Osteopontin‐driven T‐cell accumulation and function in adipose tissue and liver promoted insulin resistance and <scp>MAFLD</scp>

Abstract

Abstract Objective This study investigated the contribution of osteopontin/secreted phosphoprotein 1 (SPP1) to T‐cell regulation in initiation of obesity‐driven adipose tissue (AT) inflammation and macrophage infiltration and the subsequent impact on insulin resistance (IR) and metabolic‐associated fatty liver disease (MAFLD) development. Methods SPP1 and T‐cell marker expression was evaluated in AT and liver according to type 2 diabetes and MAFLD in human individuals with obesity. The role of SPP1 on T cells was evaluated in Spp1 ‐knockout mice challenged with a high‐fat diet. Results In humans with obesity, elevated SPP1 expression in AT was parallel to T‐cell marker expression (CD4, CD8A) and IR. Weight loss reversed AT inflammation with decreased SPP1 and CD8A expression. In liver, elevated SPP1 expression correlated with MAFLD severity and hepatic T‐cell markers. In mice, although Spp1 deficiency did not impact obesity, it did improve AT IR associated with prevention of proinflammatory T‐cell accumulation at the expense of regulatory T cells. Spp1 deficiency also decreased ex vivo helper T cell, subtype 1 (Th1) polarization of AT CD4 + and CD8 + T cells. In addition, Spp1 deficiency significantly reduced obesity‐associated liver steatosis and inflammation. Conclusions Current findings highlight a critical role of SPP1 in the initiation of obesity‐driven chronic inflammation by regulating accumulation and/or polarization of T cells. Early targeting of SPP1 could be beneficial for IR and MAFLD treatment. image