Natural Products and Obesity: A Focus on the Regulation of Mitotic Clonal Expansion during Adipogenesis
Abstract
:1. Introduction
2. Adipose Biology during the Development of Obesity
3. Regulation of Adipogenesis
3.1. Arrest and Progression of the Cell Cycle and Its Associated Regulatory Proteins
3.2. Cascade of Transcriptional Factors during Mitotic Clonal Expansion
3.2.1. CCAAT/Enhancer Binding Protein β (C/EBPβ)
3.2.2. CCAAT/Enhancer Binding Protein α (C/EBPα)
3.2.3. Peroxisome Proliferator-Activated Receptor γ (PPARγ)
3.2.4. Gene Markers for Terminal Differentiation
3.3. Signaling Pathways Involved in Adipogenesis
3.3.1. Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/AKT) Pathway
3.3.2. Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase (MAPK/ERK) Pathway
3.3.3. Wingless/INT-1 Protein (Wnt)/β-Catenin Signaling
3.3.4. AMP-Activated Protein Kinase (AMPK) Pathway
4. Regulation of Adipogenesis by Various Phytochemicals
4.1. Cell-Cycle Arrest and Its Regulatory Proteins
4.2. Cell Proliferation
4.3. Transcription Factors
4.4. Intracellular Signaling Pathways
4.4.1. Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/AKT) Pathway
4.4.2. Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase (MAPK/ERK) Pathway
4.4.3. Wingless/INT-1 Protein (Wnt)/β-Catenin Signaling
4.4.4. AMP-Activated Protein Kinase (AMPK) Pathway
5. Inhibition of Adipogenesis by Natural Product-Derived Bioactive Components
5.1. Combination of Different Phytochemicals
5.2. Combination of Phytochemicals with Other Compounds Isolated from Natural Product
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Family | Active Component | Tested Dose | Cell Proliferation | Cell Cycle | Cell-Cycle Regulators | Transcription Factor | Signaling Cascade | Intracellular Lipid Accumulation | Reference |
---|---|---|---|---|---|---|---|---|---|
Alkaloids | Berberine | 0.625–10 μM | ↓PPARγ, C/EBPα mRNA and protein levels | ↓ | [129] | ||||
Berberine | 1.5–12 μM | ↓PPARγ, C/EBPα mRNA levels ↑CHOP, DEC2 mRNA levels | ↓ | [121] | |||||
Caffeine | 0.1–5 mM | ↓ | ↑p21, p27 protein levels ↓CDK2 protein level | ↓PPARγ, C/EBPα, C/EBPβ protein levels ↓C/EBPα, PPARα, FAS, aP2 mRNA levels ↑KLF2 mRNA level | ↓ p-AKT, p-GSK3β protein levels = p-ERK protein level | ↓ | [116] | ||
Anthocyanins | Delphinidin | 10–150 μM | ↑ G0/G1 | ↑p27 protein level ↓CDK2, CDK6 protein levels= CDK4, Cyclin D3 protein levels ↑cyclin D1 mRNA & protein levels | ↓ C/EBPβ, C/EBPδ, C/EBPα mRNA levels ↓ PPARγ mRNA and protein levels | ↑Wnt1, Wnt10b, Fzd2, and Lrp5 mRNA levels ↑β-catenin mRNA & protein levels, ↑β-catenin nuclear translocation ↑ mRNA & nuclear translocation of β-catenin ↓GSK3β mRNA & protein levels ↑c-Myc protein levels | ↓ | [97] | |
Asteraceae | Dehydroleu-codine | 5–12.5 μM | ↓ | ↑ G0/G1 | ↓CDK2, CDK4 protein level ↑p27 protein level | ↓C/EBPβ, PPARγ mRNA levels | ↓ p-AKT, p-Akt protein levels | ↓ | [103] |
Coumarins | p-Coumaric acid | 125–1000 μg/mL | ↓PPARγ, C/EBPα protein levels | ↑p-AMPK | ↓ | [130] | |||
Coumaric acid | 0.1–0.2 mM | ↓PPARγ2, C/EBPα mRNA and protein levels | ↓ | [131] | |||||
Coumestans | Coumestrol | 20–60 μM | ↓PPARγ, C/EBPα protein levels | ↓ p-AKT, p-GSK3β ↑LRP6 protein level ↑β-catenin protein level ↑Wnt10b mRNA and protein levels ↑c-Myc, cyclin D1 mRNA and protein levels | ↓ | [127] | |||
Phenolic acid | Curcumin | 5–20 μM | ↓ C/EBPα, PPARγ mNRA levels | ↓ | [132] | ||||
Curcuminoids | Curcumin | 10–25 μM | ↓ C/EBPα, PPARγ protein levels | ↑Wnt10b, Fzd2, and Lrp5 mRNA levels ↑nuclear β-catenin protein ↓GSK-3β, CK1α, Axin protein levels ↑c-Myc, cyclin D1 mRNA and protein levels ↓p-ERK, p-JNK, p-p38 MAPK | ↓ | [128] | |||
Curcumin | 5–30 μM | ↓ C/EBPβ, PPARγ, C/EBPα mRNA levels | ↓ | [125] | |||||
Curcumin | 5–35 μM | ↓ | ↓S and/or G2/M | ↓Cyclin A, CDK2 protein levels | ↓ KLF5, C/EBPβ, PPARγ, C/EBPα mRNA levels | ↓ | [100] | ||
Bisdemethoxycurcumin (BDMC) | 5–25 μM | ↑G0/G1 | ↓cyclin A, cyclin B protein levels ↑p21 protein level = CDK2 and 4, Cyclin D and E protein levels | ↓PPARγ, C/EBPα protein levels | ↓p-ERK1/2, p-JNK/ = p-p38 MAPK ↓p-Akt | ↓ | [107] | ||
Curcumin-3,4-dichloro phenyl pyrazole | 5–20 uM | ↑G1, S | ↓CyclinD1, CyclinD3, CDK2, CDK4, CDK6 protein levels ↑p27 protein level | ↓PPARγ2, C/EBPα mRNA and protein levels | = Wnt3a, GATA, β-catenin, p-AMPK protein levels ↓ p-AKT, mTOR protein levels | ↓ | [102] | ||
Flavanols | Catechin 3 -gallate (CG) | 5–30 μM | ↓ C/EBPα, PPARγ protein levels | ↓ | [133] | ||||
Epicatechin 3-gallate (ECG) | 5–30 μM | ↓ C/EBPα, PPARγ protein levels | ↓ | [133] | |||||
Epigallocatechin-3-gallate (EGCG) | 0.1–10 μM | ↓ | ↑G2/M | ↓ C/EBPα, PPARγ mRNA levels | ↓ | [111] | |||
Epigallocatechin-3-gallate (EGCG) | 100 μM | ↓ | ↓G0/G1 ↑S | ↓ C/EBPα, PPARγ mRNA levels | ↓ FoxO1 mRNA level | ↓ | [66] | ||
Flavones | Apigenin | 30–70 μM | ↓ | ↑G0/G1 | ↓CyclinD1, CDK4 protein levels ↑p27 protein level | ↓DNA-binding activity of C/EBPβ ↓C/EBPβ protein level ↑p- C/EBPβ, CHOP-10 protein levels | ↓ | [98] | |
Flavonoids | Isorhamnetin | 1–50 μM | ↓C/EBPβ, C/EBPδ mRNA levels ↓PPARγ, C/EBPα mRNA levels | ↓ | [126] | ||||
Flavonoids | Rhamnetin | 10–40 μM | ↓ | ↓PPARγ, C/EBPα mRNA and protein levels | ↓ | [118] | |||
Flavonoids | Fisetin | 10–30 μM | ↓ | ↓cyclin A, cyclin D1, CDK4 protein levels ↑p27 protein level = Cyclin E, CDK2 protein levels | ↓PPARγ protein level | = p-ERK and p-AKT ↓ p-S6 (p70S6K activity) | ↓ | [108] | |
Glucosinolates | Sinigrin (2-propenyl glucosinolate) | 1–100 μg/mL | ↑G0/G1 | ↑p21, p27 protein levels ↓CDK2 protein level | ↓p-C/EBPβ ↓PPARγ, C/EBPα protein & mRNA levels | ↓ p-ERK, p-JNK and p-p38 MAPK ↑p-AMPK | ↓ | [99] | |
Flavonoids: Isoflavonoids | Genistein | 5–100 μM | - | - | ↓PPARγ protein level | ↓ | [134] | ||
Genistein | 100 μM | ↓PPARγ, C/EBPα protein levels = C/EBPβ protein level ↓DNA-binding activity of C/EBPβ ↑CHOP protein level | ↓ | [122] | |||||
Genistein | 50 μM | ↓ | ↑S | ↑cyclin A protein level = p27, p21, cyclin E, CDK2 protein levels | ↓Centromeric localization of C/EBPβ | = p-MAPK, GSK3β protein levels | ↓ | [112] | |
Isothiocyanates | Sulforaphane | 5–20 μM | ↓ | ↑G0/G1 | ↑ p27 protein level / ↓p-Rb ↓ cyclin D1, CDK2, CDK4, cyclin A protein levels | ↓PPARγ, C/EBPα protein levels | ↓p-AKT, p-ERK | ↓ | [67] |
Phenolic acid | Cocoa | 100–200 μg/mL | ↑G1-S | ↓PPARγ, C/EBPα mRNA and protein levels | ↓p- ERK, p-AKT, mTOR, p70S6K protein levels ↓ Insulin receptor kinase | ↓ | [109] | ||
Phenolic acids | Caffeic acid phenethyl ester | 10–40 μM | ↑G1/S | ↓cyclin D1 mRNA and protein levels | ↓PPARγ, C/EBPα protein levels | ↓p-ERK, p-AKT | ↓ | [110] | |
Secoiridoids | Hydroxytyrosol | 50–150 μM | ↑G0/G1 ↑S | ↓PPARγ, C/EBPα mRNA levels | ↓ | [106] | |||
Oleuropein | 100–300 μM | ↑G0/G1 ↑S | ↓PPARγ, C/EBPα mRNA levels | ↓ | [106] | ||||
Stilbenes | Vitisin A | 1–10 μM | ↓ | ↑G0/G1 | ↓p-Rb ↑p21 protein level | ↓PPARγ protein level and activity | = p-ERK, p-AKT | ↓ | [104] |
Ellagic acid | 10–20 μM | ↑G0/G1 | ↓p-Rb, cyclin A protein levels | ↓C/EBPα protein level and DNA-binding activity ↓PPARγ mRNA and protein levels | ↓ | [105] | |||
Piceatannol | 10–50 μM | NS | ↓S and G2/M | ↓PPARγ, C/EBPα protein and mRNA levels ↓C/EBPβ mRNA level | ↓ p-IR, p-IRS-1, p-AKT, p-ERK1/2 | ↓ | [113] | ||
Resveratrol | 25–50 μM | ↓ | ↑G1/S | ↓ cyclin A, CDK2 protein levels | ↓PPARγ, C/EBPα protein levels | ↓p-AKT, p-IR ↓IR kinase activity | ↓ | [114] | |
Resveratrol | 20 μM | ↓p-Rb, Cyclin A and D1, p21 protein levels | ↓PPARγ, C/EBPα protein level ↓PPARγ activity | ↓p-AKT, p-ERK ↑p-AMPK | ↓ | [117] | |||
Tannins | Dieckol | 25–100 μM | ↓ | ↑G1↓S | ↓ cyclin A and D, p-Rb, CDK2 protein levels ↑p27 protein level | ↓C/EBPβ, C/EBPδ, KLF4, KLF5, ETS2 mRNA levels | ↓p- ERK, p-AKT ↑p-AMPK | ↓ | [115] |
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Chang, E.; Kim, C.Y. Natural Products and Obesity: A Focus on the Regulation of Mitotic Clonal Expansion during Adipogenesis. Molecules 2019, 24, 1157. https://doi.org/10.3390/molecules24061157
Chang E, Kim CY. Natural Products and Obesity: A Focus on the Regulation of Mitotic Clonal Expansion during Adipogenesis. Molecules. 2019; 24(6):1157. https://doi.org/10.3390/molecules24061157
Chicago/Turabian StyleChang, Eugene, and Choon Young Kim. 2019. "Natural Products and Obesity: A Focus on the Regulation of Mitotic Clonal Expansion during Adipogenesis" Molecules 24, no. 6: 1157. https://doi.org/10.3390/molecules24061157
APA StyleChang, E., & Kim, C. Y. (2019). Natural Products and Obesity: A Focus on the Regulation of Mitotic Clonal Expansion during Adipogenesis. Molecules, 24(6), 1157. https://doi.org/10.3390/molecules24061157