Emodin improves glucose and lipid metabolism disorders in obese mice via activating brown adipose tissue and inducing browning of white adipose tissue

Background: Obesity has become a worldwide health threat related to type 2 diabetes, hypertension, cardiovascular disease, etc. Activating brown adipocytes and inducing browning of white adipocytes has been proposed as a potential molecular target for obesity treatment. In the present study, we investigated the effects of emodin on browning in mice with high-fat diet (HFD) and explore its underlying pharmacological mechanisms. Methods: The positive effects of emodin (40, 80 mg/kg/day, i.g. for 6 weeks) on lipid metabolism were evaluated in mice model of hyperlipidemia. Hyperlipidemia mice were induced by high-fat diet (60% of kilocalories from fat, 5.24 Kcal/kg) for 8 weeks. Body weight and food intake were monitored every week. After 6 weeks of treatment, fasting blood glucose, oral glucose tolerance, Lee's index, the ratio of fat weight to body weight, blood lipids, and adipose tissues morphology were assayed. Then uncoupling protein 1 (UCP1), CD36, fatty acid transporter 4 (FATP4), peroxisome proliferator activated receptor α (PPARα) and prohibitin (PHB) protein of subcutaneous white adipose tissue (scWAT) and brown adipose tissue (BAT) were analyzed. In addition, the lipid metabolites in adipose tissues were analyzed by ultra-high- performance liquid chromatography with electrospray ionization tandem mass spectrometry.Results: Emodin treatment decreased body weight gain, fasting blood glucose, Lee's index, the ratio of scWAT weight to body weight, and the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c) and Leptin in serum, and increased serum adiponectin content and improved glucose tolerance. Furthermore, emodin enhanced the expression of UCP1, CD36, FATP4, PPARα and PHB protein in scWAT and BAT. Meanwhile, emodin can significantly up-regulated lipid levels in scWAT of mice fed with HFD such as PC(O-18:2/22:5), PE(O-18:1/18:2), PE(O-18:2/20:4), PE(O-20:1/20:5), Cer(d14:1/20:0) and SM(d18:0/23:0), and reduced the lipid levels such as PC(O-18:0/20:0), PE(O-18:2/22:2), PE(O-18:0/22:5). In addition, emodin significantly up-regulate lipid levels in BAT of mice fed with HFD such as PC(14:0/16:0), PC(16:0/16:1), PC(16:1/16:1), PC(15:1/18:3), PC(18:0/20:0), LysoPC(20:0), LysoPC(22:0) and LysoPC(22:1), and reduced the lipid levels PC(12:0/20:4) and PC(17:0/22:5). Conclusions: These results indicated that hyperlipidemia could be alleviated by treatment of emodin via promoting browning of white adipose tissue. In addition, the disturbance of some small lipid metabolites in adipose also could be reversed by emodin.