Epigenetic regulation of gremlin-1 and lipocalin-2 in obesity and type 2 diabetes: Pathophysiology and therapy

Obesity and type 2 diabetes mellitus (T2DM) are complex metabolic disorders arising from the interplay of genetic, environmental, and epigenetic factors. Adipose tissue dysfunction and altered adipokine secretion are central to the development of systemic insulin resistance. Among adipokines, Gremlin-1 (GREM1) and Lipocalin-2 (LCN2) have emerged as critical mediators of metabolic homeostasis, adipogenesis, and inflammation. GREM1, a bone morphogenetic protein antagonist, shifts adipose tissue differentiation toward white adipocytes and impairs insulin signaling, whereas LCN2 exerts context-dependent effects on glucose metabolism and inflammatory responses. Emerging evidence suggests that epigenetic mechanisms, particularly DNA methylation, regulate the expression of these adipokines, linking environmental exposures to metabolic phenotypes. This review synthesizes current knowledge on GREM1 and LCN2 biology, their roles in obesity and T2DM, and the epigenetic mechanisms influencing their expression, highlighting gaps in research and potential clinical applications.