Sex-specific cardiometabolic remodeling induced by DPP-4 inhibition under high-fat diet: insights from cardiac proteomics

Background and aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the management of type 2 diabetes and are generally considered cardiovascularly safe. However, their mechanistic actions on the heart under metabolic stress remain incompletely understood. Methods and results: In this study, we investigated sex-specific cardiac proteomic responses to the DPP-4 inhibitor linagliptin (L) in a mouse model of diet-induced obesity. Male and female C57BL/6 N mice were fed a normal chow or high-fat diet for 15 weeks and received L (0.003% w/w in the diet; estimated exposure ∼120 μg/day) through dietary supplementation. Cardiac tissues were analyzed using label-free shotgun proteomics. High-fat diet induced marked, sex-dependent remodeling of the cardiac proteome. L exerted distinct effects according to both sex and metabolic context, partially counteracting obesity-induced alterations, particularly in females. Under high-fat conditions, L modulated sex-specific proteomic signatures related to mitochondrial energetics, lipid metabolism, cardiac conduction, calcium-channel activity, and myocardial structural organization, biological processes that have previously been associated with cardiac remodeling in experimental and clinical studies. Notably, distinct molecular signatures emerged between males and females, highlighting a strong sexual dimorphism in cardiac responses to both metabolic stress and pharmacological intervention. Conclusion: These findings reveal a dual and context-dependent role of DPP-4 inhibition in the heart and suggest that metabolic status and sex may critically influence its cardiovascular effects. This study provides novel insights into the molecular mechanisms underlying the cardiac response to DPP-4 inhibition under conditions of metabolic stress and supports further investigation of sex-specific cardiometabolic effects.