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Brown adipose tissue (BAT) has long been recognized as an energy-consuming organ and a possible target for combating metabolism disorder. Although numerous studies have demonstrated the ability of phytochemical phenolic acids to improve obesity by activating BAT, the underlying mechanism or mechanism therein remain obscure. In this study, diet-induced obese mice, genetically obese mice, and C3H10T1/2 cells were used to examine the effects of p-Coumaric acid (CA) on metabolism profiles. The results showed that CA prevented metabolic syndromes in the two mice models through the activation of BAT. This phenomenon was closely linked to the upregulation of uncoupling protein 1 (UCP1) and the accelerated burning of fatty acids and glucose, which consequently enhanced the energy expenditure and thermogenesis. Similar results were also obtained in vitro. Importantly, these effects were mediated by the mammalian target of rapamycin complex 1 (mTORC1)-RPS6 pathway. These findings reveal, to the best of our knowledge for the first time, the close correlation between mTORC1-RPS6 and BAT-mediated thermogenesis, and, in addition, the key role played by mTORC1-RPS6 in mediating phenolic acids-induced activation of BAT, thus preventing obesity., (© 2020 Federation of American Societies for Experimental Biology.)

Scope: Although the physiological function of grape extract (GE) has long been recognized, the precise mechanism remains obscure. This study is designed to investigate the effects of GE on metabolism and the association between GE activation of brown adipose tissue (BAT) and the restoration of gut microbiota (GM)., Methods and Results: Diet-induced obese mice are used to investigate the function of GE. GE administration increases energy metabolism and prevents obesity. Also, GE restores the dysbiosis of GM by augmenting the observed species, enhancing the Firmicutes-to-Bacteroidetes ratio and increasing the abundance of the Bifidobacteria, Akkermansia, and Clostridia genera. This restoration of GM alters the bile acid (BA) pool in the serum. The abundance of Akkermansia, Clostridium, and Bifidobacterium is negatively correlated with the concentrations of TαMCA, TβMCA, and TCA but is positively correlated with DCA. The changes in BA promoted TGR5 in BAT, which contributed to thermogenesis. The metabolites of GE in blood do not stimulate TGR5 in vitro., Conclusion: GE stimulates the thermogenesis of BAT through a pathway involving the regulation of GM and BA in diet-induced obese mice. This study reveals the mechanism by which dietary polyphenols promote thermogenesis by regulating BA, which is altered by GM., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Anthocyanins have a positive effect on resistant obesity; however they cannot usually be absorbed directly but, instead, are metabolized by gut microbiota. This study will examine the effects and the mechanism of vanillic acid on the prevention of obesity induced by diet, which is one of the anthocyanin metabolites. We fed C57BL/6J mice vanillic acid supplements in a high fat and high fructose diet for 16 weeks. Body weight, fat pat weight, and food and water intake were monitored. Glucose homeostasis was assessed with a glucose or insulin tolerance test. The sizes of adipose cells and lipid droplets were analyzed by histology staining, while the expression of genes and proteins was analyzed by quantitative real-time PCR, western blot and tissue-blot immunoassay. The results demonstrated that vanillic acid contributed to the reduction of body weight gain, improved glucose tolerance and insulin resistance, and maintained body temperature. Furthermore, vanillic acid was found to promote thermogenesis and mitochondrial synthesis of brown adipose tissue and inguinal white adipose tissue. This study demonstrated that vanillic acid could prevent obesity by activating BAT thermogenesis and the promotion of inguinal WAT browning.

Scope: Obesity develops when energy intake exceeds energy expenditure. Promoting brown adipose tissue (BAT) formation and function increases energy expenditure and may protect against obesity. Cyanidin-3-glucoside (C3G) is an anthocyanin compound that occurs naturally in many fruits and vegetables. In this study, we investigated the effect and mechanism of C3G on the prevention of obesity., Methods and Results: Db/db mice received C3G dissolved in drinking water for 16 wk; drinking water served as the vehicle treatment. The total body weight, energy intake, metabolic rate, and physical activity were measured. The lipid droplets, gene expression and protein expression were evaluated by histochemical staining, real-time PCR, and western blots. We found that C3G increased energy expenditure, limited weight gain, maintained glucose homeostasis, reversed hepatic steatosis, improved cold tolerance, and enhanced BAT activity in obese db/db mice. C3G also induces brown-like adipocytes (beige) formation in subcutaneous white adipose tissue (sWAT) of db/db mice model. We also found that C3G potently regulates the transcription of uncoupling protein 1 (UCP1) both in BAT and sWAT through increasing mitochondrial number and function., Conclusion: Our results suggest that C3G plays a role in regulating systemic energy balance, which may have potential therapeutic implications for the prevention and control of obesity., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Increasing energy expenditure through activation of brown adipose tissue (BAT) is a critical approach to treating obesity and diabetes. In this study, rutin, a natural compound extracted from mulberry and a drug used as a capillary stabilizer clinically for many years without any side effects, regulated whole-body energy metabolism by enhancing BAT activity. Rutin treatment significantly reduced adiposity, increased energy expenditure, and improved glucose homeostasis in both genetically obese (Db/Db) and diet-induced obesity (DIO) mice. Rutin also induced brown-like adipocyte (beige) formation in subcutaneous adipose tissue in both obesity mouse models. Mechanistically, we found that rutin directly bound to and stabilized SIRT1, leading to hypoacetylation of peroxisome proliferator-activated receptor γ coactivator-1α protein, which stimulated Tfam transactivation and eventually augmented the number of mitochondria and UCP1 activity in BAT. These findings reveal that rutin is a novel small molecule that activates BAT and may provide a novel therapeutic approach to the treatment of metabolic disorders.-Yuan, X., Wei, G., You, Y., Huang, Y., Lee, H. J., Dong, M., Lin, J., Hu, T., Zhang, H., Zhang, C., Zhou, H., Ye, R., Qi, X., Zhai, B., Huang, W., Liu, S., Xie, W., Liu, Q., Liu, X., Cui, C., Li, D., Zhan, J., Cheng, J., Yuan, Z., Jin, W. Rutin ameliorates obesity through brown fat activation., (© FASEB.)

Increasing evidence indicates that brown adipose tissue (BAT) transplantation enhances whole-body energy metabolism in a mouse model of diet-induced obesity. However, it remains unclear whether BAT also has such beneficial effects on genetically obese mice. To address this issue, we transplanted BAT from C57/BL6 mice into the dorsal subcutaneous region of age- and sex-matched leptin deficient Ob/Ob mice. Interestingly, BAT transplantation led to a significant reduction of body weight gain with increased oxygen consumption and decreased total body fat mass, resulting in improvement of insulin resistance and liver steatosis. In addition, BAT transplantation increased the level of circulating adiponectin, whereas it reduced the levels of circulating free T3 and T4, which regulate thyroid hormone sensitivity in peripheral tissues. BAT transplantation also increased β3-adrenergic receptor and fatty acid oxidation related gene expression in subcutaneous and epididymal (EP) white adipose tissue. Accordingly, BAT transplantation increased whole-body thermogenesis. Taken together our results demonstrate that BAT transplantation may reduce obesity and its related diseases by activating endogenous BAT.

Mulberry extract (ME) has been shown to possess beneficial effects towards obesity, but its mechanism is still unclear. In small mammals, mitochondria enriched brown adipose tissue (BAT) is known to convert protein's electrochemical energy to heat and maintain a constant body temperature. Improving the mitochondrial function or increasing the number of mitochondria could promote the metabolism of carbohydrate and fat. Thus, this study was designed to investigate the mitochondrial function regulated by ME and mulberry wine extract (MWE) during the brown adipogenesis. The C3H10T1/2 mesenchymal stem cell was treated with ME and MWE, both of which significantly (p < 0.05) increased the expression levels of fatty acid oxidation related genes such as peroxisome proliferator-activated receptor-γ coactivator-1α, PR domain-containing 16 and carnitine palmitoyltransferase 1α during brown adipogenesis. These changes were accompanied with increases in mitochondrial oxidative complex proteins upon ME and/or MWE exposure. Notably, ME and/or MWE also significantly (p < 0.05) increased the expression of the transcription factor A and the nuclear respiratory factor-1, which are the key transcription factors of mitochondrial biogenesis. In parallel, the mitochondrial copy number and brown adipose tissue specific gene-uncoupling protein-1 expression were dramatically (p < 0.05) elevated after ME or MWE treatment. Cyanidin-3-glucoside (Cy-3-glu) was found to be one of the most abundant anthocyanins in ME and MWE. Therefore, the BAT regulatory activity of ME and MWE might be, at least in part, due to the effect of Cy-3-glu. These results suggested that ME and MWE could ameliorate metabolic disease through an improvement in mitochondrial functions.