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Objective: To study the preventive effects of Fructus Phyllanthiin (FP) alone and combined with tea polyphenols (FP-TP) or L-carnitine (FP-LC) on high-fat diet-induced obesity in rats. Methods: The experimental, model control and positive control groups were fed a high-fat diet while the negative control group was fed a normal diet. Meanwhile, the experimental group was gavaged with FP, FP-TP or FP-LC for seven weeks. At the end of the gavage period, body mass, perirenal fat mass and peritesticular fat mass were measured, and four items of blood lipid tests in serum and liver lipid levels were detected. The levels of serum leptin, resistin and lipocalin were measured, and the activities of related enzymes and total protein levels in the liver and mRNA expression in adipose tissues were measured to observe the effects of FP and its combination with TP or LC on obesity alleviation and protection against liver injury in experimentally obese rats. Results: The body mass and body fat content of the rats in the model control group increased significantly when compared with the negative control group (P < 0.001). The rats in the FP and FP-LC intervention groups showed significant decreases in body mass, and perirenal fat and peritesticular fat contents and indexes. The levels of total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) in the serum and liver decreased significantly, and the level of high-density lipoprotein cholesterol (HDL-C) increased significantly. Moreover, serum leptin and resistin levels significantly dropped, and lipocalin levels increased; the activities of alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and the content of malondialdehyde (MDA) in the liver decreased, and the activity of superoxide dismutase (SOD) increased; the mRNA expression of adenosine 5’-monophosphate-activated protein kinase (AMPK) α-2 was significantly up-regulated in adipose tissues. On the other hand, FP-TP intervention had no significant anti-obesity effect. Conclusion: FP can prevent high-fat diet-induced obesity in rats, being more effective when used alone than when combined with TP or LC.