Editors' ChoiceImmunology

Fat and Susceptible to Infection

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Science Signaling  07 Jul 2009:
Vol. 2, Issue 78, pp. ec224
DOI: 10.1126/scisignal.278ec224

Obesity is associated with increased susceptibility to infection, an effect that may be due to the decreased function of macrophages. Zhou et al. investigated the response of mouse bone marrow macrophages (BMM) from lean mice and those with diet-induced obesity (DIO) to Porphyromonas gingivalis, a cause of periodontitis in humans. DIO mice exhibited decreased induction of inducible nitric oxide synthase (iNOS), affecting both the mRNA and protein. P. gingivalis is recognized by Toll-like receptor 2 (TLR2) and, compared with that of BMM from the lean mice, the abundance of the TLR2 transcript in BMM from DIO mice was markedly reduced, as were the transcripts for iNOS and tumor necrosis factor–α, even after infection with P. gingivalis. Out of several phosphorylated signaling proteins analyzed for activation in response to P. gingivalis, only Akt phosphorylation was reduced in the BMM from DIO mice compared with that in the BMM from lean mice. Indeed, knockdown of Akt in BMM from lean mice produced a similarly compromised response in cytokine production and iNOS induction to P. gingivalis as that seen in BMM from DIO mice. The authors found that of the possible negative regulators of Akt, only the abundance of C-terminal modulator protein (CTMP) was altered (in this case increased) in BMM from DIO mice; the abundance of the lipid phosphatase PTEN and the protein phosphatase PP2A were unchanged. The importance of CTMP was confirmed by reduced basal and P. gingivalis–stimulated Akt phosphorylation in a human monocyte cell line overexpressing CTMP. Treatment of BMMs from lean mice with the free fatty acids palmitate and oleate increased the abundance of CTMP and reduced the phosphorylation of Akt and induction of iNOS, as well as the production of cytokines, in response to P. gingivalis. Thus, free fatty acids, which contribute to DIO, also attenuate macrophage responsiveness, thereby compromising the body's response to infection.

Q. Zhou, S. E. Leeman, S. Amar, Signaling mechanisms involved in altered function of macrophages from diet-induced obese mice affect immune responses. Proc. Natl. Acad. Sci. U.S.A. 106, 10740–10745 (2009). [Abstract] [Full Text]

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