Addressing the adverse effects of high-carbohydrate diets (HCD) on fish growth and health has been a critical area of aquaculture research, as it remains a key factor limiting the broader application of HCD in the industry. Recent studies have focused on the liver mechanisms involved in HCD-induced challenges, while limited attention has been given to adipose tissue. This study investigated the impact of enhancing adipocyte hyperplasia on growth performance, immunity, antioxidative capacity, inflammation, and metabolism in grass carp (Ctenopharyngodon idellus) subjected to an HCD. Rosiglitazone (R), a peroxisome proliferator-activated γ agonist, was used to promote adipocyte hyperplasia. A total of 225 grass carp (initial body weight, 19.05 ± 0.06 g) were divided into three groups (control, HCD, and HCD + R) and fed for 8 weeks, with three replicates per group. The findings indicated that HCD induced inflammation, fibrosis, and metabolic disorders in adipose tissue, which were significantly alleviated following the promotion of adipocyte hyperplasia (P <
0.05). Improvement in the health status of adipose tissue resulted in a significant reduction in the pro-inflammatory cytokine interleukin-1β (IL-1β) produced and secreted by adipose tissue. In contrast, IL-1 receptors and downstream related genes in the liver and muscle were significantly downregulated (P <
0.05). Furthermore, promoting adipocyte hyperplasia alleviated hepatic steatosis and enhanced muscle protein synthesis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TG), glucose (GLU), and lactate dehydrogenase (LDH) returned to normal after promoting adipocyte hyperplasia. Notably, promoting adipocyte hyperplasia enhanced anti-oxidant enzyme activities in the serum and significantly improved immune function in the grass carp (P <
0.05). These enhancements contributed to improved growth performance and feed efficiency. Conclusively, modifying the pattern of adipose tissue expansion by promoting adipocyte hyperplasia mitigated the adverse effects of HCD on health and growth performance while enhancing both anti-oxidant and immune capacities in grass carp.