Hyaluronan has diverse biological activities depending on its molecular size. The hyaluronan fragments (50 kDa) can decrease adipogenic differentiation in vitro. However, in vivo anti-obesitic effects of hyaluronan fragments have not been elucidated. Therefore, we examined the anti-obesity effects of hyaluronan fragments on high-fat diet induced obesity in C57BL/6 mice. Oral administration of hyaluronan fragments (200 mg/kg for 8 weeks) decreased body weight, adipose tissues, serum lipid (low-density lipoprotein cholesterol, triglyceride), and leptin level. Hyaluronan fragments decreased the hypertrophy of adipose tissue and ameliorated liver steatosis. The mRNA expression of leptin was reduced in adipocyte by treatment with hyaluronan fragments. Additionally, hyaluronan fragments enhanced the mRNA expression of PPAR-alpha and its target genes UCP-2 and decreased mRNA expression of PPAR- gamma and fatty acid synthase in liver. In conclusions, hyaluronan fragments had marked effects on inhibiting the development of obesity in obese mice fed the high-fat diet. It suggested that enhancing PPAR-alpha and suppressing PPAR-gamma expression are two possible mechanisms for the anti-obesitic effect of hyaluronan fragments. (C) 2016 Elsevier Inc. All rights reserved.