2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reverses hyperglycemia in a type II diabetes mellitus rat model by a mechanism unrelated to PPAR gamma.

It has been asserted that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases the risk for diabetes mellitus in humans, observable as hyperglycemia resulting from insulin resistance. There is no animal model for the induction of diabetes by TCDD. On the contrary, TCDD has been shown to increase insulin sensitivity in rats. Therefore, a diabetic rat model was used to study the effects of TCDD on preexisting diabetes. Type II diabetes was induced in male rats by a high-fat diet and streptozotocin. After manifestation of the disease, these rats received loading dose rates (LDRs) of 3.2, 6.4, and 12.8 microg/kg of TCDD p.o., followed by weekly maintenance dose rates. Rats fed a high-fat diet and not dosed with streptozotocin nor with TCDD served as nondiabetic controls. By day 2, serum-glucose levels in diabetic rats treated with the high LDR of 12.8 microg/kg TCDD were already significantly reduced. By day 8, serum-glucose levels had decreased to control levels and were maintained for the duration of the study (32 days). Thus, TCDD effectively counteracted hyperglycemia in this diabetic rat model. In healthy animals, TCDD induced PPAR gamma transcription and activity in a different dose range than that observed for the hypoglycemic effect.

Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development.

Increased dietary fat consumption is associated with colon cancer development. The exact mechanism by which fat induces colon cancer is not clear, however, increased bile acid excretion in response to high-fat diet may promote colon carcinogenesis. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, and bile acids are endogenous ligands of FXR. FXR is highly expressed in the intestine and liver where FXR is essential for maintaining bile acid homeostasis. The role of FXR in intestine cancer development is not known. The current study evaluated the effects of FXR deficiency in mice on intestinal cell proliferation and cancer development. The results showed that FXR deficiency resulted in increased colon cell proliferation, which was accompanied by an up-regulation in the expression of genes involved in cell cycle progression and inflammation, including cyclin D1 and interleukin-6. Most importantly, FXR deficiency led to an increase in the size of small intestine adenocarcinomas in adenomatous polyposis coli mutant mice. Furthermore, after treatment with a colon carcinogen, azoxymethane, FXR deficiency increased the adenocarcinoma multiplicity and size in colon and rectum of C57BL/6 mice. Loss of FXR function also increased the intestinal lymphoid nodule numbers in the intestine. Taken together, the current study is the first to show that FXR deficiency promotes cell proliferation, inflammation, and tumorigenesis in the intestine, suggesting that activation of FXR by nonbile acid ligands may protect against intestinal carcinogenesis.

NF-E2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet.

NF-E2-related factor 2 (Nrf2) is a transcription factor that is activated by oxidative stress and electrophiles that regulates the expression of numerous detoxifying and antioxidant genes. Previous studies have shown that Nrf2 protects the liver from xenobiotic toxicity; however, whether Nrf2 plays a role in lipid homeostasis in liver is not known. Accordingly, wild-type and Nrf2-null mice were fed a high-fat diet (HFD) for up to 4 weeks. Hepatic gene expression and lipid profiles were analyzed for changes in fatty acid, triglyceride, and cholesterol status. It is interesting to note that HFD reduced the mRNA expression of Nrf2 and its target genes in wild-type mice. The mRNA expression of lipogenic and cholesterologenic transcriptional factors and their target genes, such as sterol regulatory element-binding proteins 1c and 2, fatty acid synthase, acetyl-CoA carboxylase 1, fatty acid elongase, 3-hydroxy-3-methylglutaryl coenzyme A synthase and reductase, and low-density lipoprotein receptor mRNA expression were higher in Nrf2-null mice compared with wild-type mice after feeding a HFD, suggesting that Nrf2 may suppress these pathways. Hepatic triglycerides and cholesterol levels were not different between genotypes, whereas concentrations of hepatic free fatty acid and malondialdehyde equivalents were higher in Nrf2-null mice compared with wild-type mice 4 weeks after HFD feeding. Overall, these results suggest that Nrf2 inhibits lipid accumulation and oxidative stress in mouse liver after feeding a HFD, probably by interfering with lipogenic and cholesterologenic pathways.

Gender disparity of hepatic lipid homoeostasis regulated by the circadian clock.

The mammalian clock regulates major aspects of energy metabolism, including glucose and lipid homoeostasis as well as mitochondrial oxidative metabolism. This study is to identify specific patterns of circadian rhythms for lipid homoeostasis in both female and male mouse livers, and to clarify gender disparity in coupling the peripheral circadian clock to lipid metabolic outputs by nuclear receptors. To achieve this, profiling the diurnal hepatic expression of genes encoding circadian clocks, nuclear receptors and lipid metabolic enzymes was performed. Hepatic lipid levels including cholesterol, triglyceride and non-esterified fatty acids (NEFAs) were monitored over a 24-h period. The cosinor analysis revealed that several genes encoding nuclear receptors and enzymes involved in the lipid metabolic pathway were rhythmically expressed in liver in phase with the peripheral clocks, which were correlated with the diurnal changes of hepatic lipid levels. Gender disparity was observed for circadian characteristics including mesor and amplitude values, accompanied with advances in acrophases in female mouse livers. Accordingly, gender differences were also observed in diurnal lipid homoeostasis. The identification of cycling patterns for lipid metabolic pathways in both female and male mouse livers may shed light on the development of gender-based treatment for human diseases related to the coordination of the cellular clock and control of lipid homoeostasis.