Purpose <p>Exercise and probiotic supplementation are often investigated together as lifestyle-type strategies that may influence metabolic liver injury, but their combined effects on hepatic gene expression require further clarification. This paper investigates the impact of 6&#xa0;weeks of aerobic exercise (AE) and probiotic administration on changes in the liver genes Asprosin, betaterophin, Leap-2, and ORM2 in a high-fat diet (HFD) rat model.</p> Methods <p>This experimental research used 32 male Wistar rats (8&#xa0;weeks), assigned to HFD, HFD + AE, HFD + probiotic, and HFD + AE + probiotic groups. Rats in the HFD group received a 2-month high-fat diet, while animals in the aerobic exercise groups had to run on a rodent treadmill for 6&#xa0;weeks, 5&#xa0;days per week. The probiotic groups received <i>Bifidobacterium bifidum</i> BB-12 by gavage at 10⁹ CFU/ml after each aerobic exercise session. The real-time PCR method was utilized for gene expression measurement of asprosin, betaterophin, Leap-2, and ORM2 in the liver.</p> Results <p>The results showed that asprosin, betaterophin, and Leap-2 significantly decreased in all treatment groups (HFD + AE, HFD + probiotic, and HFD + AE + probiotic) compared to the HFD group (p &lt; 0.05). However, the combined intervention yielded greater reductions than individual treatments, particularly for ORM2 (p &lt; 0.05 vs. singles). In fact, liver ORM2 significantly declined in the HFD + AE + Pro animals compared to the HFD (p = 0.0025), the HFD + AE (p = 0.0266), and the HFD + Pro (p = 0.0176).</p> Conclusion <p>Lifestyle modifications, such as exercise and dietary probiotics, may be effective strategies to mitigate liver-related metabolic disorders.</p>