Attenuation of Diet-Induced Obesity and Impaired Glucose Homeostasis by IL-2/Anti-IL-2 Complex and Hyperbaric Oxygen

Abstract

Obesity is characterized by chronic inflammation and impaired glucose homeostasis. Regulatory T cells (Tregs) preserve immunometabolic balance, and their reduction contributes to metabolic disturbances. Although IL-2/anti–IL-2 complex (IL-2C) and hyperbaric oxygen (HBO) therapy expand Tregs, their combined effects on obesity remain unclear. Male C57BL/6 mice fed a low-fat diet (LFD) or high-fat diet (HFD) for 16 weeks and treated with IL-2C and/or HBO. Both interventions significantly reduced HFD-induced body weight (9–22%, P < 0.05) independent of caloric intake, with no significant changes in LFD groups. Glucose tolerance and insulin sensitivity improved, showing significant reductions in IPGTT and IPITT area under the curve values (20–25% and 30–35%, respectively, P < 0.05) compared to the HFD control. Combination therapy produced the most consistent metabolic improvements. Histological analysis demonstrated reduced adipocyte hypertrophy and crown-like structures in epididymal adipose tissue (P < 0.05). Treatments restored CD4+FoxP3+ Tregs, suppressed pro-inflammatory M1 macrophages, and decreased hypoxia-inducible factor-1α expression (P < 0.05). Consistent with these findings, histological examination revealed tissue-specific structural remodeling, characterized by restored multilocular adipocytes in iBAT and reduced adipocyte hypertrophy in iWAT under HFD conditions. These findings suggest that IL-2C and HBO improve immunometabolic dysfunction associated with obesity, in parallel with favorable adipose tissue remodeling and metabolic adaptation. Thus, IL-2C and HBO may represent complementary therapeutic strategies for enhancing metabolic health.