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Flavonoids, Obesity and Metabolic Syndrome
Obesity is a medical condition, defined by WHO as an abnormal or excessive accumulation of fat that can compromise health. Energy imbalance in which energy intake is greater than energy expenditure is the primary cause of visceral or central obesity, as excess energy is stored as triglycerides within adipocytes, which increase in size (hypertrophy phynotype), and number (hyperplasic phenotype), or both. By accumulating excess energy, adipocytes become hypertrophic, which causes the release of free fatty acids into the circulation (lipotoxicity), adipocytes change their immunological balance, which promotes, with adipose tissue resident immunes cells (macrophages), the production and the circulating levels of proinflammatory cytokines and decreases the concentration of anti-inflammatory adipokines, such as adiponectin. These changes in adipose tissue lead to the development of chronic state of low-grade inflammation that secondarily generates obesity-related complications, commonly known as metabolic syndrome. This syndrome includes insulin resistance, hyperglycemia type 2 diabetes mellitus (T2DM), cardiovascular diseases, dyslipidemia (decreased concentration of cholesterol and triglycerides), steatosis, fibrosis, hypertension, heart attack. The literature strongly suggests that flavonoids demonstrate an important biological effect on obesity, as demonstrated by their ability to lower fat mass, lipid droplets in the liver, and total triglycerides/cholesterol in both in vitro and in vivo models.
1. Effects of Flavonoids on Lipid Accumulation
Lipids accumulate is caused by an increase in the size of adipocyte (hypertrophy) and an increase in their number (hyperplasia). Hyperplasia is regulated by the differentiation of multipotent mesenchymal stem cells into preadipocytes that, under appropriate stimulation, can differentiate terminally into mature adipocytes. These adipocytes are capable to storing excess energy as cytoplasmic neutral lipid droplets of different sizes which can exceed 100 micrometers . In this regard, it has been reported that flavonoids have great potential. They deal with lipid accumulation through numerous mechanisms, including the inhibition of adipocyte differentiation, primarily caused by the reduced expression of important regulatory adipogenic transcription factors, decreased lipogenesis, and induction of adipocyte apoptosis . Thus, quercetin, a plant flavonol found in a wide variety of vegetables and fruits, reduces the lipid accumulation through decreasing preadipocyte differentiation, lipogenesis, and induction of adipocyte apoptosis . The inhibition of adipogenesis was regulated by the downregulation of central transcriptional regulators of adipogenesis (SREBP-1, C/EBPα, and PPARγ) and FAS, a key adipogenic enzyme. Quercetin increasing apoptosis involved mitogen-activated protein (MAP) kinases, specifically the decrease in extracellular signal-regulated kinases (ERKs). Thus, inhibition of the extracellular signal-regulated kinases enhances apoptosis . Kaempferol, another flavonoid, negatively regulates adipogenesis by downregulating PPARγ, aP2, and SREBP-1C  and CCAAT-enhancer-binding protein alpha  in 3T3-L1 adipocytes. In zebrafish, kaempferol has anti-adipogenic properties that regulate early adipogenic factors (KLF5, KLF4, KLF2, and C/EBPβ) . Upregulation of lipolysis regulatory enzymes (Adipose triglyceride lipase (Pnpla2)) is one of the anti-adipogenic mechanism of kaempferol . In addition, baicalein, a type of flavonoid originating from Scutellaria baicalensis, has a significant capacity to decrease lipid accumulation in zebrafish in a dose-dependent manner . In 3T3-L1 cells, baicalein inhibit lipid accumulation during adipogenesis by arresting cell cycle in the G0/G1 phase through cyclin downregulation, suppressing the mRNA expression of early adipogenic factors. The above-mentioned factor shortage leads to the downregulation of late adipogenic factors, negatively regulating the m-TOR signaling pathway, involved in lipid accumulation during adipogenesis and decreased p-p38 MAPK and pERK levels in adipocytes . Puerariae Lobatae radix flavonoids and puerarin successfully limited lipid accumulation in the abdomens of zebrafish larvae in a dose dependent manner .
2. Effects of Flavonoid on Triglycerides
3. Flavonoid and Cholesterol
4. Effects of Flavonoid on Inflammation
5. Insulin Resistance
6. Flavonoid Effects on Non-Alcoholic Fatty Liver Disease
The entry is from 10.3390/molecules26103014
- Ghaddar, B.; Veeren, B.; Rondeau, P.; Bringart, M.; Lefebvre D’hellencourt, C.; Meilhac, O.; Bascands, J.-L.; Diotel, N. Impaired brain homeostasis and neurogenesis in diet-induced overweight zebrafish: A preventive role from A. borbonica extract. Sci. Rep. 2020, 10, 14496.
- Haselgrübler, R.; Lanzerstorfer, P.; Röhrl, C.; Stübl, F.; Schurr, J.; Schwarzinger, B.; Schwarzinger, C.; Brameshuber, M.; Wieser, S.; Winkler, S.M.; et al. Hypolipidemic effects of herbal extracts by reduction of adipocyte differentiation, intracellular neutral lipid content, lipolysis, fatty acid exchange and lipid droplet motility. Sci. Rep. 2019, 9, 10492.
- Khalilpourfarshbafi, M.; Gholami, K.; Murugan, D.D.; Abdul Sattar, M.Z.; Abdullah, N.A. Differential effects of dietary flavonoids on adipogenesis. Eur. J. Nutr. 2019, 58, 5–25.
- Seo, M.-J.; Lee, Y.-J.; Hwang, J.-H.; Kim, K.-J.; Lee, B.-Y. The inhibitory effects of quercetin on obesity and obesity-induced inflammation by regulation of MAPK signaling. J. Nutr. Biochem. 2015, 26, 1308–1316.
- Ahn, J.; Lee, H.; Kim, S.; Park, J.; Ha, T. The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem. Biophys. Res. Commun. 2008, 373, 545–549.
- Lee, Y.-J.; Choi, H.-S.; Seo, M.-J.; Jeon, H.-J.; Kim, K.-J.; Lee, B.-Y. Kaempferol suppresses lipid accumulation by inhibiting early adipogenesis in 3T3-L1 cells and zebrafish. Food Funct. 2015, 6, 2824–2833.
- Torres-Villarreal, D.; Camacho, A.; Castro, H.; Ortiz-Lopez, R.; de la Garza, A.L. Anti-obesity effects of kaempferol by inhibiting adipogenesis and increasing lipolysis in 3T3-L1 cells. J. Physiol. Biochem. 2019, 75, 83–88.
- Seo, M.-J.; Choi, H.-S.; Jeon, H.-J.; Woo, M.-S.; Lee, B.-Y. Baicalein inhibits lipid accumulation by regulating early adipogenesis and m-TOR signaling. Food Chem. Toxicol. 2014, 67, 57–64.
- Fang, P.; Yu, M.; Min, W.; Han, S.; Shi, M.; Zhang, Z.; Bo, P. Beneficial effect of baicalin on insulin sensitivity in adipocytes of diet-induced obese mice. Diabetes Res. Clin. Pr. 2018, 139, 262–271.
- Liu, Y.-S.; Yuan, M.-H.; Zhang, C.-Y.; Liu, H.-M.; Liu, J.-R.; Wei, A.-L.; Ye, Q.; Zeng, B.; Li, M.-F.; Guo, Y.-P.; et al. Puerariae Lobatae radix flavonoids and puerarin alleviate alcoholic liver injury in zebrafish by regulating alcohol and lipid metabolism. Biomed. Pharm. 2021, 134, 111121.
- Lin, H.; Zhou, Z.; Zhong, W.; Huang, P.; Ma, N.; Zhang, Y.; Zhou, C.; Lai, Y.; Huang, S.; An, H.; et al. Naringenin inhibits alcoholic injury by improving lipid metabolism and reducing apoptosis in zebrafish larvae. Oncol. Rep. 2017, 38, 2877–2884.
- Hotamisligil, G.S. Inflammation, metaflammation and immunometabolic disorders. Nature 2017, 542, 177–185.
- Masschelin, P.M.; Cox, A.R.; Chernis, N.; Hartig, S.M. The Impact of Oxidative Stress on Adipose Tissue Energy Balance. Front. Physiol. 2020, 10, 1638.
- Cirmi, S.; Randazzo, B.; Russo, C.; Musumeci, L.; Maugeri, A.; Montalbano, G.; Guerrera, M.C.; Lombardo, G.E.; Levanti, M. Anti-inflammatory effect of a flavonoid-rich extract of orange juice in adult zebrafish subjected to Vibrio anguillarum-induced enteritis. Nat. Prod. Res. 2020, 1–4.
- Sivamani, S.; Joseph, B.; Kar, B. Anti-inflammatory activity of Withania somnifera leaf extract in stainless steel implant induced inflammation in adult zebrafish. J. Genet. Eng. Biotechnol. 2014, 12, 1–6.
- Zang, L.; Shimada, Y.; Kawajiri, J.; Tanaka, T.; Nishimura, N. Effects of Yuzu (Citrus junos Siebold ex Tanaka) peel on the diet-induced obesity in a zebrafish model. J. Funct. Foods 2014, 10, 499–510.
- Frühbeck, G.; Catalán, V.; Rodríguez, A.; Ramírez, B.; Becerril, S.; Salvador, J.; Portincasa, P.; Colina, I.; Gómez-Ambrosi, J. Involvement of the leptin-adiponectin axis in inflammation and oxidative stress in the metabolic syndrome. Sci. Rep. 2017, 7, 6619.
- Kim, J.-Y.; Hong, J.-H.; Jung, H.K.; Jeong, Y.S.; Cho, K.-H. Grape skin and loquat leaf extracts and acai puree have potent anti-atherosclerotic and anti-diabetic activity in vitro and in vivo in hypercholesterolemic zebrafish. Int. J. Mol. Med. 2012, 30, 606–614.
- Les, F.; Cásedas, G.; Gómez, C.; Moliner, C.; Valero, M.S.; López, V. The role of anthocyanins as antidiabetic agents: From molecular mechanisms to in vivo and human studies. J. Physiol. Biochem. 2020, 77, 109–131.
- Alkhalidy, H.; Wang, Y.; Liu, D. Dietary Flavonoids in the Prevention of T2D: An Overview. Nutrients 2018, 10, 438.
- Ren, N.; Kim, E.; Li, B.; Pan, H.; Tong, T.; Yang, C.S.; Tu, Y. Flavonoids Alleviating Insulin Resistance through Inhibition of Inflammatory Signaling. J. Agric. Food Chem. 2019, 67, 5361–5373.
- Delgadillo-Silva, L.F.; Tsakmaki, A.; Akhtar, N.; Franklin, Z.J.; Konantz, J.; Bewick, G.A.; Ninov, N. Modelling pancreatic β-cell inflammation in zebrafish identifies the natural product wedelolactone for human islet protection. Dis. Model. AMP Mech. 2019, 12, dmm036004.
- Matsuda, H.; Kogami, Y.; Nakamura, S.; Sugiyama, T.; Ueno, T.; Yoshikawa, M. Structural requirements of flavonoids for the adipogenesis of 3T3-L1 cells. Bioorganic Med. Chem. 2011, 19, 2835–2841.
- Van De Wier, B.; Koek, G.H.; Bast, A.; Haenen, G.R.M.M. The potential of flavonoids in the treatment of non-alcoholic fatty liver disease. Crit. Rev. Food Sci. Nutr. 2017, 57, 834–855.
- Schlegel, A. Studying non-alcoholic fatty liver disease with zebrafish: A confluence of optics, genetics, and physiology. Cell. Mol. Life Sci. 2012, 69, 3953–3961.
- Hiramitsu, M.; Shimada, Y.; Kuroyanagi, J.; Inoue, T.; Katagiri, T.; Zang, L.; Nishimura, Y.; Nishimura, N.; Tanaka, T. Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis. Sci. Rep. 2014, 4, 3708.
- Sarwar, R.; Pierce, N.; Koppe, S. Obesity and nonalcoholic fatty liver disease: Current perspectives. Diabetes. Metab. Syndr. Obes. 2018, 11, 533–542.
- Chen, B.; Zheng, Y.-M.; Zhang, J.-P. Comparative Study of Different Diets-Induced NAFLD Models of Zebrafish. Front. Endocrinol. 2018, 9, 366.
- Lee, S.-H.; Kim, H.-W.; Lee, M.-K.; Kim, Y.J.; Asamenew, G.; Cha, Y.-S.; Kim, J.-B. Phenolic profiling and quantitative determination of common sage (Salvia plebeia R. Br.) by UPLC-DAD-QTOF/MS. Eur. Food Res. Technol. 2018, 244, 1637–1646.
- Xiong, G.; Deng, Y.; Cao, Z.; Liao, X.; Zhang, J.; Lu, H. The hepatoprotective effects of Salvia plebeia R. Br. extract in zebrafish (Danio rerio). Fish. Shellfish Immunol. 2019, 95, 399–410.
- Ke, J.-Y.; Kliewer, K.L.; Hamad, E.M.; Cole, R.M.; Powell, K.A.; Andridge, R.R.; Straka, S.R.; Yee, L.D.; Belury, M.A. The flavonoid, naringenin, decreases adipose tissue mass and attenuates ovariectomy-associated metabolic disturbances in mice. Nutr. Metab. 2015, 12, 1.
- Zobeiri, M.; Belwal, T.; Parvizi, F.; Naseri, R.; Farzaei, M.H.; Nabavi, S.F.; Sureda, A.; Nabavi, S.M. Naringenin and its Nano-Formulations for Fatty Liver: Cellular Modes of Action and Clinical Perspective. Curr. Pharm. Biotechnol. 2018, 19.