Anti-obesity effects of narirutin and hesperidin in immature Citrus reticulata extract via AMPK activation in high-fat diet-fed mice

Obesity, a major global health concern, increases the risk of various diseases. Citrus reticulata, commonly used in traditional medicine, contains bioactive compounds that have potential metabolic benefits. The aim of the study was to assess the effects of immature C. reticulata extract (ICRE) and its key bioactive compounds, narirutin and hesperidin, in a mouse model of obesity. Six-week-old C57BL/6N mice were fed either a normal or high-fat diet for 12 weeks and treated with 100, 150, or 200 mg/kg ICRE or 2 mg/kg narirutin and hesperidin. Body weight, adipocyte size, serum lipase activity, and serum levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and blood glucose were measured. Leptin and leptin receptor mRNA expression levels were analyzed in adipose tissue, along with mRNA and protein expression levels of AMP-activated protein kinase (AMPK) pathway-related molecules and markers of fatty acid oxidation and lipid synthesis. ICRE significantly reduced body weight and adipocyte size, improved lipid profiles, and decreased leptin levels and lipase activity in mice receiving a high-fat diet. It also enhanced AMPK activation, promoted fatty acid oxidation, and inhibited lipid synthesis. These effects were more pronounced than those observed with narirutin and hesperidin. ICRE demonstrated superior efficacy compared with narirutin and hesperidin by more effectively regulating lipid metabolism and energy expenditure through the AMPK pathway, leading to greater reductions in fat accumulation and improved metabolic outcomes. These findings suggest that ICRE is a promising natural therapeutic agent for obesity management.