[Effects of bariatric surgery on glucose and lipid metabolism in obese mice: An integrated transcriptomic and LC-MS-based untargeted metabolomics analysis].

OBJECTIVES

Obesity and its associated disorders of glucose and lipid metabolism have become increasingly significant public health concerns. Bariatric surgery is an effective intervention for severe obesity and related metabolic comorbidities. This study aims to investigate the effects of bariatric surgery on glucose and lipid metabolism in high-fat diet (HFD)-induced obese mice.

METHODS

An obesity mouse model was established. Four-week-old male C57BL/6J mice (n=32) were randomly divided into a control (CTL) group (n=8) and an HFD group (n=24). At 20 weeks of age, HFD mice were further divided into 3 subgroups (n=8 per group): a HFD-HFD group, a sham-operated group (HFD-SHAM group), and an HFD-sleeve gastrectomy (SG) group. Body weight and food intake were recorded weekly. Intraperitoneal glucose tolerance tests (IPGTT) and intraperitoneal insulin tolerance tests (IPITT) were performed at 20 weeks (preoperatively) and 24 weeks (4 weeks postoperatively). At 24 weeks, fasting blood samples and beige, white, and brown adipose tissues were collected. Serum levels of free fatty acids (FFA), total cholesterol (TC), triglycerides (TG), and insulin were measured. Transcriptomic and metabolomic analyses were conducted to identify differentially expressed genes (DEGs) and differential metabolites between the HFD-SHAM and HFD-SG groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed, followed by integrative analysis of transcriptomic and metabolomic data.

RESULTS

Four weeks after surgery, compared with the HFD-HFD and HFD-SHAM groups, the HFD-SG group showed significantly reduced body weight and food intake (all P<0.05), improved glucose tolerance and insulin sensitivity (both P<0.05), and decreased levels of insulin, free fatty acids (FFA), total cholesterol (TC), and triglycerides (TG) (all P<0.05). Transcriptomic analysis identified 763 DEGs between the HFD-SG and HFD-SHAM groups, including 384 upregulated and 379 downregulated genes. GO and KEGG enrichment analyses revealed activation of pathways such as steroid hormone biosynthesis. Metabolomic analysis identified 16 differential metabolites enriched in pathways including ascorbate and aldarate metabolism and folate-mediated one-carbon metabolism. Integrative analysis revealed that steroid biosynthesis and folate-mediated one-carbon metabolism pathways were significantly associated between the two groups. In the steroid biosynthesis pathway, genes including LSS, Nsdhl, DHCR24, Hsd17b7, MSMO1, SQLE, and CYP51 were upregulated in all three adipose tissues in the HFD-SG group but downregulated in the HFD-SHAM group, whereas the metabolite androstenediol was decreased in the HFD-SG group. In the folate-mediated one-carbon metabolism pathway, Aldh1l2 and GNMT were upregulated only in beige adipose tissue of the HFD-SHAM group, while TYMS and Sardh were upregulated in beige and white adipose tissues of the HFD-SG group. The metabolite deoxythymidine monophosphate was increased in the HFD-SG group, consistent with gene expression trends.

CONCLUSIONS

SG significantly reduced body weight and food intake, improved glucose tolerance and insulin sensitivity, and corrected lipid metabolism disorders in HFD-induced obese mice. Bariatric surgery regulates steroid biosynthesis and folate-mediated one-carbon metabolism pathways in adipose tissue, altering key gene and metabolite expression profiles. These findings suggest that bariatric surgery improves systemic glucose and lipid metabolism by remodeling metabolic pathways in adipose tissue, providing novel molecular insights for the treatment of obesity and related metabolic diseases.