The epidemic of obesity and its related insulin resistance have contributed significantly to the incidence of diabetes. It is now generally Masitinib accepted that both obesity and T2D are associated with low grade chronic inflammation and that adipose tissue appears to be the first organ that is affected. The development of inflammation and oxidative stress in adipose tissue leads to insulin resistance. Furthermore, accelerated hepatic lipogenic gene expression and reduced liver fat export may also contribute to the development of obesity. Many naturally occurring dietary polyphenols possess antioxidant and anti-inflammatory properties. This could be achieved by modulating an inflammatory or oxidative signaling pathway, including NF-kB, Nrf2, and/or MAPK-dependent signaling pathways. Certain dietary polyphenols, such as curcumin, also possess the anti-carcinogenic effects. One potential mechanism of curcumin to repress tumorigenesis has been suggested to be the inhibition of Wnt signaling, an essential pathway for embryogenesis and cell proliferation. Curcumin, a low-molecular-weight polyphenol derived from the herbal remedy and dietary spice turmeric, was found to prevent obesity and diabetes in mouse models. Mechanistically, curcumin may exert its beneficial effects via reducing insulin and leptin resistance, attenuating inflammatory cytokine expression, accelerating fatty acid oxidation, as well as increasing antioxidant enzyme expression. In addition, curcumin could also function as an inhibitor of p300 histone acetyltransferase, a potential molecular mechanism for cancer prevention and cardiovascular improvement. The Wnt/b-catenin signaling pathway was initially discovered in colon cancer and in developmental studies of Drosophila and frogs. The role of the canonical Wnt signaling pathway in metabolic homeostasis has recently received increasing attention. Activation of Wnt pathway increases cellular and nuclear b-cat level, which represses adipogenesis, while the inhibition of Wnt signaling is required for PPARc induction and preadipocyte differentiation. A very recent study showed that curcumin stimulates Wnt/b-cat signaling in 3T3-L1 preadipocytes and hence suppresses adipogenic differentiation. It is contradictory with other reports in two ways. First, numerous studies have indicated that curcumin exerts its anti-cancer effect via repressing Wnt signaling. Second, Wnt activation in mature adipocytes was shown to induce insulin resistance, while curcumin is known to attenuate insulin resistance. In this study we have examined the effect of dietary curcumin in a HFD mouse model in which the development of obesity and insulin insensitivity was relatively slow due to the administration of 45% rather than 60% of calories from fat. In this mouse model as well as in primary rat adipocytes, we did not observe stimulation of curcumin on Wnt pathway components or Wnt target gene expression. However, curcumin attenuated lipogenic gene expression in hepatocytes, and blocked the effect of HFD on the inflammatory response in the adipose tissue, associated with decreased weight/fat gain, and the maintenance of normal glucose tolerance and insulin sensitivity.