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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.
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 [1][2]. 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 [3]. 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 [4][5]. 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 [5]. Kaempferol, another flavonoid, negatively regulates adipogenesis by downregulating PPARγ, aP2, and SREBP-1C [6] and CCAAT-enhancer-binding protein alpha [7] in 3T3-L1 adipocytes. In zebrafish, kaempferol has anti-adipogenic properties that regulate early adipogenic factors (KLF5, KLF4, KLF2, and C/EBPβ) [6]. Upregulation of lipolysis regulatory enzymes (Adipose triglyceride lipase (Pnpla2)) is one of the anti-adipogenic mechanism of kaempferol [7]. 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 [8]. 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 [8][9]. Puerariae Lobatae radix flavonoids and puerarin successfully limited lipid accumulation in the abdomens of zebrafish larvae in a dose dependent manner [10].