Integrated multi-omics unravels solanesol's multi-organ protection mechanisms against insulin resistance in type 2 diabetic mice.

INTRODUCTION

Integrated multi-omics analysis has revolutionized the investigation of plant-derived compounds for type 2 diabetes mellitus (T2DM). Solanesol, a bioactive constituent from Solanaceae plants, exhibits high oral bioavailability and translational potential for multi-target therapeutics.

OBJECTIVES

This study aimed to elucidate the multi-target mechanisms and multi-organ protective effects of solanesol in T2DM management through integrated multi-omics approaches, to bridge the gap between phytochemical discovery and clinical translation.

METHODS

In Leprdb/db murine models (8-13 weeks), solanesol (1-15 mg/kg/day, i.g.) was compared with metformin (200 mg/kg/day). ​​Serum biochemical parameters were quantified using ELISA/colorimetric assays. Quantitative pathology analysis was performed on H&E/PAS/Masson-stained sections for assessment of hepatic steatosis and glycogenesis. Mitochondrial respiratory chain complexes (I-V) expression and activities were validated by qRT-PCR and ELISA assay, respectively. Multi-omics profiling included gut microbiota sequencing (16S rRNA), fecal metabolomics/lipidomics (UHPLC-Q LC-MS/MS), and hepatic transcriptome/proteome analysis (RNA-seq, 4-Dimensional Label-Free Quantification (4D-LFQ)). Long-/medium-/short-chain fatty acids were detected by GC-MS.

RESULTS

Solanesol improved glucose tolerance, insulin sensitivity, and reduced serum lipids, hepatic gluconeogenesis, uric acid, white adipose mass, pancreatic/hepatic inflammation, and renal fibrosis. Mechanistically, solanesol: 1) enriched beneficial gut microbiota (Alistipes, Anaerotruncus, and Parasutterella) and increased levels of long-chain unsaturated fatty acids; 2) rebalanced the dysfunctional mitochondrial oxidative phosphorylation​​ microenvironment by modulating the expression and the activities of respiratory chain Complexes I-V; 3) modulated hepatic lipid metabolism by ​inhibiting​​ de novo ​​lipogenesis​​ via the Acly-Acaca-Fasn pathway, promoting cholesterol efflux and fatty acid oxidation​​ through Abca1/Fabp5, and attenuating inflammation​​ via Lpl-PPARδ downregulation.

CONCLUSION

Solanesol demonstrates multi-organ protective effects through gut microbiota-metabolite crosstalk and hepatic lipid/redox homeostasis regulation. Its multi-target efficacy and oral bioavailability position it as a novel, clinically translatable candidate for T2DM management.