Simulation Effect and Mechanism of High-Polymeric Persimmon Tannin on Simulating Alternate-Day Fasting on Regulating Lipid Metabolism in Obese Mice

Background/Objectives: Obesity represents a significant global health challenge. Although alternate-day fasting (ADF) has been shown to effectively improve metabolic parameters, long-term adherence to this regimen remains limited. This study aimed to investigate whether highly polymerized persimmon tannin (DP31) could serve as a practical alternative to ADF for the prevention of high-fat diet (HFD)-induced obesity in mice. Methods: Male C57BL/6J mice (n = 10 per group) were subjected to an HFD for 11 weeks, during which they concurrently received either DP31 or ADF. Body weight, fat mass, serum lipid levels, glucose tolerance, fasting glucose, and insulin levels were assessed. Additionally, hepatic transcriptomics, Western blotting, 16S rRNA sequencing, and short-chain fatty acids (SCFAs) analysis were conducted. Results: DP31 demonstrated comparable efficacy to ADF in reducing body weight gain and improving lipid profiles, while exhibiting superior effects on glucose tolerance and fasting glucose levels (p < 0.05). Both interventions effectively reversed HFD-induced hepatic gene dysregulation, leading to the upregulation of genes involved in processes related to steroid metabolism. In addition, both treatments activated the hepatic AMPK-mTORC1-Lpin1 axis, suppressed lipogenesis, upregulated PGC1α, and increased β-hydroxybutyrate levels, indicating enhanced fatty acid oxidation (p < 0.05). Notably, DP31 outperformed ADF in enriching beneficial gut genera, such as Akkermansia, and boosting SCFAs production, which may elucidate its superior glycemic control. Overall, DP31 exhibits comparable effects to ADF in preventing obesity-related metabolic disorders, while demonstrating superior effects on glucose homeostasis.