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

Qingde Zhou^a, Susan E. Leeman^b,1, and Salomon Amar^a,1

^aDepartment of Periodontology and Oral Biology, School of Dental Medicine; and ^bDepartment of Pharmacology, School of Medicine, Boston University, Boston, MA 02118

Received for publication April 3, 2009.

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 (BMM) from mice with DIO exposed to an oral pathogen, Porphyromonas gingivalis. BMM from lean mice pre-treated with free fatty acids (FFAs) and exposed to P. gingivalis also exhibit a diminished induction of iNOS and cytokines. BMM from lean and obese mice exposed to P. gingivalis and analyzed by a phosphorylation protein array show a reduction of Akt only in BMM from mice with DIO. This reduction is responsible for diminished NF-B activation and diminished induction of iNOS and cytokines. We next observed that Toll-like receptor 2 (TLR2) is suppressed in BMM 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 BMM from lean mice, both FFAs and TNF-—via separate pathways—induce an increase in CMTP. However, in BMM from DIO mice, TLR2 can no longer inhibit the TNF--induced increase in CTMP caused by P. gingivalis challenge. This defect can then be restored by transfecting WT TLR2 into BMM 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--induced CTMP. These findings unveil a link between obesity and innate immunity.

Key Words: Akt phosphorylation • CTMP • innate immunity • iNOS • TLR2

Author contributions: S.A. designed research; Q.Z. and S.A. performed research; Q.Z. and S.A. contributed new reagents/analytic tools; Q.Z., S.E.L., and S.A. analyzed data; and Q.Z., S.E.L., and S.A. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0904412106/DCSupplemental.

¹To whom correspondence may be addressed. E-mail: samar{at}bu.edu or sleeman{at}bu.edu

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