The alteration of the phenotype and function of tissue resident macrophages due to changes in the tissue microenvironment after a local injury or infection has been studied well. However, how tissue resident macrophages respond to an injury in a distant organ is not understood. Using samples from patients with acute myocardial injury and mouse models of myocardial and skeletal muscle injuries, we observed that the number of visceral adipose tissue (VAT) resident macrophages significantly reduced due to apoptosis and they became pro-inflammatory after a distant organ injury. This loss of VAT resident macrophages after the injury led to systemic insulin resistance in non-diabetic patients and mice. Mechanistically, VAT resident macrophage apoptosis and de novo insulin resistance were due to diminished macrophage-colony stimulating factor signaling. Collectively, these findings demonstrate a previously unappreciated role of tissue resident macrophages in sensing remote organ injury and causing disease pathogenesis.