This plant polyphenolic compound has anti-tumor, anti-proliferative, anti-oxidant, and anti-inflammatory properties. Since the last decade, a few clinical trials have been conducted, showing the therapeutic effects of curcumin on various cancers and Alzheimer’s disease. In C57BL/6J HFD fed mice, oral curcumin supplementation was shown to prevent the development of obesity-associated inflammation, insulin resistance, as well as diabetes. The beneficial effect of curcumin in that study was mainly attributed to the reduction of macrophage infiltration of the adipose tissue, the increase of adiponectin production, as well as the decrease of hepatic NF-kB activity. The anti-adipogenic effect of curcumin was then demonstrated in the 3T3-L1 cell model by other groups. The stimulation of HFD on hepatic NF-kB level, however, was not observed in the current study with our chronic HFD model, although curcumin supplementation decreased NF-kB level in the liver. Insulin resistance and obesity in C57BL/6J mice are often induced in the short-term by feeding a diet containing saturated fatty acids or with a mixed fatty acid diet with 60% energy from fat. In the current study we utilized a chronic HFD feeding model, in which mice did not develop obesity before 16 weeks, and the deleterious effect of HFD on both the morphology of the liver and plasma metabolic profiles were not as severe as the utilization of regular HFD. As presented, although our HFD reduced plasma adiponectin level, it did not reach statistical significance. Nevertheless, curcumin consumption generated a significant increase of plasma adiponectin. Furthermore, instead of routinely providing curcumin-containing HFD with every meal, we provided the curcumin-supplemented diet only two days per week. This model may more closely mimic the natural development of insulin resistance, associated with modest dietary changes along with intermittent curcumin consumption in human subjects that we can expect. We show in this model that curcumin supplementation blocked the effect of HFD on fat gain, improved insulin sensitivity and glucose disposal, and reduced intra-hepatic lipid content. In addition to the confirmation of the effect of curcumin in stimulating anti-oxidative signaling and attenuating inflammatory signaling in hepatocytes, we found that curcumin reduces mRNA levels of ChREBP and SREBP1-c, two key transcription factors for hepatic lipogenesis, as well as L-PK, an important downstream target of ChREBP. However, we did not observe that in mature ASP1517 HIF inhibitor adipocytes curcumin stimulates Wnt signaling components or Wnt target genes. We therefore suggest that curcumin exerts its beneficial effect in our HFD fed mouse model via attenuating oxidative stress and inflammatory response in the adipose tissue, and reducing lipogenesis in the liver, without the stimulation Wnt activity in mature adipocytes. It should be noted that the activation of Wnt signaling is strongly associated with the development and progression of colon cancer and other tumors. For example, in the LNCaP prostate cancer cells, curcumin represses total b-cat level, as well as GSK-3 phosphorylation, associated with reduced c-Myc and cyclin D1 expression.