Astragalus membranaceus (AM) is a food and medicinal homologous plant. The current research is aimed to investigate the beneficial effects and mechanisms of AM in treating acquired hyperlipidemia. The network pharmacology and bioinformatics analysis results showed 481 AM-related targets and 474 acquired hyperlipidemia-associated targets, and 101 candidate targets were obtained through the intersection, mainly enriched in endocrine resistance, AGE-RAGE in diabetic complications and p53 signaling pathways. Quercetin, kaempferol, calycosin, formononetin and isorhamnetin were determined as the candidate active components of AM in the treatment of acquired hyperlipidemia. Moreover, key targets of AM, namely, AKT serine/threonine kinase 1 (AKT1), vascular endothelial growth factor A (VEGFA), cyclin D1 (CCND1) and estrogen receptor 1 (ESR1), were screened out, which were closely related to adipogenesis, fatty acid metabolism and bile acid metabolism. The subsequent animal experiments showed that AM extract treatment improved the lipid profiles of the high-fat diet (HFD)-fed mice by reducing lipogenesis and increasing lipolysis and lipid β-oxidation, which were associated with the downregulating of AKT1 and CCND1, and the upregulating of VEGFA and ESR1 in liver and adipose tissue. Overall, AM alleviated acquired hyperlipidemia through regulating lipid metabolism, and AKT1, VEGFA, CCND1 and ESR1 might be the key targets.

Chronic high-fat diet (HFD) is associated with the onset and progression of hepatic steatosis, and oxidative stress is highly involved in this process. The potential role of sesamol (SEM) against oxidative stress and inflammation at the transcriptional level in a mice model of hepatic steatosis is not known. In this study, we aimed to investigate the scavenging effects of SEM towards reactive oxygen generated by lipid accumulation in the liver of obese mice and to explore the mechanisms of protection. Markers of oxidative stress, vital enzymes involved in stimulating oxidative stress or inflammation, and nuclear transcription of Nrf2 were examined. Our results showed that SEM significantly inhibited the activity of the HFD-induced hepatic enzymes CYP2E1 and NOX2, associated with oxidative stress generation. Additionally, SEM reversed HFD-induced activation of NF-κB, a redox-sensitive transcription factor, and attenuated the expression of hepatic TNF-α, a proinflammatory molecule. Moreover, SEM enhanced HFD-induced hepatic Nrf2 nuclear transcription and increased the levels of its downstream target genes Ho1 and Nqo1, which indicated antiinflammation and antioxidant properties. Our study suggests that chronic HFD led to hepatic steatosis, while SEM exhibited protective effects on the liver by counteracting the oxidative stress and inflammation induced by HFD. The underlying mechanism might involve multiple pathways at the transcriptional level; the antioxidant defense mechanism was in partly mediated by the upregulation of Nrf2.

Genistein (GEN) has been shown to significantly inhibit hepatic triglyceride accretion triggered by estrogen deficiency. The main purpose of this in vitro study was to investigate the function and molecular mechanism of estrogen receptor β (ERβ) in regulating hepatic lipid metabolism induced by GEN. Different doses of GEN or GEN with an ERβ antagonist were treated with HepG2 cells. Results showed that 25 μM GEN significantly diminished triglyceride levels. Meanwhile, GEN downregulated the levels of genes and proteins involved in lipogenesis, such as sterol-regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FASN), and stearoyl-coenzyme A desaturase 1 (SCD1), and upregulated the gene and protein levels of the regulation factors responsible for fatty acid β-oxidation, such as carnitine palmitoyltransferase 1α (CPT-1α) and peroxisome proliferator-activated receptor α (PPARα). Furthermore, 25 μM GEN reduced the levels of phosphorylation of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR). Moreover, most of these effects from GEN were reverted by pretreatment with the antagonist of ERβ. In conclusion, GEN improved hepatic lipid metabolism by activating ERβ and further modulation of Akt/mTOR signals. The results provide novel aspects of the regulatory mechanism of ERβ on hepatic lipid metabolism and might help to profoundly understand the functions of food-derived phytoestrogens in preventing and treating hepatic steatosis in postmenopausal women.

Liquiritigenin (LQG) is a natural flavonoid from the herb Glycyrrhiza uralensis Fisch that exhibits multiple biological activities. However, its specific role in antiobesity and its related underlying molecular mechanisms remain unknown. The primary purpose of this study is to explore the effects and regulatory mechanisms of LQG on lipid accumulation in 3T3-L1 adipocytes. The results show that LQG significantly reduced triglyceride levels and downregulated the expression of transcription factors such as CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) in 3T3-L1 adipocytes. Additionally, the expression of sterol-regulatory element-binding protein 1c (SREBP1c), acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FASN) involved in lipogenesis was reduced by treatment with LQG. The protein expression levels of light chain 3B (LC3B), autophagy-related protein 7 (ATG7) and p62 were also modulated by LQG, leading to the suppression of autophagy. Further, LQG activated the phosphorylation of the mammalian target of rapamycin (mTOR), the inhibition of which was followed by the restored expression of autophagy-related proteins. Pretreatment with an mTOR inhibitor also reverted the expression of several genes or proteins involved in lipid synthesis. These results suggest that LQG inhibited lipid accumulation via mTOR-mediated autophagy in 3T3-L1 white adipocytes, indicating the role of LQG as a potential natural bioactive component for use in dietary supplements for preventing obesity.

Obesity can evoke changes of skeletal muscle structure and function, which are characterized by the conversion of myofiber from type I to type II, leading to a vicious cycle of metabolic disorders. Reversing the muscle fiber-type conversion in obese states is a novel strategy for treating those with obesity. Sesamol, a food ingredient compound isolated from sesame seeds, exerted potential antiobesity effects. The present research aimed to explore the therapeutic effects of sesamol on obesity-related skeletal muscle-fiber-type conversion and elucidate the underlying molecular mechanisms through utilizing a high-fat-diet-induced obese C57BL/6J mice model and palmitic acid-exposed C2C12 myotubes. The results showed that sesamol attenuated obesity-related metabolic disturbances, elevated exercise endurance of obese mice, and decreased lipid accumulation and insulin resistance in skeletal muscle. After the treatment with sesamol, the muscular mitochondrial content and biogenesis were increased, accompanied by the enzyme activities and myosin heavy-chain isoform changed from type II fiber to type I fiber. Mechanistic studies revealed that the effects of sesamol on reversing skeletal muscle-fiber-type conversion in obese states were associated with the stimulation of the muscular sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK) signal pathway, and these effects could be inhibited by a specific inhibitor of SIRT1, EX-527. In conclusion, our research provided novel evidence that sesamol could regulate myofiber-type conversion to treat obesity and obesity-related metabolic disorders by stimulating the muscular SIRT1/AMPK signal pathway.