The Proteomic Analysis of Intermittent Fasting Alone or with GLP-1RA in NAFLD Rats

Intermittent fasting (IF) and glucagon-like peptide-1 receptor agonists (GLP-1RA) offer effective therapeutic options for nonalcoholic fatty liver disease (NAFLD). This study aimed to examine the effects of alternate-day fasting (ADF) alone and with liraglutide, and to explore the mechanisms behind each treatment.

To establish the model for NAFLD, Sprague-Dawley rats were given a high-fat diet for 25 weeks. Subsequently, the rats were assigned to the ADF, ADF combined with liraglutide (A+L), and control groups for an additional 5 weeks. Evaluations were performed on liver morphology, body weight, serum lipid profiles, insulin sensitivity, and liver proteomics.

Compared to the control group, ADF alone demonstrated a reduction in body weight (37.1±15.56 g vs -20.68±15.58 g, p<0.05), food intake (0.30±0.002 g/d/rat vs 0.18±6.21 g/d/rat), blood lipid levels, and ALT concentration (139.0±15.57 U/L vs 91.25±41.9 U/L, p<0.05), while also improving the NAFLD score. Furthermore, ADF in conjunction with liraglutide exhibited superior effects in reducing body weight (-96.15±15.78 g), food intake (-10.25±0.01 g/d/rat), triglyceride (17.53±0.25 nmol/L), and LDL concentrations (6.93±0.35mmol/L), as well as ameliorating insulin resistance and lowering the NAFLD score relative to the ADF group (p<0.05). The proteomic analysis indicates that G protein-coupled receptor 39 (GPR39) and transmembrane protein 41b (Tmem41b) were significantly upregulated in the A+L group compared to the other two groups. Additionally, hydroxysteroid 17β-dehydrogenase 2 (HSD17B2) was significantly diminished in both the ADF and A+L groups relative to the control group.

Intermittent fasting, in conjunction with GLP-1RA, further enhances metabolic health in individuals with NAFLD as a result of obesity. This study provides support for forthcoming clinical trials and aims to establish new therapeutic targets in the context of NAFLD.