Signaling mechanisms involved in altered function of macrophages from diet-induced obese mice affect immune responses

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Abstract
Recent research links diet-induced obesity (DIO) with impaired immunity, although the underlying mechanisms remain unclear. We find that the induction of inducible NO synthase (iNOS) and cytokines is suppressed in mice with DIO and in bone marrow macrophages (BMMΦ) from mice with DIO exposed to an oral pathogen, Porphyromonas gingivalis. BMMΦ from lean mice pre-treated with free fatty acids (FFAs) and exposed to P. gingivalis also exhibit a diminished induction of iNOS and cytokines. BMMΦ from lean and obese mice exposed to P. gingivalis and analyzed by a phosphorylation protein array show a reduction of Akt only in BMMΦ from mice with DIO. This reduction is responsible for diminished NF-κB activation and diminished induction of iNOS and cytokines. We next observed that Toll-like receptor 2 (TLR2) is suppressed in BMMΦ from DIO mice whereas carboxy-terminal modulator protein (CTMP), a known suppressor of Akt phosphorylation, is elevated. This elevation stems from defective TLR2 signaling. In BMMΦ from lean mice, both FFAs and TNF-α—via separate pathways—induce an increase in CMTP. However, in BMMΦ from DIO mice, TLR2 can no longer inhibit the TNF-α-induced increase in CTMP caused by P. gingivalis challenge. This defect can then be restored by transfecting WT TLR2 into BMMΦ from DIO mice. Thus, feeding mice a high-fat diet over time elevates the CTMP intracellular pool, initially via FFAs activating TLR2 and later when the defective TLR2 is unable to inhibit TNF-α-induced CTMP. These findings unveil a link between obesity and innate immunity.