Simulated Microgravity Enhances Adipocyte Maturation and Glucose Uptake via Increased Cortical Actin Remodeling

Abstract

Adipose tissue (AT) regulates whole-body metabolism and is subject to various forces during movement, exercise, and during rest. Adipocytes are mechanically responsive cells, yet little is known about how the lack of mechanical loading may affect adipocytes and their function. To model the lack of mechanical loading, we exposed engineered AT constructs to simulated microgravity (s{micro}g) conditions for 28 days. We found s{micro}g enhanced lipid accumulation (lipogenesis) and lipid mobilization (lipolysis). Adipocyte maturation involves a phenotypic switch from actin stress fiber disruption and cortical actin formation. S{micro}g exposure increased cortical actin formation through mechanoresponsive signaling pathways involving Ras homolog family member A (RhoA) and Rho Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1) downstream targets, cofilin and actin-related protein 2/3 (ARP2/3). Adipocytes cultured in s{micro}g have increased glucose transporter type 4 (GLUT4) translocation to the cell membrane and insulin-stimulated glucose uptake, independent of the canonical Akt pathway. GLUT4 translocation to the cell membrane and insulin-stimulated glucose uptake was limited when we inhibited new formation of branched cortical actin using an ARP2/3 inhibitor, CK-666. This study demonstrated that s{micro}g enhances adipocyte maturation via increased lipogenesis and lipolysis and cortical actin remodeling which further enhanced glucose uptake. Therefore, targeting these mechanosensitive pathways pharmacologically or simulating microgravity on earth as a non-pharmacological modality are novel approaches to improving adipocyte function and AT metabolism and possibly for treating related comorbidities such as type 2 diabetes and obesity.