Abstract
OBJECTIVE: Caloric restriction (CR) is known to enhance insulin sensitivity and reduce the risk of metabolic disorders; however, its molecular mechanisms are not fully understood. This study aims to elucidate specific proteins and pathways responsible for these benefits. METHODS: We examined adipose tissue from participants in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE 2) study, comparing proteomic profiles from individuals after 12 and 24 months of CR with baseline and an ad libitum group. Biochemical and cell-specific physiological approaches complemented these analyses. RESULTS: Our data revealed that CR upregulates prostacyclin synthase (PTGIS) in adipose tissue, an enzyme crucial for producing prostacyclin (PGI2). PGI2 improves the ability of insulin to stimulate the tether-containing UBX domain for GLUT4 (TUG) cleavage pathway, which is essential for glucose uptake regulation. Additionally, iloprost, a PGI2 analog, was shown to increase insulin receptor density on cell membranes, increasing glucose uptake in human adipocytes. CR also reduces carbonylation of GLUT4, a modification that is detrimental to GLUT4 function. CONCLUSIONS: CR enhances insulin sensitivity by promoting PTGIS expression and stimulating the TUG cleavage pathway, leading to increased GLUT4 translocation to the cell surface and decreased GLUT4 carbonylation. These findings shed light on the complex molecular mechanisms through which CR favorably impacts insulin sensitivity and metabolic health.