OC30 - Effects of liraglutide and exercise on liver function in middle-aged rats

Hepatic function progressively declines with age, contributing to metabolic dysregulation and increased susceptibility to chronic diseases. The liver plays a central role in metabolism regulation, detoxification, and systemic homeostasis, thus, preserving its function is essential for healthy aging. While liraglutide and strength- endurance training have demonstrated efficacy in managing type 2 diabetes and obesity, their potential benefits in healthy middle-aged individuals remains poorly understood. To address this, we first compared young (CY; 4-month-old) and middle-aged (C; 16- month-old) male rats to assess age-related changes. Next, middle-aged rats were treated with liraglutide (L; Saxenda® 0.186 mg/kg/day subcutaneously, human equivalent dose 1.8 mg), subjected to strength-endurance training (E; ladder climbing 3x/week with 25–50% body weight load), or both (L+E), to evaluate effects on liver morphology and function. Middle-aged males showed lower (p<0.05) serum testosterone, increased (p<0.05) adipose tissue-to-body weight ratio, decreased (p<0.05) liver-to-body weight ratio, and elevated (p<0.05) serum cholesterol and non-HDL cholesterol, but preserved glycemic control compared to young rats. Liraglutide significantly reduced (p<0.001) body mass and visceral fat. Triglycerides serum concentration decreased (p<0.05) in L and L+E groups compared to C. Hepatic Hmgcr expression, encoding the rate-limiting enzyme in cholesterol biosynthesis, was downregulated (p<0.05) in the E group, while Cyp7a1, responsible for cholesterol catabolism, was significantly upregulated (p < 0.001) in L+E. Additionally, Fasn expression, essential for lipogenesis, decreased (p<0.05) in E and L+E groups. Hepatic ALT levels were reduced (p< 0.05) in L group, indicating hepatoprotection. Oxidative stress and lipid peroxidation indexes in the liver were elevated by exercise alone but were significantly lower (p<0.05) in both L and L+E groups compared to controls or exercise alone, demonstrating that liraglutide mitigated the exercise-induced redox imbalance. However, PAS staining revealed increased (p<0.05) glycogen content only in the E group. In summary, liraglutide improved metabolic health and liver function while reducing exercise-induced oxidative stress. When combined with exercise, it modulated the expression of hepatic genes involved in lipid metabolism. These findings suggest overall benefits for liver health in middle-aged rats.