Leptin–cholesterol crosstalk in pregnancy: Mechanistic implications for placental function and cardiometabolic programming

Abstract

Pregnancy requires the coordinated maternal reorganization of lipid and endocrine pathways to sustain fetal growth and anticipate neonatal nutrition. Leptin, produced by adipose tissue and the placenta, acts as an integrative signal linking maternal energy status with trophoblast function and vascular adaptation, while cholesterol provides essential structural and hormonal substrates required for steroidogenesis and neurodevelopment. Emerging evidence indicates that leptin and cholesterol act as convergent regulators of metabolic and cardiovascular (CV) adaptation during pregnancy. We propose that excessive hyperleptinaemia and maternal hypercholesterolaemia, frequently coexisting, form a convergent axis that modulates placental signalling, alters the epigenetic regulation of lipid transporters and disrupts mitochondrial homeostasis. Mechanistically, this convergence operates through hepatic, epigenetic and renal pathways detailed throughout this review. Beyond the placenta, dysregulation of the leptin–cholesterol axis may extend to maternal organs central to CV homeostasis, particularly the kidney. Emerging evidence suggests that similar leptin‐driven renal pathways may operate during pregnancy, amplifying vascular dysfunction and susceptibility to hypertensive complications. This perspective highlights the leptin–cholesterol axis as a mechanistic link connecting placental, kidney and CV pathways within the Developmental Origins of Health and Disease (DOHaD) paradigm, with potential implications for long‐term cardiometabolic risk. This review integrates molecular, epigenetic and clinical evidence to emphasize lipoprotein‐centred mechanisms, identify critical knowledge gaps and discuss translational opportunities for nutritional intervention, biomarker development and early‐life preventive strategies.