Introduction: Metabolic stress from prolonged hyperglycemia leads to adipocyte dysfunction, contributing to the pathogenesis of metabolic disorders such as obesity and type 2 diabetes. Numerous studies have shown that natural compounds are promising alternative therapies for alleviating metabolic alterations. However, their effects on human models are limited. Our objectives are to elucidate the metabolic alterations in human adipocytes under hyperglycemic conditions compared to mature adipocytes and to study the potential effect of compound A on antioxidant-related metabolism in hyperglycemic human adipocytes.

Methods: Hypertrophic human Simpson–Golabi–Behmel syndrome (SGBS) adipocytes, obtained by 2-week incubation with 25 mM of glucose, were used as a hyperglycemic model. Compound A was incubated during the last 48 h to study its effect on ROS production, on the expression of key target proteins like AKT (by Western blot), and on the modulation of metabolic pathways by profiling using UPLC-MS.

Results: Our findings revealed profound metabolic disruptions in adipocytes exposed to hyperglycemia, characterized by increased ROS, decreased AKT phosphorylation and adiponectin levels, and the downregulation of multiple metabolites and their associated pathways, like cysteine metabolism. Importantly, treatment with compound A demonstrated marked efficacy in mitigating these metabolic alterations and restoring adipocyte homeostasis. Compound A increased AKT phosphorylation and decreased ROS. Regarding metabolic pathways, it increased metabolites from cysteine and glutathione metabolism, partially reverting metabolic stress through an antioxidant environment.

Conclusions: These results provide insights into the metabolic pathways underlying adipocyte dysfunction in hyperglycemic conditions. In addition, they highlight the potential therapeutic effect of natural compound A in ameliorating metabolic disturbances associated with long-term hyperglycemia.