Matrix Metalloproteinase-2 as a novel regulator of glucose utilization by adipocytes

Abstract

Glucose transporter 4 (GLUT4) expression on white adipocytes is critical for absorbing excess blood glucose, failure of which promotes hyperglycemia. Matrix metalloproteinases (MMPs) play a crucial role in remodeling the white adipose tissue (WAT) during obesity. MMPs have multiple protein substrates, and surprisingly, it is unknown if they can directly target GLUT4 on the adipocyte surface and impair glucose absorption. We identified MMP2 as the highly active gelatinase, a class of MMP, in the gonadal WAT of high-fat diet-induced obese mice. In vitro, metabolic studies in 3T3-L1 adipocytes revealed MMP2 attenuated glucose absorption and glycolysis, which were recovered by an MMP2 inhibitor. In silico structural analysis using AlphaFold identified a putative MMP2 cleavage site on the extracellular domain of GLUT4. Further, in a substrate competition assay, a peptide mimicking the MMP2 cleavage motif on GLUT4 attenuated the cleavage of an MMP substrate by MMP2. Altogether, our results suggest a novel mechanism of impaired glucose absorption by adipocytes, which may contribute to hyperglycemia during obesity. ARTICLE HIGHLIGHTSO_LIIt is unknown if MMPs directly affect adipocyte metabolism via targeting adipocyte surface proteins. C_LIO_LIWe aimed to determine the highly active gelatinases, a class of MMP, in the white adipose tissue of obese mice, and examined its effect on adipocyte glucose metabolism. C_LIO_LIMMP2 was the highly active gelatinase in obese adipose tissue and, in vitro, MMP2 reduced adipocyte glucose metabolism, in part, by targeting the GLUT4 receptor. C_LIO_LIA harmful role of MMP2 is implicated in cardiometabolic diseases and our novel finding on the role of MMP2 on glucose metabolism may add to the pathogenesis of the diseases. C_LI