Decoding the Anti-Obesity Mechanisms of Isoliquiritigenin: AMPK Activation Modulates Adipogenesis, Lipolysis, Oxidative Stress, and Inflammation in High-Fat Diet Rat Models

Abstract

This study investigated the effects of Isoliquiritigenin (ISL) on adiposity in Wistar rats fed a high-fat diet (HFD), positing that ISL mitigates adiposity by inhibiting adipogenesis and promoting lipolysis via AMPK activation. Adult male Wistar rats were divided into six groups (n=8): Control (vehicle), Control + ISL (40 mg/kg), HFD (vehicle), HFD + ISL (20 mg/kg), HFD + ISL (40 mg/kg), and HFD + ISL (40 mg/kg) + Dorsomorphin (0.2 mg/kg) for 12 weeks. In a dose-dependent manner, ISL (thrice a week) significantly attenuated the increase in body weight and adipocyte size, improving glucose and insulin tolerance, HbA1c, and HOMA-IR without affecting food intake in HFD rats. Particularly, the higher dose of ISL (40 mg/kg) significantly increased the phosphorylation of AMPK (+193.3%), resulting in a p-AMPK/AMPK activity ratio increase of 191.0% in the white adipose tissue (WAT) of HFD rats. This dose also reduces body weight (24.6%), weight gain (28.7), fat deposit weight (-39.2% %), HOMA-IR (-67.62%), and serum triglycerides (-62.4%), cholesterol (56.7%), IL-6 (-66.1%) and TNF-α (-79.5%) in these HFD rats. It also increased p-ACC levels (+86.7%), Nrf2 mRNA (+392.7%), and PPARα mRNA (+255.0%), as well as the levels of HSL (+149.7 %) and ATGL (139.62%). ISL (40 mg/kg) also decreased WAT levels of IL-6 (-57.86%), TNF-α (-74.96%), mRNA of SREBP1 (-38/8%), FAS (-50%) & NF-kB (58.8%), and levels of PLIN1 (-50.1) in these HFD rats. Dorsomorphin treatment reversed these effects in ISL + HFD rats. In conclusion, ISL demonstrates anti-obesity effects in HFD-induced rats through AMPK activation.