Diabetes has been associated with metabolic disorder, insulin resistance and neuroinflammation. However, the pathogenesis for HFD-induced injury of central nervous system (CNS) is still unclear. Tripartite Motif Containing 13 (TRIM13), also known as RFP2, is a member of TRIM proteins, and is associated with multiple cellular processes, such as apoptosis, survival and inflammation. However, the effects of TRIM13 on brain injury, especially the HFD-induced CNS damage, have not been investigated. To address this issue, the TRIM13(flox/flox) ((fl/fl)) mice were produced and then crossed them with Nestin-Cre mice to delete TRIM13 specifically in the brain (cKO). Then, T2D mice with obesity were established by chronic feeding of HFD. We found that brain-specific deletion of TRIM13 accelerated HFD-induced metabolic disorder, insulin resistance and systematic inflammatory response. In addition, HFDcKO mice exhibited significantly higher pro-inflammatory cytokines, including interleukin (IL)-6, IL-1 beta and tumor necrosis factor-alpha (TNF-alpha), in cortex, hippocampus and hypothalamus tissues, which were comparable to the HFDfl/fl mice. Consistently, the activation of nuclear factor-kappa B (NF-kappa B) induced by HFD was further aggravated in mice with brain-specific loss of TRIM13. Moreover, glial activation in CNS stimulated by HFD was further promoted by TRIM13 knockout in brain, as evidenced by the up-regulated expression of glial fibrillary acidic protein (GFAP) and Iba-1. In hypothalamus, HFD reduced proopiomelanocortin (POMC) and enhanced neuropeptide Y (NPY) expression, which were further promoted in mice with brain-specific deletion of TRIM13. Meanwhile, insulin signaling pathway was disrupted by HFD in hypothalamus of mice, and these effects were exacerbated in HFDcKO mice. The in vitro analysis confirmed that TRIM13 knockout in glial cells considerably promoted palmitate (PAL)-induced inflammatory response by accelerating NF-kappa B signal, contributing to the insulin resistance in the isolated primary neurons. Together, these findings demonstrated that TRIM13 was involved in HFD-induced CNS injury and insulin resistance through regulating neuroinflammatory response, contributing to the modulation of peripheral metabolic disorders. (c) 2020 Published by Elsevier Inc.