According to the Global Burden of Disease report, the incidence of metabolic diseases has increased in the past 20 years, posing a great threat to global health [1], and the incidence of metabolic diseases is closely related to body fat content. Adipose tissue not only stores and provides energy, but also responds to changes in the body in a timely manner, and regulates whole-body energy metabolism by influencing food intake, glucose regulation, and inflammatory response [2], which is an important part of the endocrine system and plays an important role in maintaining the body's energy homeostasis.
Studies have shown that the use of drugs to regulate lipid production, transport, and decomposition can be used to improve lipid metabolism disorders, and can be used as an effective method for the prevention and treatment of metabolism-related diseases [3]. At present, it has been found that a variety of active ingredients of traditional Chinese medicine can affect lipid metabolism and improve fat metabolism disorders. According to the structure and type of chemical components of traditional Chinese medicine, this paper summarizes the research on the regulation of the structure and function of fat cells by the effective active ingredients of traditional Chinese medicine in recent years, so as to provide ideas for the research on the regulation of lipid metabolism in traditional Chinese medicine, the research and development of new drugs, and the new use of old drugs.
1 Adipose tissue type, distribution and function
脂肪组织根据功能和形态的不同主要分为白色脂肪组织（white adipose tissue，WAT）和棕色脂肪组织（brown adipose tissue，BAT）。 WAT根据分布位置不同分为皮下脂肪组织（subcutaneous adipose tissue，sWAT）和内脏脂肪组织（visceral adipose tissue，vWAT）。 其中，sWAT主要分布在腹部、臀部和大腿；vWAT围绕着内部器官，主要在网膜、肠系膜、腹膜后等部位[4]。 WAT具有储能、隔热、缓冲及分泌多种脂肪因子的作用[5]。 BAT主要分布在成人颈部、锁骨、纵隔、椎旁和肾周区域[6]，通过其含有的高密度线粒体和线粒体内膜上特异表达的解偶联蛋白1（uncoupling protein 1，UCP1）实现非颤栗产热。
In addition, BAT also has the function of secreting adipokines. Activation of UCP1 results in an electrochemical gradient short circuit that drives adenosine triphosphate synthesis, resulting in uncoupling, which releases chemical energy in the form of heat, alters intracellular values of adenosine triphosphate/adenosine diphosphate, increases the rate of metabolic substrate oxidation [7], and accelerates lipid transport, thereby regulating lipid metabolism [8]. When WAT is affected by certain external stimuli such as cold and exercise, beige adipose tissue (BeAT) with similar structure and function to BAT is produced [9], a process called browning of WAT and can also be used to promote fat metabolism and regulate energy balance.
2 The role of active ingredients in traditional Chinese medicine in lipid metabolism
Traditional Chinese medicine has accumulated rich practical experience in the treatment of various diseases, and its multi-component and multi-target characteristics make it play a unique role in the prevention and treatment of diseases. At present, traditional Chinese medicine has been reported to enhance leptin sensitivity, regulate fat metabolism, improve basal metabolism, and improve metabolic diseases [10-11], and the active ingredients of traditional Chinese medicine can play a regulatory role in lipid metabolism such as lipid absorption, lipid synthesis, lipid decomposition, and lipid transport [12].
2.1 Quinones
Quinones are divided into benzoquinones, naphthraquinones, phenanthrene, anthraquinones and derivatives according to different structures, among which phenanthrene, anthraquinone and their derivatives have extensive physiological activities and are more studied. Phenanthrene is mainly distributed in Lamiaceae, and anthraquinone is mainly distributed in Polygonaceae, Fabaceae, and Rubiaceae [13].
2.1.1 Tanshinone I, cryptotanshione
Tanshinone with fat-soluble phenanthroquinone structure is the main active ingredient in Danshen, including Tanshinone I, Tanshinone IIA, and cryptotanshinone [14], which has physiological activities such as cardioprotective, antioxidant, anti-inflammatory, and antitumor [15-16]. Among them, tanshinone I can up-regulate the expression of PR domain protein 16 (PRDM16) in BAT in high-fat diet-induced obese mice. PRDM16 acts as a coactivator of the transcriptional coactivator protein-activated peroxisome proliferator-activating receptor γ-1α (PGC-1α) to further up-regulate the expression of brown adipose specific gene UCP1, cell death-induced DFFA-like effector A (CIDEA), and iothyronine deiodarase 2 (DIO2). It can also activate BAT by up-regulating PGC-1α and related genes that induce mitochondrial biogenesis, such as mitochondrial transcription factor A (Tfam) and nuclear factor E2-related factor 2 (Nrf2).
丹参酮I可增强小鼠胚胎成纤维3T3-L1细胞来源脂肪细胞的线粒体发生和脂肪酸氧化相关基因表达，诱导WAT棕色化，增加体内、外腺苷酸活化蛋白激酶（adenosine phosphate activated protein kinase，AMPK）磷酸化[17]，进一步降低过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor γ，PPARγ）、脂肪酸合酶（fatty acid synthase，FASN）水平，抑制脂肪生成[18]。
隐丹参酮可通过AMPKα、p38丝裂原活化蛋白激酶（mitogen-activated protein kinases，MAPK）和Smad家族蛋白信号传导，抑制小鼠胚胎成纤维C3H/10T1/2细胞脂肪生成，并促进线粒体生物发生，使C3H/10T1/2细胞分化为具有棕色脂肪细胞特征的脂肪细胞[19]。 隐丹参酮还可通过AMPK/沉默调节蛋白1（sirtuin 1，SIRT1）/PGC-1α信号通路减少紫外线辐射诱导的线粒体功能障碍，促进线粒体生物合成[20]。
2.1.2 Emodin
大黄素是一种天然蒽醌衍生物，存在于大黄、虎杖、芦荟、决明子等中药中，具有抗癌、抗炎、抗菌、抗病毒等作用[21]。 大黄素可上调高脂饮食诱导的肥胖小鼠sWAT中肿瘤坏死因子（tumor necrosis factor，TNF）受体超家族成员9（TNF receptor superfamily 9，Cd137），跨膜蛋白26（transmembrane protein 26，TMEM26）和T盒转录因子1（T-box transcription factor 1，TBX1）等BeAT标志物的表达，促进sWAT棕色化；提高BAT中UCP1，各种转运蛋白脂肪酸转运蛋白血小板糖蛋白4（platelet glycoprotein 4，CD36）和脂肪酸结合蛋白4（fatty acid-binding protein 4，FABP4）的水平，加速脂肪酸的运输和消耗，增强高脂饮食小鼠BAT活性，特异性改变sWAT和BAT中甘油磷脂和鞘脂的质量分数，改善脂质代谢紊乱[22]。
In addition to increasing lipid consumption, emodin can also reduce the production and accumulation of fat in the liver by decreasing the level of sterol regulatory element binding transcription factor 1 (SREBP1), down-regulating the expression of its downstream molecule FASN [23]. 11β-hydroxysteroid dehydrogenase (11β-HSD1) is involved in the conversion of cortisol and corticosterone as an oxidoreductase, and is highly expressed in fat, which can improve hyperglycemia and hyperlipidemia and promote metabolism after being knocked out [24]. As an 11β-HSD1 inhibitor, emodin can inhibit its activity in C57BL/6J mouse fat, reduce triacylglycerol and total cholesterol levels, and reduce body weight and sWAT mass fraction. In summary, emodin has the potential value of improving metabolic disorders and treating metabolic syndrome [25].
2.1.3 Hypericin perforated
Hypericin is the main active ingredient of St. John's wort and a component of the Chinese patent medicine Shugan Jieyu Capsule, which has obvious antidepressant effects and few adverse reactions [26]. Hypericin can bind to dihydrolipamide S-acetyltransferase expressed in the adipose tissue of obese population, activate the AMPK/PGC-1α/UCP1 pathway, up-regulate the expression of UCP1 and other thermogenic genes in the adipose tissue of obese mice and homozygous mutant mice with leptin gene induced by high-fat diet, increase the abundance of sWAT and BAT mitochondrial transmission chain protein and increase the oxygen consumption of the body. After 3 weeks of stopping the intervention, the body weight of mice remained at a relatively stable plateau, and there was a long-lasting anti-obesity effect. In summary, hypericin can promote the browning of sWAT and activate BAT to alleviate the metabolic disorders caused by obesity [27].
2.2 Phenylpropanoids
Phenylpropanoids include a variety of natural aromatic compounds, such as simple phenylpropanoids, lignans, and coumarins, and most studies have shown that these compounds have anti-angiogenic and antiviral biological activities [28].
2.2.1 Magnolol
Magnolia officinalis has broad-spectrum antibacterial, anti-tumor, anti-inflammatory and other effects, and contains a variety of active ingredients such as volatile oils and alkaloids. The most important active ingredients are the biphenyl lignans honokiol and honokiol [29]. In terms of lipid metabolism, honokiol up-regulated the expression of UCP1, PGC-1α, Cd137 and TBX1 brown adipose marker genes in 3T3-L1 cells by mediating AMPK, PPARγ and protein kinases A (PKA) pathways, and promoted the browning of 3T3-L1 cells. At the same time, activation of AMPK could inhibit the transcriptional activity of SREBP1 and reduce the level of adipogenic marker proteins such as the target gene FASN. Enhance the expression of carnitine palmitoyltransferase 1 (CPT1), long-chain acyl-CoA synthetase 1, SIRT1 fatty acid oxidation, and mitochondrial biogenesis marker proteins. These results indicated that honokiol had the ability to promote lipolysis while inhibiting fat accumulation and synthesis. In addition, honokiol can also reduce the production and release of reactive oxygen species and inhibit the occurrence of oxidative stress in 3T3-L1 cells [30].
2.2.2 and honokiol
和厚朴酚能够抑制高脂饮食诱导的小鼠类固醇O-酰基转移酶1上调，下调CCAAT增强子结合蛋白α（CCAAT/enhancer binding protein α，C/EBPα）表达，减少脂肪生成；上调sWAT和vWAT中UCP1、CPT1、乙酰辅酶A羧化酶（acetyl-CoA carboxylase，ACC）的表达，促进WAT棕色化[31]。 和厚朴酚通过细胞外信号调节激酶（extracellular signal-regulated kinase，ERK）提高3T3-L1细胞中UCP1、PGC-1α、PRDM16的表达水平诱导其棕色化，增加酰基辅酶A氧化酶1（acyl-CoA oxidase 1，ACOX1）、CPT1脂肪氧化相关蛋白水平；促进激素敏感性脂肪酶（hormone-sensitive triglyceride lipase，HSL）和围脂滴蛋白磷酸化，促进脂质水解，维持代谢平衡[32]。
2.2.3 Schizandra B
Lignans accounted for 2%~8% of the total components in Schisandra chinensis, and Schizandra B was one of the main components [33], which had pharmacological effects such as antitumor, antioxidant, anti-inflammatory, and hepatoprotective effects [34]. Schizandra B reduced lipid production and accumulation in 3T3-L1 cells by inhibiting the expression of PPARγ, C/EBPα and FASN fat-specific regulators, phosphorylated HSL, promoted the hydrolysis of triacylglycerol to glycerol and fatty acids, and up-regulated fatty acid oxidation marker genes PPARα and CPT1. Lipid metabolism is improved by increasing the levels of AMPK phosphorylation and thermogenesis markers UCP1, PRDM16, and PGC-1α, promoting browning, increasing energy expenditure, and decreasing lipogenesis [35]. Schizandra B significantly increased PKA-mediated HSL phosphorylation in high-fat diet mice, decreased the levels of triacylglycerol, diacylglycerol, and monoacylglycerol, up-regulated the expression of lipid oxidation genes such as ACOX1, CPT1, and ultra-long chain acyl-CoA dehydrogenase in sWAT, promoted fatty acid oxidation, and regulated fat metabolism [36].
2.3 Flavonoids
Flavonoids are a class of compounds with C6-C3-C6 as the basic carbon frame, mostly in the form of glycosides, which are divided into multiple isoforms according to their structure. Flavonoids have been shown to have anti-tumor [37], anti-hyperlipidemia, antioxidant [38], anti-osteoarthritis [39] effects, and flavonols mainly include rutin, quercetin, silybinin, etc.
2.3.1 Ashicho
As a natural flavonoid glycoside, rutin is easily extracted from the dried flower buds of the leguminous plant Sophora japonica L. [40], which has anti-inflammatory, antioxidant, analgesic, and neuroprotective effects [41], and can treat hemorrhage caused by capillary fragility. Rutin up-regulated the expression of thermogenesis-related genes UCP1, PRDM16, PGC-1α and mitochondrial biogenesis-related genes Nrf1 and Tfam in C3H/10T1/2 cells. Reduce the increase in body weight and increase oxygen consumption in obese mice and homozygous mutant mice with leptin receptor genes induced by high-fat diet.
As a SIRT1 activator, rutin can increase BAT activity and up-regulate the expression of thermogenesis-related genes UCP1, CIDEA, PRDM16, fatty acid oxidation-related genes CPT1α and medium-chain acyl-CoA dehydrogenase (MCAD) in BAT through SIRT1/PGC-1α/Tfam signaling pathway. It can also up-regulate the expression of thermogenesis, BeAT markers, and mitochondrial biomarkers of sWAT in high-fat diet mice, and promote the browning of sWAT [42]. In addition, Hu et al. [43] found that rutin can also significantly improve insulin resistance and ovarian dysfunction caused by dehydroepiandrosterone-induced polycystic ovary syndrome in rats by activating BAT, providing a new option for the clinical treatment of related diseases.
2.3.2 Quercetin
槲皮素作为一种黄酮醇类化合物，可由芦丁经过胃肠道中的葡萄糖苷水解得到[44]。 槲皮素可上调高脂饮食小鼠脂肪组织中产热基因UCP1、PGC-1α和线粒体生物发生基因Tfam的表达，促进肾上腺素能受体β3表达，并通过其下游PKA增加p38 MAPK磷酸化水平，进一步激活转录因子2（activating transcription factor 2，ATF2）、环磷腺苷效应元件结合蛋白（cAMP-response element binding protein，CREB）磷酸化水平，激活多种靶基因转录；同时槲皮素还可通过调节AMPK提高SIRT1蛋白水平，促使PGC-1α去乙酰化，增加PGC-1α和UCP1的表达[45]。
2.3.3 Silybinin
Silybin is the main active ingredient of Silybum marianum (L.) Gaertn., which has hepatoprotective and antitumor effects. In cell-level studies, silybin inhibits the expression of FABP4 and C/EBPα in 3T3-L1 cells in a dose-related manner, thereby inhibiting their differentiation into mature adipocytes. In animal-level studies, silybin inhibits lipid accumulation in zebrafish by activating AMPKα signaling to reduce perilipid droplet protein and FASN levels [46].
Proteomic studies have found that silybin can reduce the expression of vWAT lipid synthesis and transport-related proteins, upregulate the expression of reduced CoI in high-fat diet mice, improve mitochondrial dysfunction, increase energy expenditure, and improve lipid metabolism in vivo [47]. Silybin can increase the level of UCP1 by affecting the expression of SIRT1, PPARα and PGC-1α in human adipose tissue mesenchymal stem cells. It also has certain anti-inflammatory effects while improving thermogenesis and promoting the browning of adipocytes, which can reduce the expression of pro-inflammatory factors TNF-α and interleukin-6 (IL-6) in adipose tissue, and improve insulin resistance caused by inflammatory damage [48].
2.3.4 Baicalin
Baicalin is the main active ingredient extracted and isolated from the dried root of Scutellaria baicalensis Georgi., a plant in the Lamiaceae family, and has pharmacological effects such as antibacterial, antiviral, anti-inflammatory, antitumor, and antioxidant [49]. Zhang et al. [50] found that baicalin could enhance the adaptability of mice to cold conditions by increasing thermogenesis at rest and slowing down the drop in body temperature in cold environments. Baicalin can up-regulate the expression of CD36 and fatty acyl-CoA dehydrogenase, which are related genes of fatty acid decomposition in the liver, and alleviate liver steatosis induced by high-fat diet.
Baicalin can also up-regulate the expression of thermogenesis-related genes UCP1, PGC-1α, PRDM16, TBX1 and Cd137 in BAT, and activate BAT. Inhibited the enlargement of fat cells in vWAT caused by high-fat diet, up-regulated the expression of thermogenesis-related genes, and promoted the browning of vWAT. Baicalin increased the expression level of thermogenesis-related proteins in C3H/10T1/2 cells, promoted the phosphorylation of AMPK, and regulated UCP1 transcription through the AMPK/PGC-1α pathway. In addition, it has also been shown that baicalin can phosphorylate ERK1/2 in sWAT cultured primary adipocytes, thereby up-regulating the expression of thermogenic genes UCP1 and PGC-1a, promoting thermogenesis, increasing metabolic rate, and improving metabolic disorders [51].
In addition to the above-mentioned active ingredients of traditional Chinese medicine, kaempferol in kaempferin, nobiletin widely found in Citrus genus Rutaceae, licochalcone A in licorice, and puerarin in Pueraria lobata are all flavonoids (Table 1), which can reduce the content of systemic and visceral fat, improve liver steatosis, and reduce the level of inflammation in adipose tissue.
2.4 Terpenoids
Terpenoids are divided into hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, triterpenoids, and tetraterpenoids according to the number of isoprene units they contain, and have physiological activities such as antimicrobial, anticancer, hypotensive, antihyperlipidemia, anti-inflammatory, antioxidant, antiparasitic, and immunomodulatory activities [65].
2.4.1 Gardenin
Gardenia glycoside is a cyclidoid extracted from Gardenia jasminoides Ellis., a plant of the Rubiaceae family, which belongs to monoterpenoids and has physiological activities such as neuroprotective, hepatoprotective, anti-inflammatory, antioxidant, antidepressant, immune-modulating, and antithrombotic [66]. In terms of fat metabolism, gardeniside can down-regulate the expression of thermogenic genes UCP1, PRDM16 and DIO2 in BAT and sWAT in mice, negatively regulate the thermogenic ability of adipose tissue, and reduce the body temperature and cold tolerance of mice. Gardenin can downregulate the expression of thermogenesis genes in 3T3-L1 cells, reduce the rate of mitochondrial oxygen consumption, and inhibit thermogenesis, thereby inversely regulating the thermogenesis of adipocytes [67].
2.4.2 Artemisinin derivatives
Artemisinin is a sesquiterpene lactone with a peroxy group, which has physiological activities such as antibacterial, antifungal, antiviral, and antitumor, and can treat malaria. In addition, dihydroartemisinin, artemether, and artesunate synthesized from artemisinin derivatives have good biological activity or solubility [68]. Artemether and dihydroartemisinin inactivate the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway by activating the p38 MAPK/ATF2 axis, inducing fat browning.
Artemether can dose-correlate the levels of the electron-transporting proteins UCP1, PGC-1α, PRDM16, and mitochondrial membrane proteins cytochrome C oxidase in C3H/10T1/2 cells, C57BL/6J mouse sWAT primary adipocytes, and the differentiated cells have brown adipocyte characteristics. Artemether can also inhibit the increase of body weight in mice induced by high-fat diet, improve the thermogenesis of mice, and enhance the ability of mice to maintain body temperature at 4 °C by increasing the level of UCP1 in sWAT. Dihydroartemisinin also has a similar effect to artemether, increasing the expression levels of UCP1 and PGC-1α in C3H/10T1/2 cells and inducing browning [69].
2.4.3 Panax notoginseng saponins
Panax notoginseng (Burk.) F. H. Chen is one of the main components of Panax notoginseng (Burk.) F. H. Chen, which has pharmacological effects such as cardioprotective, anti-atherosclerosis, enhanced β amyloid degradation, anti-osteoporosis, and anticancer [70]. Panax notoginseng saponins promote the phosphorylation of AMPKα and signal transducer and activator of transcription 3 (STAT3) in obese mice and C3H/10T1/2 cells by modulating the signal of the intestinal microbiota to activate the leptin-AMPK/STAT3 pathway. Panax notoginseng saponins can also up-regulate the expression of thermogenic genes in the adipose tissue of high-fat diet mice, increase the levels of UCP1 and PRDM16 proteins, and reduce the size of adipocytes in sWAT, vWAT, and BAT in high-fat diet mice, and promote BAT thermogenesis and WAT browning [71].
2.4.4 Ginsenosides
Ginsenosides are important triterpenoid saponins in Panax ginseng C. A. Mey., which has the effects of antioxidant, lowering blood pressure, improving heart function, and inhibiting platelet aggregation. There are about 200 ginsenosides in ginseng, including ginsenoside Rb1 and ginsenoside Rg1 in higher amounts and ginsenoside Rg3 and ginsenoside Rh2 in smaller amounts [72]. Ginsenoside Rb1 can increase the protein levels of UCP1, PRDM16, and PGC-1α in 3T3-L1 cells and sWAT in a dose-dependent manner through the AMPK pathway, promoting browning of 3T3-L1 cells and sWAT [73].
Ginsenoside Rg3 can up-regulate the expression of BeAT cell-specific marker genes Cd137 and TMEM26, and up-regulate the expression of adipogenesis-related genes SREBP and FASN, as well as fatty acid oxidation genes MCAD, by increasing AMPK phosphorylation, thereby reducing the accumulation of lipid droplets, thereby browning white adipocytes and affecting lipid metabolism [74]. The saponins extracted from ginseng stems and leaves can inhibit the increase of leptin in the serum of mice induced by high-fat diet in a dose-related manner, increase the level of high-density lipoprotein cholesterol in serum, reduce the levels of low-density lipoprotein cholesterol, total cholesterol, and triacylglycerol, alleviate the disorders of blood lipid metabolism caused by obesity, and down-regulate the expression of lipid-related marker genes and thermogenic marker genes in adipose tissue, accelerate the transport and oxidation of free fatty acids, and increase energy expenditure [75].
In addition, menthol in peppermint, crocin, the colored ingredient of saffron, platycodon saponin D, saikosaponin A and D in Bupleurum chinensis, madecassoside in Centella asiatica, and gynostemma in gynostemma (Table 1) are all terpenoids, which inhibit fat anabolism, promote fat catabolism, and further maintain fat metabolism homeostasis by activating the AMPK pathway.
2.5 Alkaloids
Alkaloids are a class of nitrogen-containing alkaline organic compounds existing in nature, which can be divided into heterocyclic alkaloids and non-heterocyclic alkaloids based on their heterocyclic properties. Heterocyclic alkaloids include pyridines, hyosanes, quinoline alkaloids, isoquinoline alkaloids, etc. [76], which have physiological activities such as antiviral, antitumor, antioxidant, and cardiovascular protection [77].
2.5.1 Berberine
Berberine, as a natural pentacycloisoquinoline alkaloid, is an effective active ingredient in many natural medicines, accounting for 8%~9% in rhizomes, and is also the main active ingredient of Coptis chinensis. Modern pharmacological studies have shown that berberine is one of the most effective natural products for improving inflammatory gastroenterology and other related diseases [78]. Zhang et al. [79] intervened with berberine in mice with homozygous mutants of the leptin receptor gene for 4 weeks, and found that the mice had significantly increased oxygen consumption and carbon dioxide production, and their ability to maintain body temperature was enhanced, suggesting that berberine can increase energy expenditure and promote adaptive thermogenesis. At the same time, berberine could significantly enhance BAT activity and brownize sWAT, increase the number of mitochondria, increase the content of UCP1 and PGC1-α and the phosphorylation level of AMPK protein, and up-regulate the expression of thermogenesis marker genes.
AMPK activation inhibits transforming growth factor-β1/Smad3 signaling, downregulates fibrosis gene expression, reduces pro-inflammatory macrophage infiltration in vWAT in mice induced by a high-fat diet, and alleviates tissue fibrosis [80]. Berberine can directly bind to SIRT3 in mitochondria to enhance its activity and regulate mitochondrial metabolism. Inhibits TNF-α-mediated inflammatory response and abnormal extracellular matrix deposition in adipocytes, alleviates adipose tissue inflammation, and promotes adipose tissue remodeling [81]. Wu et al. [82] found that berberine can promote brown adipocyte differentiation through the AMPK/PRDM16 axis, inhibit the DNA demethylation activity of PRDM16 promoters, promote the transcription of PRDM16, and increase BAT thermogenesis and systemic energy expenditure.
2.5.2 Marine
Matrine is one of the quinolicidine alkaloids in pyridine derivatives, which has a wide range of pharmacological activities, such as antitumor, analgesic, antifibrotic, antiviral, antiarrhythmic, and immunity-enhancing [83]. In terms of lipid metabolism, the levels of triacylglycerol and free fatty acids in the plasma of mice induced by Ig matrine in high-fat diet for 6 weeks significantly increased, while the oxygen consumption and carbon dioxide production rate were increased, energy expenditure was increased, and the body temperature was maintained in a cold environment. In addition, the size of BAT lipid droplets decreased and the mitochondrial DNA copy number increased in matrine-treated mice on a high-fat diet, indicating that matrine has a certain effect on maintaining body temperature and increasing adaptive thermogenesis. Matrine enriches heat shock factor 1 (HSF1) into the promoter region of PGC-1α, activates the HSF1/PGC-1α axis, up-regulates brown fat marker genes, biogenesis genes, and fatty acid oxidation-related genes, promotes the activation of thermogenic programs in BAT, increases sWAT browning, and alleviates metabolic disorders [84].
3 Conclusion and outlook
The pleiotropy of traditional Chinese medicine can better reflect the advantages of treating both the symptoms and the root cause in clinical application, so that the correlation between traditional Chinese medicine and a variety of diseases is increasingly studied. Among the active ingredients of traditional Chinese medicine, such as quinones, phenylpropanoids, flavonoids, terpenoids, and alkaloids, there are active ingredients in traditional Chinese medicine that have the functions of up-regulating the expression of thermogenic genes, increasing the number and activity of mitochondria, increasing oxygen consumption, promoting fatty acid oxidation, and adaptive thermogenesis (Fig. 1). These suggests that the active ingredient of TCM may be one of the potential treatment options for improving metabolic disorders.
However, the current research on the correlation between traditional Chinese medicine and lipid metabolism is still in the early stage of exploration, which is mainly reflected in two aspects. (1) There is a lack of research on cell-cell and inter-organ interactions. Adipose tissue contains not only adipocytes, but also various cell types, including adipose progenitor cells, immune cells, endothelial cells, smooth muscle cells, pericytes, neurons, and Schwann cells. While adipocytes play an important role in maintaining energy homeostasis, other types of cells can also respond to external stimuli such as temperature and diet, and regulate the function of adipose tissue through extensive cellular crosstalk, influencing its renewal, expansion, and remodeling. In addition, a variety of cytokines released from adipose tissue and other organs, such as muscles and liver, can target the corresponding organs and regulate thermogenesis and metabolism [85-86]. At present, most of the research on drugs and fat metabolism is only based on the adipose tissue itself, ignoring the integrity of the body. (2) The active ingredients of traditional Chinese medicine are complex and the target is not clear, which makes it difficult to deeply explore its molecular mechanism, which affects the modernization and international development of traditional Chinese medicine.
Based on the above problems, in future research, multi-omics joint analysis can be used to integrate and analyze genome, transcriptome, proteomic, metabolomic and other data, so as to reflect the state of tissues and organs after drug intervention from more levels and perspectives, which is more conducive to the discovery of drug targets and the evaluation of drug efficacy. Secondly, most of the active ingredients of traditional Chinese medicine act on proteins, and their interactions with proteins can be predicted by molecular docking technology, molecular target "hook fishing" technology for screening, surface plasmon resonance technology, fluorescence resonance energy transfer technology, biofilm interference technology and other technical means to verify and determine the domain or amino acid site of its binding to protein.
Finally, the structure of the active ingredients of traditional Chinese medicine can be modified and transformed, or with the help of various preparation processes and various drug carriers, the stability of small molecule compounds of traditional Chinese medicine can be enhanced, the solubility of traditional Chinese medicine can be improved, the contact area between traditional Chinese medicine and the administration site can be increased to improve bioavailability, and nanoparticles made of traditional Chinese medicine can be transported to the designated location to achieve drug delivery, and the function of drugs can be maximized with the help of new research technologies and means, so as to achieve the last mile between drugs and lesions.
At present, it has been demonstrated that the hydrophobic active ingredients quercetin and berberine can be added to nanoemulsions to improve solubility and bioavailability, and cryptotanshinone and curcumin can enhance their targeting ability through folic acid or polymer nanoparticles modified with SP94-targeting peptides [87]. In addition, since most of the current in vitro studies are based on rodent BAT, adults have less BAT, and are more structurally and functionally similar to mouse BeAT rather than BAT [88], so whether the reported active ingredients can effectively exert pharmacological activity in humans is still lacking sufficient basis and needs to be further studied.
Source: Yang Yutao, Zhang Guanyu, Yang Danfeng, Zhang Yongqiang, Zhang Li, Wu Shuai, Li Xi, Zhou Yuzhi. Research Progress on the Effect of Active Ingredients of Traditional Chinese Medicine in Regulating Body Lipid Metabolism [J]. Chinese Herbal Medicine, 2024, 55(9): 3127-3136.