Abstract
Sanye Tablet (SYT) is a patent prescription widely used in treating T2D and pre-diabetes, especially T2D comorbid with hypertriglyceridemia, for many years in China. However, the underlying mechanism that accounts for the anti-diabetic potential of SYT by regulating lipid-related intermediates remains to be elucidated. This study aimed to investigate the mechanism of SYT on lipid metabolism and insulin sensitivity in high-fat diet (HFD)-induced obese mice by means of combining lipidomics and proteomics. The obese mice models were developed via HFD feeding for 20 consecutive weeks. Mice in the treatment group were given metformin and SYT respectively, and the effects of SYT on body weight, blood glucose, insulin sensitivity, fat accumulation in the organs, and pathological changes in the liver were monitored. Lipid metabolism was examined by lipidomics. Further determination of signaling pathways was detected by proteomics. The biological contributions of the compounds detected in SYT’s chemical fingerprint were predicted by network pharmacology. SYT treatment reduced body weight, inhibited viscera and hepatic steatosis lipid accumulation, and prevented insulin resistance. Furthermore, it was found that circulatory inflammatory cytokines were reduced by SYT treatment. In addition, lipidomics analysis indicated that SYT targets lipid intermediates, including diacylglycerol (DAG) and Ceramide (Cer). Mechanistically, SYT positively affected these lipid intermediates by suppressing liver lipogenesis via downregulation of SREBP1/ACC and the JAK/STAT signaling pathway. Our results predicted that astragalin and rosmarinic acid might regulate the JAK-STAT pathway by targeting PIM2 and STAT1, respectively, while paeoniflorin and rosmarinic acid were likely to regulate inflammatory responses by targeting TNFα, IL-6, and IL-4 during T2D. Overall, our study provides supportive evidence for the mechanism of SYT’s therapeutic effect on dysregulated lipid metabolism in diabesity.
Highlights
According to the latest epidemiologic data from the International Diabetes Federation, there are 463 million diabetics worldwide
Average daily food and caloric intake in chow-fed mice were 3.89 ± 0.18 g and 11.69 ± 0.54 kcal, respectively, while those in high-fat diet (HFD) mice were 3.03 ± 0.13 g and 15.93 ± 0.71 kcal (Figures 2B,C). Though these intakes noticeably changed after HFD feeding (p < 0.01), there was no change by Sanye Tablet (SYT) and MET treatment as compared to HFD
Subcutaneous fat, and epididymal fat were significantly elevated in HFD mice, which were attenuated by MET and SYT treatment (Figures 2D–H)
Summary
According to the latest epidemiologic data from the International Diabetes Federation, there are 463 million diabetics worldwide. It has gradually become a public health problem that seriously affects the global population and brings great economic burden to society (Saeedi et al, 2019). T2D is characterized by relatively deficient insulin secretion from pancreatic islet β-cells combined with insulin resistance in target organs (Li et al, 2020). Its dominant cause is obesity, with ectopic fat accumulation in vital organs. Exercise, and other factors can lead to the occurrence of obesity. The western diet, especially, featured by high fat and high sugar foods, has been widely considered the contributing factor to the recent rapid increase in obesity (Lean, 2019)
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