The up arrow means an increase, and the down arrow means a decrease. Specifically, miR-122 and miR-33 are two of the best-studied miRNAs involved in the regulation of lipid metabolism [53]. As is shown in Table 1 and Table 2, numerous pieces of evidence have revealed that grape seed proanthocyanidin extract treatments reduced fatty acid synthesis and de novo lipogenesis, increased liver cholesterol efflux to high-density lipoprotein (HDL) formation by decreasing the expression of miR-122 and miR-33, which could regulate several genes that control fatty acid and transcriptional regulatory factors, such as fatty acid synthase (FAS) and peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), as well as genes that regulate fatty acid β-oxidation, such as ATP-binding cassette transporter A1 (ABCA1) and carnitine palmitoyltransferase 1a (CPT1a), respectively ^{[16][25][26][27][29][54]}[16,25,26,27,29,54]. Further detection revealed that the levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) were reduced while the level of high-density lipoproteins cholesterol (HDL-C) was enhanced in a dose-dependent manner ^{[16][25][26][27]}[16,25,26,27]. Averrhoa carambola-free phenolic extract, citrus peel flavonoids, lychee pulp phenolics, mulberry fruit extract, and portulaca oleracea extract treatments could also improve lipid metabolism in in vitro and in vivo studies; the underlying mechanism was miR-33 or miR-122-mediated changes in the signaling pathways ^{[20][22][33][34][37][38]}[20,22,33,34,37,38]. However, the opposite expression of miR-122 was reflected in a natural product experiment using coffee polyphenols, which could enhance energy metabolism and reduce lipogenesis by targeting sterol regulatory element binding protein (SREBP) 1c mediated by miR-122 [23]. Accountably, SREBP1c, one of the three isoforms of SREBPs, comes into play in fatty acid synthesis and metabolism ^[55][56][55,56]. It potentially illustrates the point that the same type of miRNAs can act on a variety of target genes with different expressions. Similarly, the same target gene may also be regulated by multiple miRNAs. Recent studies have shown that miR-103 and miR-107 reduced obesogenic diet-induced hepatic steatosis via decreasing the protein expression of SREBP1 in resveratrol-treated rats [49], and pseudoprotodioscin promoted cholesterol effluxion through targeting SREBP1c and SREBP2 mediated by miR-33a/b in an in vitro experiment [48]. In addition, distinctively, the overexpression of hepatic miR-98 induced by oleanolic acid, an active component of the traditional Chinese herb olea europaea, increased the degradation of peroxisome proliferator-activated receptor gamma coactivator-1beta (PGC1β), known as a transcriptional co-activator of SREBP-1 and the master regulator of hepatic lipogenesis ^[46][57][46,57]. Intuitively, both FAS and SREBP1 are involved in the process of fatty acid synthesis, and the connection between them is found in the following experiments. SP1 transcription factor (SP1), an important member of the ubiquitously expressed SP/KLF transcription factor family, acts together with SREBP1 to synergistically activate the promoter of the FAS gene and is involved in de novo lipogenesis [58]. Hence, resveratrol reduced the expression of SP1 through upregulating miR-539, along with decreasing the expression of the SREBP1 protein and FAS gene in vivo and in vitro [50]. Nevertheless, the correlation between them still needs to be systematically and intensively investigated beyond all doubt. Lipid metabolism is a complex process, and natural products can regulate lipogenesis and lipodieresis in a variety of ways. Zerumbone is a cyclic sesquiterpene isolated from the wild ginger Zingiber zerumbet smith. It has been proved that zerumbone could improve lipid metabolism disorder by reducing lipogenesis and increasing fatty acid oxidation [52]. For one thing, zerumbone acted as a miR-146b inhibitor and downregulated miR-146b, leading to the activation of sirtuin type 1 (Sirt1), which induced the de-acetylation of forkhead box O1 (FOXO1) and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC1α); for another, zerumbone induced the phosphorylation of AMP-activated protein kinase (AMPK), which could limit fatty acid efflux from adipocytes and favor fatty acid oxidation, as well as decrease de novo fatty acid synthesis through the phosphorylation-mediated inhibition of acetyl-CoA carboxylase (ACC) ^[59][60][61][59,60,61] and also activated Sirt1 indirectly [52]. With these similar natural product experiments, miR-27a/b, miR-96, miR-34a, miR-194, and miR-355 also participated in the process of lipid metabolism by targeting Sirt1 or FOXO1, which could both increase energy expenditure and the clearance of lipid accumulation ^{[21][28][30][31][35][36]}[21,28,30,31,35,36]. And ginger extract could enhance AMPK activity and ameliorate obesity and inflammation by regulating miRNAs expressions in high-fat diet (HFD)-fed rats [24]. Based on the present studies, regulating miRNAs is potentially becoming a dominant feature in terms of natural products regulating lipid metabolism (Figure 1). On the one hand, it can inhibit fatty synthesis by reducing fatty acid synthesis and increasing fatty acids mobilization. On the other hand, it can also accelerate lipodieresis by enhancing the oxidation and phosphorylation of fatty acids.

2.2. Inhibitory Effects on Adipocyte Differentiation and Accumulation

From the perspective of the cellular level, however, the growth of adipose tissue is the result of an increase in the number of adipocytes and the volume of individual cells [51]. The former contributes to promoting pre-adipocyte differentiation into mature adipocytes, whereas the latter is due to lipid accumulation. The functional role of natural products in this regard, as well as their potential mechanisms of action was summarized  (Figure 1 and Table 1 and Table 2). Adipocyte differentiation is a highly precisely regulated cellular process. Ahead of terminal differentiation, the mitotic clonal expansion (MCE) of stimulated pre-adipocytes is an essential procedure in adipocyte differentiation. Moreover, the transcriptional activation of adipocyte-specific functional genes is closely related to their differentiation [62]. 3T3-L1 pre-adipocytes have long been considered as the “gold standard” for investigating pre-adipocyte differentiation in vitro ^[63][64][63,64]. There has been evidence that the MCE process could be delayed by persimmon tannin by enhancing the expression of miR-27 in 3T3-L1 pre-adipocytes [47]. Furthermore, multiple transcriptional factors, including peroxisome proliferator-activated receptor-gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα) were also attenuated by miR-27, resulting in a decrease in adipocyte-specific genes, such as adipocyte fatty acid binding protein (aP2) and lipoprotein lipase (LPL). Similarly, the MCE process was blocked by miR-27a/b in the study of a-type ECG and EGCG dimers [40]. Lipids are important structural components in cell membranes [65]. Notably, with different molecular structures, a-type ECG and EGCG dimers strongly disturbed the structures of cell membranes by decreasing fluidity and hydrophobicity and increasing the permeability of the membrane of 3T3-L1 pre-adipocyte cells, thus displaying significant inhibition on differentiation [40]. EGCG also suppressed 3T3-L1 cell growth via miR-143/MAPK7 pathways [43]. Nonivamide-induced reduction in lipid accumulation was mediated by transient receptor potential cation channel subfamily V member 1 (TRPV1) activation [45]. Although miRNAs are involved in the adipocyte differentiation process, whether they affect membrane structure remains to be intensively studied in natural product therapy. The activation of C/EBPα and PPARγ is not only necessary for adipocyte differentiation in the early stage but is also crucial for terminal adipocyte differentiation [66]. The evidence suggests that grape seed procyanidin B2 could inhibit pre-adipocyte differentiation and reduce intracellular lipid accumulation by modulating the miR-483/PPARγ axis [42]. Resveratrol reduced the expression of CEBP/α by boosting miR-155, resulting in decreasing lipogenesis [51]. Consistent with these, as shown in Table 2, similar results were also obtained in the research of lycopene by regulating the expression of miR-21 [44]. What is noteworthy is that accompanied with the involvement of multiple miRNAs, Rosmarinus officinalis extract significantly reduced triglyceride incorporation during pre-adipocyte maturation in a dose-dependent manner and decreased the expression of cell cycle genes, such as cyclin-dependent kinase 4, cyclin D1, and cyclin-dependent kinase inhibitor 1A [39]. The final and most studied phase of adipocyte differentiation involves terminal differentiation and the induction of a signaling cascade to promote the expression of the genes necessary for adipocyte function ^[67][68][67,68]. The canonical Wnt signaling cascade is an effective approach to suppress adipogenesis ^[69][70][71][69,70,71]. Recently, investigators found that curcumin repressed 3T3-L1 pre-adipocyte cell adipogenic differentiation by inhibiting the expression of miR-17 and stimulating transcription factor 7-like 2 (TCF7L2), which is the Wnt signaling pathway effector and a direct downstream target of miR-17 [41]. And guarana extract also exerted an anti-adipogenic effect by regulating the Wnt signaling pathway, mediated by miRNAs [32]. In summary, natural products may inhibit adipocyte differentiation and accumulation by regulating miRNAs, which play a crucial role in the process of lipogenesis.