | Anti-adipogenic | Activation of Wnt/β-catenin pathway | 3T3-L1 cells (100, 150, 200 µM) | Reduces expression of adipogenic markers such as PPARG, C/EBPα, FABP4 and fatty acid synthase while increases β-catenin in the nucleus | [112] |
| Terminal differentiation | Anti-adipogenic | Apoptosis | 3T3-L1 cells (50–200 µM) | Increases apoptosis in mature adipocytes without affecting viability of preadipocytes | [113] | |
| Flavonols | ||||||
| Fisetin | Terminal differentiation | Anti-adipogenic | Inhibition of mTORC1 signaling | 3T3-L1 cells (50 µM) /HFD mice (HFD supplemented with 0.2% or 0.5% (w/w) fisetin) | Reduces adipogenesis by suppression of mTORC1 activity | [140] |
| Clonal expansion | Anti-adipogenic | Inhibition of mitotic clonal expansion | 3T3-L1 cells (10, 30 µM) | Suppresses cell cycle regulatory proteins such as cyclin A, cyclin D1 and CDK4 expression and inhibits cell proliferation | [141] | |
| Terminal differentiation | Anti-adipogenic | Inhibition of mTOR-C/EBPα Signaling | 3T3-L1 cells (10 µM) | Downregulates Pparg and Cebpαexpression during adipogenesis | [142] | |
| Isorhamnetin | Terminal differentiation | Anti-adipogenic | Suppression of Pparg | 3T3-L1 cells (50 µM) | Reduces Pparg and Cebpα expression. However Cebpβ and Cebpδ expression remains unchanged | [114] |
| Determination/terminal differentiation | Anti-adipogenic | Stabilization of β-catenin protein | hA-MSCs/3T3-L1 cells (1, 25 µM) | Inhibits Wnt receptor and co-receptor genes expression, increases β-catenin, but no effect on β-catenin mRNA levels | [115] | |
| Kaempferol | Clonal expansion | Anti-adipogenic | Inhibition of cell-cycle progression, AKT and mTOR signaling pathway | 3T3-L1 cells (30 µM)/zebra fish (5, 10, 20 µM) | Inhibits cell-cycle progression via regulation of cyclins. In addition, inhibits phosphorylation of AKT and mTOR signaling pathway. Many transcriptional factors such as C/EBPβ, KLF4 and KLF5 are downregulated, while nKLF2 and Pref-1 are upregulated | [118] |
| Terminal differentiation | Anti-adipogenic | Suppression of Pparg | 3T3-L1 cells (40, 80 µM) | Downregulates expression of Pparg, Cebpβ, Srebp1, Rxrβ, Lxrβ, Rorα and also genes involved in triglyceride biosynthesis such as Gpd1, Agpat2, Dgat2 | [106, 143] | |
| Myricetin | Terminal differentiation | Anti-adipogenic | Suppression of Pparg | 3T3-L1 cells (100 µM) | Reduces expression of Cebpα, Pparg, Cebpβ, Sreb1c, Fabp4, Lpl and Glut4. Also, inhibits phosphorylation of ERK and JNK during differentiation of adipocytes | [144] |
| Determination | Anti-adipogenic | Suppression of Pparg | hA-MSCs (30 µM) | Reduces expression of Cebpα, Pparg, Lpl and Fabp | [145] | |
| Rhamnetin | Clonal expansion/terminal differentiation | Anti-adipogenic | Inhibition of mitotic clonal expansion, and suppression of Pparg | 3T3-L1 cells | Decreases expression of Pparg,Cebpα, and perilipin (Plin) Also completely inhibits triglyceride biosynthesis and clonal expansion | [122] |
| Rutin | Terminal differentiation | Anti-adipogenic | Suppression of Pparg and Cebpα | 3T3-L1 cells (0.25, 0.5, 1.0 mg/ml)/3T3-L1 cells (10, 30, 100 µM)/HFD mice (25, 50 mg/kg, orally) | Reduces mRNA expression of Pparg and Cebpα | [125, 146] |
| Quercetin | Terminal differentiation | Anti-adipogenic | Activation of AMPK pathway | 3T3-L1 cells (10, 50, 100 µM) | Stimulates activation of AMPK pathway and phosphorylation of acetyl-CoA carboxylase | [129] |
| Clonal expantion | Anti-adipogenic | Inhibition of mitotic clonal expansion | 3T3-L1 cells (50, 100 µM) | Decreases adipocyte differentiation by inhibition of clonal expansion during early adipogenesis via suppression of cyclin A | [147] | |
| Determination | Anti-adipogenic | Suppression of PPARG, C/EBPα and SREBP-1c | OP9 mouse stromal cells (50 µM) | Downregulates mRNA and protein expression of C/EBPα, PPARG, SREBP-1c, FAS, FABP4 and mRNA level of Hsl and Lpl | [148] | |
| Flavanones | ||||||
| Hesperetin | Determination | Anti-adipogenic | Apoptosis | hBM-MSCs (10, 20, 40, 80, 160 µM) | Decreases expression of Adipoq, Retn, Fabp4, Pparg, Lpl and Tnf-α, while upregulates proapoptotic genes | [130] |
| Naringenin | Terminal differentiation | Anti-adipogenic | Suppression of PPARG | 3T3-L1 cells (25, 50 µg/ml) | Reduces expression of FABP4, PPARG, STAT5A, and adiponectin | [149] |
| Isoflavones | ||||||
| Biochanin A | Determination | Anti-adipogenic | Suppression of Pparg | hA-MSCs (0.1, 0.3, and 1 µM) | Decreases Pparg, Leptin (Lep), osteopontin (Opn)and Lpl expression | [150] |
| Daidzein | Determination | Anti-adipogenic | Stimulation of lipolysis | hA-MSCs (0.1–100 µM) | Stimulates lipolysis by cAMP-dependent protein kinase-mediated hormone sensitive lipase | [131] |
| Formononetin | Terminal differentiation | Proadipogenic | Upregulation of PPARG | C3H10T1/2 cells (1–20 µM) | Upregulates PPARG and its target genes such as Fabp4 and Glut4 | [151] |
| Terminal differentiation | Proadipogenic | Upregulation of PPARG | 3T3-L1 cells (1–20 µM) | Upregulates PPARG and its target genes such as Fabp4 and Glut4 | [152] | |
| Genistein | Clonal expansion | Anti-adipogenic | Inhibition of mitotic clonal expansion and PPARG expression | 3T3-L1 cells (5, 50, 100 µM) | Blocks adipogenesis by inhibition of mitotic clonal expansion and suppression of PPARG expression | [153] |
| Terminal differentiation | Anti-adipogenic | Suppression of MAPK | 3T3-L1 cells (50 µM) | Increases eNOS expression, inhibits phosphorylation of JAK2 and decreases FAS expression | [119] | |
| Clonal expansion/terminal differentiation | Anti-adipogenic | Activation of AMPK and induction of apoptosis and inhibition of clonal expansion | 3T3-L1 cells (100 µM) | Induces ROS, activates AMPK and inhibits mitotic clonal expansion | [154] | |
| Determination | Anti-adipogenic | Activation of Wnt signaling via ERs-dependent pathway | hA-MSCs (0.1–100 µM) | Activates Wnt/β-catenin pathway, inhibits expression of Pparg, Srebp-1c and Glut4 | [131] | |