Previous studies have shown that high-fat diet (HFD)-induced obesity increases the acetoacetyl-CoA synthetase (AACS) gene expression in lipogenic tissue. To investigate the effect of obesity on the AACS gene in other tissues, we examined the alteration of AACS mRNA levels in HFD-fed mice. In situ hybridization revealed that AACS was observed in several regions of the embryo, including the backbone region (especially in the somite), and in the epiphysis of the adult femur. AACS mRNA expression in the adult femur was higher in HFD-fed mice than in normal-diet fed mice, but this increase was not observed in high sucrose diet (HSD)-induced obese mice. In addition, HFD-specific increases were observed in the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and interleukin (IL)-6 genes. Moreover, we detected higher AACS mRNA expression in the differentiated osteoclast cells (RAW 264), and found that AACS mRNA expression was significantly up-regulated by IL-6 treatment only in osteoclasts. These results indicate the novel function of the ketone body in bone metabolism. Because the abnormal activation of osteoclasts by IL-6 induces bone resorption, our data suggest that AACS and ketone bodies are important factors in the relationship between obesity and osteoporosis. (C) 2016 The Authors. Published by Elsevier Inc.