Chronic low-grade inflammation-induced insulin resistance is associated with neuroinflammation. Myeloid sirtuinl (SIRTI) deficiency aggravates high-fat diet (HFD)-induced insulin resistance. However, the function of myeloid-specific SIRTI in the hippocampus of obese mice is largely unknown. To address this question, we fed myeloid SIRTI knockout (KO) mice a HFD for 40 weeks. We found that HFD-fed SIRTI KO mice had increased insulin resistance and macrophage infiltration in adipose tissue than wild type (WT) mice. Levels of HFD-induced lipocalin-2 (LCN2) were lower in SIRT1 KO mice than in WT. HFD-induced hippocampal LCN2 expression was lower in HFD-fed SIRTI KO mice than in WT. Hippocampal acetylation of nuclear factor-kappa B (NF-kappa B) and amyloid precursor protein levels were higher in HFD-fed SIRT1 KO mice than in HFD-fed WT mice. Taken together, our results suggest that targeted induction of the anti-inflammatory effects of SIRTI and LCN2 may help prevent obesity-associated insulin resistance and neuroinflammation. (C) 2018 Elsevier Inc. All rights reserved.