mTOR is not only a downstream target of insulin signaling, but also serves as an effector of the Wnt signaling pathway. Thus, the repressive effect of curcumin on mTOR further supports the notion that curcumin might repress Wnt activity in cancer cells. In the current study, we show that HFD induced hepatic expression of phosphorylated S6K1, a downstream target of mTOR. Curcumin consumption suppressed S6K1 phosphorylation. The importance of Wnt signaling pathway in metabolic homeostasis has been broadly recognized recently. Wnt10b is abundantly expressed in mesenchymal precursor cells. Wnt10b mediated Wnt activation stimulates the expression of osetogenic genes at the expense of adipogenic genes. Furthermore, ectopic expression of Wnt10b in transgenic mice impairs the development of the adipose tissue and these mice are resistant to HFD induced obesity. Very recently, a study demonstrated that in the 3T3-L1 cell model, the repression of adipogenic differentiation was accompanied by Wnt/b-cat activation. The authors found that during adipocyte differentiation, curcumin reduced the expression of the components of the destructive complex that are responsible for b-cat degradation, including CK1a, GSK-3b and Axin, accompanied by increased expression of total b-cat, Wnt10b, the Wnt pathway receptor Fz2, the coreceptor LRP5, as well as the Wnt targets c-Myc and cyclin D1. This study provides a potential novel molecular mechanism to explain the repressive effect of curcumin on adipogenesis. In contrast, we found in the current study that the stimulatory effect of curcumin on Wnt signaling does not occur in mature adipocytes. How this plant dietary compound exerts opposite effects on Wnt signaling pathway in pre-adipocytes versus mature adipocytes deserves further investigations. Nevertheless, we have previously noted cell-type specific effects of Wnt and/or insulin signaling. For example, both insulin and lithium chloride, the latter mimics Wnt activation, stimulate proglucagon gene transcription in gut endocrine L cells, but repress the same gcg gene in pancreatic islets. Furthermore, we found the stimulatory effect of insulin on b-cat Ser675 phosphorylation in the gut, but not in adipocytes. Finally, one study has shown that in skeletal muscle cells, Wnt activation increases insulin sensitivity through reciprocal Z-VAD-FMK Caspase inhibitor regulation of Wnt10b and SREBP-1c, while another group showed that Wnt activation in mature adipocytes leads to adipocyte dedifferentiation and insulin resistance. In this study, curcumin blocked the effect of HFD on macrophage infiltration in adipose tissue, associated with the repression of NF-kB level and JNK activity, the improvement of insulin stimulated PKB phosphorylation in adipose tissue and liver, as well as glucose disposal. These observations are consistent with current concepts that the activation of endogenous antioxidative system and the repression of inflammatory signaling in adipocytes improve insulin resistance. Whether there are additional mechanisms underlying the improvement of insulin signaling by curcumin supplementation deserves further investigations. For example, mTOR is involved in the development of insulin resistance via a negative feedback loop, i.e. the inhibition of IRS-1 tyrosine phosphorylation.