The G-protein-coupled receptor kinase 5 (GRK5) is an important member of the threonine/serine kinase family that phosphorylates and regulates the G-protein-coupled receptor (GPCR) signaling pathway. GRK5 is highly expressed in adipose tissue and may act as an adipogenetic factor under high-fat load [1]. Insulin resistance is associated with the pathogenesis of metabolic disorders such as type 2 diabetes and obesity; however, the potential role of GRK5 in insulin resistance is unknown. We characterized the biochemical and molecular alterations related to metabolic complications observed in GRK5(-/-) mice. These mice, which are partially resistant to obesity induced by a high-fat diet, had impaired glucose tolerance and insulin sensitivity, as well as disruption of AKT signaling transduction compared with their wild-type littermates. Further study showed that the decreased insulin sensitivity was not attributable to alterations in inflammatory status such as the NF-κB signaling pathway or inflammatory gene expression. Instead, hepatic steatosis and changes of mRNA in genes involved in hepatic glucose and lipid homeostasis were found. Overall, our data identified GRK5 as a positive regulator of insulin sensitivity. Our results showed that this protein is a potential therapeutic target in the treatment of insulin resistance and related disorders.