Background and Aims: NAFLD has become a major metabolic disease worldwide. A few studies have reported the potential relationship between mitochondrial pyruvate carrier 1 (MPC1) and inflammation, fibrosis, and insulin sensitivity in obese or NASH mouse models. However, the impact of MPC1 on NAFLD-related liver lipid metabolism and its role in the NAFLD progression require further investigation. Approach and Results: MPC1 expression was measured in liver tissues from normal controls and patients with NAFLD. We characterized the metabolic phenotypes and expression of genes involved in hepatic lipid accumulation in MPC1 systemic heterozygous knockout (MPC1+/−) mice. Hepatic protein lactylation was detected using Tandem Mass Tags proteomics and verified by the overexpression of lactylation mutants in cells. Finally, the effect of MPC1 inhibition on liver inflammation was examined in mice and AML-12 cells. Here, we found that MPC1 expression was positively correlated to liver lipid deposition in patients with NAFLD. MPC1+/− mice fed with high-fat diet had reduced hepatic lipid accumulation but no change in the expression of lipid synthesis-related genes. MPC1 knockout affected the lactylation of several proteins, especially fatty acid synthase, through the regulation of lactate levels in hepatocytes. Lactylation at the K673 site of fatty acid synthase inhibited fatty acid synthase activity, which mediated the downregulation of liver lipid accumulation by MPC1. Moreover, although MPC1 knockout caused lactate accumulation, inflammation level was controlled because of mitochondrial protection and macrophage polarization. Conclusions: In NAFLD, MPC1 levels are positively correlated with hepatic lipid deposition; the enhanced lactylation at fatty acid synthase K673 site may be a downstream mechanism.

The targeted delivery of phytochemicals that promote energy expenditure for obesity therapy remains a challenge. This study assembled a functionalized adipo-8 aptamer loaded with allicin using isothermal rolling-circle techniques to form a synergistic adipocyte-targeted binarydrug delivery system for treating obesity. The functionalized adipo-8 aptamer efficiently protected allicin from adsorption, showing significant potential to encapsulate, transport, and release molecular cargos into white adipose tissue. Introducing the negatively charged allicin, a phytochemical able to induce adipose tissue browning, reduced the diameters of DNAnanoflower from 770 to 380 nm and increased cellular uptake efficiency up to 118.7%. The intracellular distribution observed via confocal microscopy confirmed the successful receptor recognition mediated by aptamers in the DNA-nanoflower-allicin (NFA) framework as well as its excellent stability to escape from lysosomes. In vivo results demonstrated that subcutaneous administration of NFA effectively promoted adipocyte browning and systematic energy expenditure with minimal side effects. Furthermore, the G-quadruplex in the mitochondrial uncoupling protein-1 promoter was found to be an interactive allicin target for regulating thermogenesis to combat obesity.

Pleurotus ostreatus (PO), a common edible mushroom, contains rich nutritional components with medicinal properties. To explore the effect of PO on ameliorating obesity and modulating the gut microbiota, we administered the mice with a low-fat diet or high-fat diet containing different dosages of PO (mass fraction: 0%, 2.5%, 5% and 10%). The body weight, adipose tissue weight, GTT, ITT, blood lipids, serum biomarkers of liver/kidney function, the gut microbiota and function were measured and analyzed after 6 weeks of PO treatment. The results showed PO prevented obesity, maintained glucose homeostasis and beneficially modulated gut microbiota. PO modified the composition and functions of gut microbiota in obese mice and make them similar to those in lean mice, which contributed to weight loss. PO significantly increased the relative abundance of Oscillospira, Lactobacillus group and Bifidobacterium, while decreased the relative abundance of Bacteroides and Roseburia. The prediction of gut microbiota function showed PO upregulated lipid metabolism, carbohydrate metabolism, bile acid biosynthesis, while it downregulated adipocytokine signaling pathway and steroid hormone biosynthesis. Correlation analysis further suggested the potential relationship among obesity, gut microbiota and the function of gut microbiota. In conclusion, all the results indicated that PO ameliorated obesity at least partly by modulating the gut microbiota.

With the prevalence of obesity all over the world, human health has been seriously affected. In particular, the number of diabetic and cardiovascular diseases has increased dramatically. The herb Coreopsis tinctoria (C. tinctoria) shows diverse biological and pharmacological activities, which are mainly attributed to its flavonoids. However, the specific functional substances that play an active role in C. tinctoria remain unclear, and its mechanism has not been deeply explored. In this study, we established a diet-induced obesity (DIO) mice model and treated mice with C. tinctoria or kaempferol for 8 weeks. The results showed that both C. tinctoria and kaempferol lowered body weight, reduced fasting blood glucose, and improved glucose tolerance and insulin resistance to alleviate obesity in DIO mice. The level of hemoglobin A1c also decreased significantly after treatment with C. tinctoria and kaempferol. Moreover, the administration of C. tinctoria and kaempferol also restored gut microbiota imbalance and significantly increased Desulfovibrio and Butyricimonas levels, which have been reported to improve glucose metabolism and intestinal health. In general, our study shows that C. tinctoria is a potential hypoglycemic substance for obesity and may reduce blood glucose by regulating gut microbiota, and that kaempferol is one of the effective substances of C. tinctoria.

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