Signaling mechanisms in the restoration of impaired immune function due to diet-induced obesity

Our previous data have linked obesity with immune dysfunction. It is known that physical exercise with dietary control has beneficial effects on immune function and the comorbidities of obesity. However, the mechanisms underlying the improvement of immune function in obesity after physical exercise with dietary control remain unknown. Here we show that moderate daily exercise with dietary control restores the impaired cytokine responses in diet-induced obese (DIO) mice and improves the resolution of Porphyromonas gingivalis-induced periodontitis. This restoration of immune responses is related to the reduction of circulating free fatty acids (FFAs) and TNF. Both FFAs and TNF induce an Akt inhibitor, carboxyl-terminal modulator protein (CTMP). The expression of CTMP is also observed increased in bone marrow-derived macrophages (BMM Phi) from DIO mice and restored after moderate daily exercise with dietary control. Toll-like receptor 2 (TLR2), which increases CTMP induction by FFAs, is inhibited in BMM Phi from DIO mice or after either FFA or TNF treatment, but unexpectedly is not restored by moderate daily exercise with dietary control. Furthermore, BMM Phi from DIO mice display reduced histone H3 (Lys-9) acetylation and NF-kappa B recruitment to TNF, IL-10, and TLR2 promoters after P. gingivalis infection. However, moderate daily exercise with dietary control restores these defects at promoters for TNF and IL-10, but not for TLR2. Thus, metabolizing FFAs and TNF by moderate daily exercise with dietary control improves innate immune responses to infection in DIO mice via restoration of CTMP and chromatin modification.