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Effects of Hydroxy-Alpha-Sanshool on Intestinal Metabolism in Insulin-Resistant Mice

ABSTRACT: To explore the hydroxy-alpha-sanshool (HAS) effects on the intestinal metabolites of insulin-resistant mice, the blank group (BG), model group (MG), and HAS dose group (DG) were designed. The insulin resistance (IR) model was induced through streptozotocin (STZ) combined with a high-fat and high-sugar diet. Based on the availability of the model, the HAS dose was given by gavage for 28 days. The determination of cecum and key serum indexes was made, including the contents of insulin (INS), triglycerides (TG), total cholesterol (TC), glycosylated serum protein (GSP), and glycosylated hemoglobin (GHb). The changes in gut microbiota and metabolites in cecal contents were detected by 16S rRNA gene amplicon sequencing and UPLC/HRMS technology, respectively. The results that the levels of GSP, GHb, TG, and TC were significantly increased; this was not the case for INS; or for the changes in the gut microbiota and metabolites in MG. However, the intervention of HAS effectively reversed these changes, for instance, it decreased levels of GSP, GHb, TG, TC, and alterations of metabolite composition for linoleic acid and tyrosine metabolism and recovered trends of declining species diversity and richness of the gut microbiota in MG. It was indicated that HAS alleviated IR by regulating the gut microbiota and metabolites and affecting lipid and amino acid metabolism pathways.

SUBMITTER: Xu F

PROVIDER: S-EPMC9322383 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Zanthoxylum bungeanum is a traditional Chinese medicine (TCM) used to relieve pain, dispel dampness, stop diarrhea, and prevent itching. The aim of this study was to investigate the antiobesity and hypolipidemic effects of hydroxy-?-sanshool (HAS) isolated from Z. bungeanum on hyperlipidemic rats. Wistar rats (n = 48) were randomly divided into six groups: (1) normal diet rats (ND), (2) high-fat diet- (HFD-) treated rats, (3) HFD+fenofibrate-treated rats (HFD+FNB), (4) HFD+low dose of HAS-treated rats (HFD+LD, 9?mg/kg), (5) HFD+middle dose of HAS-treated rats (HFD+MD, 18?mg/kg), and (6) HFD+high dose of HAS-treated rats (HFD+HD, 36?mg/kg). The body weight and food intake of the rats were recorded during the treatment period. After 4 weeks of HAS treatment, abdominal adipose tissues were observed and total cholesterol (T-CHO), triglycerides (TG), high-density lipoprotein (HDL) cholesterol (HDL-C), and low-density lipoprotein (LDL) cholesterol (LDL-C) of serum and liver tissues were determined. Furthermore, histochemical examinations using oil red O and hematoxylin-eosin staining (H&E) were carried out and levels of malondialdehyde (MDA) and glutathione (GSH) and activities of superoxide dismutase (SOD) in the liver were determined. After HFD feeding, the body weight gain and food efficiency ratio of HFD rats were significantly enhanced (p < 0.05vs. ND rats) and HAS treatment (18 and 36?mg/kg) significantly decreased the body weight gain and food efficiency ratio (p < 0.05vs. HFD rats). In addition, HAS treatment could decrease the abdominal adipose tissues and liver adipocytes. Furthermore, HAS treatment significantly decreased the T-CHO, TG, and LDL-C, whereas it increased HDL-C (p < 0.05vs. HFD rats) in serum and the liver. HAS treatment increased the GSH level and SOD activity in the liver (p < 0.05vs. HFD rats), whereas it decreased the levels of MDA (p < 0.05vs. HFD rats). mRNA analyses suggested that HAS treatment increases the expression of Pparg (proliferator-activated receptor ?) and Apoe (peroxisome apolipoprotein E). Immunohistochemistry and Western blotting indicated that HAS stimulation increased the levels of PPAR? and APOE in the liver, as a stress response of the body defense system. These results revealed that HAS exerts antiobesity and hypolipidemic activities in HFD rats by reducing liver oxidative stress and thus could be considered as a potential candidate drug to cure or prevent obesity and hyperlipidemia.

Project description:Background and objectivesRecent studies have shown that the imbalance of intestinal flora is related to the occurrence and progression of diabetic nephropathy (DN) and can affect lipid metabolism. Sodium-dependent glucose transporters 2 (SGLT2) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist are commonly used hypoglycemic drugs and have excellent renal safety. The purpose of this study was to compare the protective effects of empagliflozin and liraglutide on kidneys, lipid metabolism, and intestinal microbiota in diabetic mice.MethodsWe established a mouse model of type two diabetes by feeding rats a high-fat diet (HFD) followed by an intraperitoneal injection of STZ. The mice were randomly divided into groups: normal control (NC), diabetic model (DM), liraglutide treatment (LirT), empagliflozin treatment (EmpT), and liraglutide combined with empagliflozin treatment (Emp&LirT) groups. Blood glucose, lipids, creatinine, and uric acid, as well as urinary nitrogen and albumin levels were measured. The renal tissues were subjected to HE, PAS and Masson's staining. These parameters were used to evaluate renal function and histopathological changes in mice. Mice feces were also collected for 16sRNA sequencing to analyze the composition of the intestinal flora.ResultsAll the indexes related to renal function were significantly improved after treatment with drugs. With respect to lipid metabolism, both drugs significantly decreased the serum triglyceride levels in diabetic mice, but the effect of liraglutide on reducing serum cholesterol was better than that of empagliflozin. However, empagliflozin had a better effect on the reduction of low-density lipoproteins (LDL). The two drugs had different effects on intestinal flora. At the phylum level, empagliflozin significantly reduced the ratio of Firmicutes to Bacteroidota, but no effect was seen with liraglutide. At the genus level, both of them decreased the number of Helicobacter and increased the number of Lactobacillus. Empagliflozin also significantly increased the abundance of Muribaculaceae, Muribaculum, Olsenella, and Odoribacter, while liraglutide significantly increased that of Ruminococcus.ConclusionLiraglutide and empagliflozin were both able to improve diabetes-related renal injury. However, the ability of empagliflozin to reduce LDL was better compared to liraglutide. In addition, their effects on the intestine bacterial flora were significantly different.

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Effects of Hydroxy-Alpha-Sanshool on Intestinal Metabolism in Insulin-Resistant Mice

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