Beneficial Metabolic Effects of Mirabegron In Vitro and in High-Fat Diet-Induced Obese Mice.

Mirabegron, a ß3-adrenergic receptor agonist, has been shown to stimulate the activity of brown fat and increase the resting metabolic rate in humans. However, it is unknown whether mirabegron can reduce body weight and improve metabolic health. We investigated the antiobesity effects of mirabegron using both in vitro and in vivo models. Mouse brown preadipocytes and 3T3-L1 cells were treated with different concentrations of mirabegron (0.03-3 µg/ml), and the expression of brown fat-related genes was measured by quantitative real-time polymerase chain reaction. Furthermore, male C57BL/6J mice were fed a high-fat diet for 10 weeks, and mirabegron (2 mg/kg body weight) or a vehicle control was delivered to the interscapular brown adipose tissue (iBAT) using ALZET osmotic pumps from week 7 to 10. The metabolic parameters and tissues were analyzed. In both mouse brown preadipocytes and 3T3-L1 cells, mirabegron stimulated uncoupling protein 1 (UCP1) expression. In animal studies, mirabegron-treated mice had a lower body weight and adiposity. Lipid droplets in the iBAT of mirabegron-treated mice were fewer and smaller in size compared with those from vehicle-treated mice. H&E staining and immunohistochemistry indicated that mirabegron increased the abundance of beige cells in inguinal white adipose tissue (iWAT). Compared with vehicle-treated mice, mirabegron-treated mice had a higher gene expression of UCP1 (14-fold) and cell death-inducing DNA fragmentation factor alpha-like effector A (CIDEA) (4-fold) in iWAT. Furthermore, mirabegron-treated mice had improved glucose tolerance and insulin sensitivity. Taken together, mirabegron enhances UCP1 expression and promotes browning of iWAT, which are accompanied by improved glucose tolerance and insulin sensitivity and prevention from high-fat diet-induced obesity.

A 12-week evaluation of annatto tocotrienol supplementation for postmenopausal women: safety, quality of life, body composition, physical activity, and nutrient intake.

BACKGROUND: Evidence suggests that tocotrienols may benefit bone health in osteopenic women. However, their safety in this population has never been investigated. This study was to evaluate the safety of a 12-week supplementation of annato tocotrienol in postmenopausal osteopenic women, along with effects of the supplementation on quality of life, body composition, physical activity, and nutrient intake in this population. METHODS: Eighty nine postmenopausal osteopenic women were randomly assigned to 3 treatment arms: (1) Placebo (430 mg olive oil/day), (2) Low tocotrientol (Low TT) (430 mg tocotrienol/day from DeltaGold 70 containing 300 mg tocotrienol) and (3) High tocotrienol (High TT) (860 mg tocotrienol/day from DeltaGold 70 containing 600 mg tocotrienol) for 12 weeks. DeltaGold 70 is an extract from annatto seed with 70% tocotrienol consisting of 90% delta-tocotrienol and 10% gamma-tocotrienol. Safety was examined by assessing liver enzymes (aspartate aminotransferase, alanine aminotransferase), alkaline phosphatase, bilirubin, kidney function (blood urea nitrogen and creatinine), electrolytes, glucose, protein, albumin, and globulin at 0, 6, and 12 weeks. Serum tocotrienol and tocopherol concentrations were assessed and pills counted at 0, 6, and 12 weeks. Quality of life, body composition, physical activity, and dietary macro- and micro-nutrient intake were evaluated at 0 and 12 weeks. A mixed model of repeated measures ANOVA was applied for analysis. RESULTS: Eighty seven subjects completed the study. Tocotrienol supplementation did not affect liver or kidney function parameters throughout the study. No adverse event due to treatments was reported by the participants. Tocotrienol supplementation for 6 weeks significantly increased serum delta-tocotrienol level and this high concentration was sustained to the end of study. There was no difference in serum delta-tocotrienol levels between the Low TT and the High TT groups. No effects of tocotrienol supplementation were observed on quality of life, body composition, physical activity, and nutrient intake. CONCLUSIONS: Annatto-derived tocotrienol up to 600 mg per day for 12 weeks appeared to be safe in postmenopausal osteopenic women, particularly in terms of liver and kidney functions. Tocotrienol supplementation for 12 weeks did not affect body composition, physical activity, quality of life, or intake of macro- and micro-nutrients in these subjects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02058420 . TITLE: Tocotrienols and bone health of postmenopausal women.

Indomethacin Enhances Brown Fat Activity.

Indomethacin, a nonsteroidal anti-inflammatory drug, has been shown to induce white adipocyte differentiation; however, its roles in brown adipocyte differentiation and activation in brown adipose tissue (BAT) and obesity are unknown. To address this issue, we treated mouse brown preadipocytes with different doses of indomethacin, and delivered indomethacin to interscapular BAT (iBAT) of obese mice using implanted osmotic pumps. Indomethacin dose dependently increased brown preadipocyte differentiation and upregulated both mRNA and protein expression of uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor (PPAR) γ coactivator 1-alpha. The mechanistic study showed that indomethacin significantly activated the reporter driven by the PPAR response element, indicating that indomethacin may work as a PPARγ agonist in this cell line. Consistently, indomethacin significantly decreased iBAT mass and fasting blood glucose levels in high-fat diet-induced obesity (DIO) mice. Histologic analysis showed that brown adipocytes of indomethacin-treated mice contained smaller lipid droplets compared with control mice, suggesting that indomethacin alleviated the whitening of BAT induced by the high-fat diet. Moreover, indomethacin significantly increased UCP1 mRNA expression in iBAT. Taken together, this study indicates that indomethacin can promote mouse brown adipocyte differentiation, and might increase brown fat and glucose oxidation capacity in DIO mice.