Abstract

Midlife obesity and high adiposity are recognized as risk factors for Alzheimer's disease (AD), with visceral adipose tissue (VAT) playing a central role due to its endocrine and metabolic activity. Disturbances in VAT metabolism and adipokine secretion exacerbate AD pathology. Andrographolide (Andro), known for its anti-diabetic properties, enhances neuronal glucose uptake and alleviates AD pathology. However, its effects on VAT metabolism in AD remain unexplored. This study aimed to investigate the impact of Andro on glucose metabolism in VAT using a high-fat diet (HFD)-induced obesity model in AD mice (APP/PS1). APP/PS1 mice were fed an HFD and received Andro injections (2 mg/kg, three times a week for 16 weeks). VAT samples were analyzed for glucose uptake, glycolytic rate, pentose phosphate flux, ADP-ATP levels, gene expression, and enzymatic activity of glucose metabolic regulators. In APP/PS1 mice, HFD significantly increased glucose uptake and reduced GLUT4 expression in VAT, effects counteracted by Andro (p < 0.05). Andro-treated HFD-fed mice exhibited reduced glucose oxidation through glycolysis (p < 0.05), leading to decreased ATP production (p < 0.05). Andro administration restored the activity of key glycolytic enzymes and mitigated several HFD-induced metabolic alterations (p < 0.05). The study reveals significant metabolic changes in the VAT of obese APP/PS1 mice and highlights Andro's potential as a therapeutic agent for addressing VAT impairment induced by obesity in AD. © 2025 The Authors