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.

Acetoacetyl-CoA synthetase (AACS) is a ketone body-utilizing enzyme that converts acetoacetate to acetoacetyl-CoA in the cytosol and consequently provides acetyl units as the precursors for lipogenesis. To clarify the role of AACS in adipogenesis, we investigated the expression and localization of the AACS protein and the effect of AACS knockdown on 3T3-L1 differentiation. The protein expression of AACS is dramatically induced during 3T3-L1 differentiation and is localized in the cytoplasm of differentiated 3T3-L1 cells. Moreover, knockdown of AACS inhibits differentiation of 3T3-L1 cells and suppresses expression of the adipocyte markers, peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα). These results suggest that AACS has a crucial role in the mechanism of 3T3-L1 differentiation.

One of the activities of placental extracts (PEs) is skin-whitening effect, but the physiological and genetic mechanism for this effect has not yet been clarified. Here, we focus on PE as a regulator of antioxidant enzyme genes. Porcine PE was prepared, and its activity was investigated in B16 melanoma cells. PE treatment decreased the melanin content of UV-irradiated B16 cells in a dose-dependent manner. PE directly reduced the enzyme activity of tyrosinase in a cell-free assay. In addition, PE treatment increased the gene expression of cytosolic superoxide dismutase (SOD-1), extracellular SOD (SOD-3) and catalase but did not affect the expression of tyrosinase. Moreover, PE protected the B16 cells from H₂O₂-induced cell death. Taken together, our data suggest that PEs could play a role not only as a suppressor of melanin synthesis but also as a regulator of antioxidant genes and might protect the skin against oxidative stress.