Wen-Ying Chen

Long-term Administration of Rapamycin Reduces Adiposity, but Impairs Glucose Tolerance in High-Fat Diet-fed KK/HlJ Mice

Rapamycin is an immunosuppressant drug used to prevent organ rejection in transplant patients. In this study, we investigated the metabolic effects of rapamycin in an obese animal model, KK/HlJ mice. Mice were treated with a daily intraperitoneal injection of rapamycin at 2 mg/kg or vehicle for 42 days on a high-fat diet. Treated mice lost body weight and adiposity, reduced weight gain and retroperitoneal and epididymal fat pads/body weight, decreased serum leptin and plasma triglyceride levels and had lower liver fat concentration. However, treated mice had higher serum insulin levels and food intake. Dissection of rapamycin-treated mice revealed a marked reduction in fatty liver scores and fat cell size in retroperitoneal and epididymal adipocytes. Moreover, Western blot analysis revealed that rapamycin treatment resulted in decreasing adipophilin expression, as a marker of lipid accumulation, and reducing phosphorylation of mTOR downstream targets S6K1 compared to control group. Unfortunately, rapamycin-treated animals showed a marked decline in glucose tolerance as judged by the 180-min. area under the curve for plasma glucose levels, paralleled by increased generation of plasma reactive oxygen species. These results suggest that continual rapamycin administration may help to prevent diet-induced obesity, while prolonged use of rapamycin may exacerbate glucose intolerance.

Chromium supplementation enhances insulin signalling in skeletal muscle of obese KK/HlJ diabetic mice

Aim:u2002 Chromium is an essential nutrient required for glucose and lipid metabolism. Laboratory and clinical evidences indicate that chromium supplementation may improve insulin sensitivity by enhancing intracellular signalling. Considerable evidence suggests that serine phosphorylation of insulin receptor substrate 1 (IRS1) at 307 residue (IRS1‐Ser307) inhibits insulin signalling and results in peripheral insulin resistance. Therefore, we investigated whether chromium‐associated insulin action was mediated by modulation of IRS1‐Ser307 phosphorylation.

Chromium attenuates hepatic damage in a rat model of chronic cholestasis.

AIMSnOxidative stress is involved in cholestasis-induced hepatic damage. Therefore, antioxidant therapy is a recommended therapeutic strategy. Studies have illustrated that chromium can enhance antioxidative capacity leading to a resolution of oxidative stress. The aim of this study was to assess whether chromium has protective effects against cholestasis-related liver damage.nnnMAIN METHODSnCholestasis was produced by bile duct ligation (BDL) in male Sprague-Dawley rats for 3 weeks. Rats were randomly divided into four groups. Control and BDL groups were subjected to sham and BDL operation, respectively, and were supplemented with placebo for 3 weeks. The BDL-post Cr group was supplemented with chromium chloride for 3 weeks after BDL operation. The BDL-pre Cr group was supplemented with chromium chloride for 6 weeks starting from 3 weeks before BDL operation.nnnKEY FINDINGSnIn comparison with the control group, the BDL group showed hepatic damage as evidenced by elevation in serum biochemicals, ductular reaction, and fibrosis. These pathophysiological changes were attenuated in the BDL-Pre Cr and BDL-Post Cr groups. However, there was no significant difference between these two groups. The anti-fibrotic effect of chromium was accompanied by reductions in alpha-smooth muscle actin-positive matrix-producing cells and Smad 2/3 activity critical to the fibrogenic potential of transforming growth factor beta 1 (TGF-beta1). In addition, chromium effectively attenuated BDL-induced hepatic oxidative stress.nnnSIGNIFICANCEnThe data indicate that chromium attenuates BDL-induced cholestatic liver injury, bile duct proliferation, and fibrosis. The hepatoprotective effect of chromium is associated with antioxidative potential.

Chromium attenuates high-fat diet-induced nonalcoholic fatty liver disease in KK/HLJ mice.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with insulin resistance, oxidative stress, and inflammation. Evidence indicates that chromium has a role in the regulation of glucose and lipid metabolism and may improve insulin sensitivity. In this study, we report that chromium supplementation has a beneficial effect against NAFLD. We found that KK/HlJ mice developed obesity and progressed to NAFLD after feeding with high-fat diet for 8weeks. High-fat-fed KK/HlJ mice showed hepatocyte injury and hepatic triglyceride accumulation, which was accompanied by insulin resistance, oxidative stress, and inflammation. Chromium supplementation prevented progression of NAFLD and the beneficial effects were accompanied by reduction of hepatic triglyceride accumulation, elevation of hepatic lipid catabolic enzyme, improvement of glucose and lipid metabolism, suppression of inflammation as well as resolution of oxidative stress, probably through enhancement of insulin signaling. Our findings suggest that chromium could serve as a hepatoprotective agent against NAFLD.

Chromium supplementation improved post-stroke brain infarction and hyperglycemia

Hyperglycemia is common after acute stroke and is associated with a worse outcome of stroke. Thus, a better understanding of stress hyperglycemia is helpful to the prevention and therapeutic treatment of stroke. Chromium is an essential nutrient required for optimal insulin activity and normal carbohydrate and lipid metabolism. Beyond its nutritional effects, dietary supplement of chromium causes beneficial outcomes against several diseases, in particular diabetes-associated complications. In this study, we investigated whether post-stroke hyperglycemia involved chromium dynamic mobilization in a rat model of permanent focal cerebral ischemia and whether dietary supplement of chromium improved post-stroke injury and alterations. Stroke rats developed brain infarction, hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance. Post-stroke hyperglycemia was accompanied by elevated secretion of counter-regulatory hormones including glucagon, corticosterone, and norepinephrine, decreased insulin signaling in skeletal muscles, and increased hepatic gluconeogenesis. Correlation studies revealed that counter-regulatory hormone secretion showed a positive correlation with chromium loss and blood glucose increased together with chromium loss. Daily chromium supplementation increased tissue chromium levels, attenuated brain infarction, improved hyperglycemia, and decreased plasma levels of glucagon and corticosterone in stroke rats. Our findings suggest that stroke rats show disturbance of tissue chromium homeostasis with a net loss through urinary excretion and chromium mobilization and loss might be an alternative mechanism responsible for post-stroke hyperglycemia.

Glucagon and insulin have opposite effects on tissue chromium distribution in an obese mouse model.

Previous studies have suggested that chromium (Cr) is an essential cofactor for normal carbohydrate metabolism and affects insulin sensitivity, especially in rodent models. Several factors, such as insulin challenge, high carbohydrate intake, and response to stress (e.g., in obesity), alter Cr excretion or distribution. Glucagon is known to regulate carbohydrate metabolism and hyperglucagonemia plays a role in the development of hyperglycemia in diabetic subjects.

Chromium levels in insulin-sensitive tissues and the thigh bone are modulated by prednisolone and high-fat diets in mice

Glucocorticoids (GCs) are often prescribed in clinics but many adverse effects are also attributed to GCs. It is important to determine the role of GCs in the development of those adverse effects. Here, we investigated the impact of GCs on trivalent chromium (Cr) distribution in animals. Cr has been proposed to be important for proper insulin sensitivity, and deficits may lead to disruption of metabolism. For comparison, the effect of a high-fat diet on Cr modulation was also evaluated. C57BL/6JNarl mice were fed regular or high-fat diets for 12xa0weeks and further grouped for treatment with prednisolone or saline. Cr levels in tissues were determined 12xa0h after the treatments. Interestingly, prednisolone treatment led to significantly reduced Cr levels in fat tissue in mice fed regular diets; compared to the high-fat diet alone, prednisolone plus the high-fat diet led to a further reduction in Cr levels in the liver, muscle, and fat. Notably, a single dose of prednisolone was linked with elevated Cr levels in the thigh bones of mice fed by either regular or high-fat diets. In conclusion, this report has provided evidence that prednisolone in combination with a high-fat diet effects modulation of Cr levels in selected tissues.

Supplementation of Vitis thunbergii root extract alleviated high-fat diet-induced obesity in C57BL/6J mice.

Vitis thunbergii root, widely used as folk medicine in Taiwan, has been found to contain polyphenolic compounds and resveratrol derivatives, which have been implicated in the prevention and treatment of obesity. Thus, we hypothesized it might show beneficial effects against obesity. C57BL/6JNarl mice fed with a high fat diet for 14 weeks increased body weight and epididymal fat pad weight, and accompanied by fatty liver, hyperglycemia, hyperinsulinemia, insulin resistance, hyperleptinemia, hypercholesterolemia, hyper-LDL-cholesterol, and high level of serum GPT, GOT, creatinine, and BUN. Supplementation of VTE in the last 7 weeks remarkably decreased body weight and epididymal fat pad weight, implying a potential anti-obesity effect. Mechanistic study showed that VTE supplementation increased energy expenditure-related CPT1 mRNA expression and AMPK phosphorylation, and decreased lipogenesis-related SREBP-1 expression in liver. In conclusion, Vitis thunbergii roots could alleviate high fat diet-induced obesity and its related complications by enhancing hepatic fatty acid oxidation and inhibitng lipogenesis. Graphical Abstract Supplementation of the Vitis thunbergii roots could alleviate the high fat diet-induced obesity in mice

The Anti-cancer Effects of Resveratrol Combined with 5-fluorouracil Treatment in BALB/c Mice Bearing CT-26 Cells

Purpose. Resveratrol, a naturally phytoalexin, has antioxidant and anti-inflammatory properties and possesses chemopreventive and chemotherapeutic effects. The aim of this study was to undertake an evaluation of the therapeutic effect of resveratrol combined with 5-fluorouracil treatment on BALB/c mice (CT-26). Methods. Two experiments were used: treatment from day 1 after CT-26 cell implantation; and treatment from day 7 after CT-26 cell implantation with detection of tumor mass. Mice were randomly divided into four groups: feeding with saline; feeding with resveratrol (12.5 mg/kg/day); 5-fluorouracil injection (5-FU 100 mg/kg/week); and resveratrol feeding (12.5 mg/kg/day) combined with 5-FU injection (100 mg/kg/week). Results. The data showed resveratrol combined with 5-FU inhibited Cyclooxygenase-2 (COX-2) and β-catenin expression, increased GSK-3βexpression, suppressed Bcl-2 expression, and suppressed both tumor proliferation and mitosis. There were two major findings in this study. First, resveratrol inhibited COX-2 expression and down-regulated the WNT/β- catenin signaling pathway, which may be an apoptosis pathway. Second, resveratrol combined with 5-FU significantly decreased Bcl-2 expression and inhibited both PCNA expression and tumor proliferation. Conclusion. Resveratrol might elevate the chemosensitization of tumor cells. Resveratrol combined with 5-fluorouracil demonstrated a synergistic effect for cancer therapy. However, further research on resveratrol is required in order to confirm these findings and to develop new treatment strategies.