NYMC Faculty Publications
Signaling Mechanisms Involved in Altered Function of Macrophages From Diet-Induced Obese Mice Affect Immune Responses
Author Type(s)
Faculty
Additional Author Affiliation
Touro College of Dental Medicine at NYMC
DOI
10.1073/pnas.0904412106
Journal Title
Proceedings of the National Academy of Sciences of the United States of America
First Page
10740
Last Page
10745
Document Type
Article
Publication Date
6-30-2009
Department
Pharmacology
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 (BMMPhi) from mice with DIO exposed to an oral pathogen, Porphyromonas gingivalis. BMMPhi from lean mice pre-treated with free fatty acids (FFAs) and exposed to P. gingivalis also exhibit a diminished induction of iNOS and cytokines. BMMPhi from lean and obese mice exposed to P. gingivalis and analyzed by a phosphorylation protein array show a reduction of Akt only in BMMPhi from mice with DIO. This reduction is responsible for diminished NF-kappaB activation and diminished induction of iNOS and cytokines. We next observed that Toll-like receptor 2 (TLR2) is suppressed in BMMPhi 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 BMMPhi from lean mice, both FFAs and TNF-alpha--via separate pathways--induce an increase in CMTP. However, in BMMPhi from DIO mice, TLR2 can no longer inhibit the TNF-alpha-induced increase in CTMP caused by P. gingivalis challenge. This defect can then be restored by transfecting WT TLR2 into BMMPhi 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-alpha-induced CTMP. These findings unveil a link between obesity and innate immunity.
Recommended Citation
Zhou, Q., Leeman, S., & Amar, S. (2009). Signaling Mechanisms Involved in Altered Function of Macrophages From Diet-Induced Obese Mice Affect Immune Responses. Proceedings of the National Academy of Sciences of the United States of America, 106 (26), 10740-10745. https://doi.org/10.1073/pnas.0904412106
