Background: Type 2 diabetes mellitus (T2DM) is characterized by chronic inflammation and dysregulated energy homeostasis. Complement C3a receptor 1 (C3aR1), a component of the complement system, plays a pivotal role in hypothalamic inflammation and the disruption of appetite regulation and energy metabolism. Concurrently, uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is a key mediator of adaptive thermogenesis and energy expenditure. Aerobic exercise training may exert beneficial effects on metabolic control in diabetes through the modulation of inflammatory pathways and the enhancement of BAT function.

Methods: In this experimental study, 36 male Wistar rats (age: 8 weeks; initial body weight: 180–220 g) were randomly allocated into four groups (n=9 per group): control, diabetic, exercise, and diabetic + exercise. T2DM was induced using a high-fat diet combined with a low-dose streptozotocin injection. The aerobic exercise protocol consisted of treadmill running at progressive speeds of 18–33 m/min, 5 sessions per week, with session duration incrementally increasing from 20 min in the first week to 60 min in the final week, over a 12-week intervention period. Gene expression and protein levels of C3aR1 and UCP1 in hypothalamic tissue and BAT were quantified using real-time polymerase chain reaction (RT-PCR) and western blotting, respectively. Histomorphological changes in BAT, including adipocyte area, adipocyte number, and mitochondrial density and area, were evaluated by stereological analysis. Serum metabolic parameters were also assessed. Data were analyzed using one-way analysis of variance (ANOVA) followed by the least significant difference (LSD) post hoc test, with statistical significance set at 𝑝 < 0.05.

Results: Diabetes significantly downregulated hypothalamic c3ar1 gene expression while concurrently upregulating its protein levels. Aerobic exercise training reversed this pathological pattern, as evidenced by increased c3ar1 mRNA expression and decreased protein levels. UCP1 protein levels in BAT were significantly elevated in the diabetic + exercise group, although hypothalamic ucp1 gene expression did not differ significantly across groups. Stereological analysis revealed that aerobic exercise significantly reduced brown adipocyte size, increased adipocyte number, and enhanced both mitochondrial area and count in the exercise-trained groups. Furthermore, the diabetic + exercise group exhibited a significant reduction in food intake alongside improved metabolic indices, including decreased fasting blood glucose and a favorable lipid profile.

Conclusion: Aerobic exercise training confers metabolic improvements, modulates complement-dependent inflammatory signaling in the hypothalamus, and promotes structural remodeling of BAT. Stereological analysis of BAT demonstrated increased cell number, reduced cell area, and enhanced mitochondrial number and area in the exercise-trained groups. These findings suggest that the hypothalamus–BAT axis plays a critical role in mediating the beneficial effects of exercise on T2DM.