Osteopontin promotes age-related adipose tissue remodeling through senescence-associated macrophage dysfunction
Daigo Sawaki, Yanyan Zhang, Amel Mohamadi, Maria Pini, Zaineb Mezdari, Larissa Lipskaia, Suzain Naushad, Lucille Lamendour, Dogus Murat Altintas, Marielle Breau, Hao Liang, Maissa Halfaoui, Thaïs Delmont, Mathieu Surenaud, Déborah Rousseau, Takehiko Yoshimitsu, Fawzia Louache, Serge Adnot, Corneliu Henegar, Philippe Gual, Gabor Czibik, Geneviève Derumeaux
Daigo Sawaki, Yanyan Zhang, Amel Mohamadi, Maria Pini, Zaineb Mezdari, Larissa Lipskaia, Suzain Naushad, Lucille Lamendour, Dogus Murat Altintas, Marielle Breau, Hao Liang, Maissa Halfaoui, Thaïs Delmont, Mathieu Surenaud, Déborah Rousseau, Takehiko Yoshimitsu, Fawzia Louache, Serge Adnot, Corneliu Henegar, Philippe Gual, Gabor Czibik, Geneviève Derumeaux
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Research Article Aging Immunology

Osteopontin promotes age-related adipose tissue remodeling through senescence-associated macrophage dysfunction

Abstract

Adipose tissue macrophages (ATMs) play an important role in obesity and inflammation, and they accumulate in adipose tissue (AT) with aging. Furthermore, increased ATM senescence has been shown in obesity-related AT remodeling and dysfunction. However, ATM senescence and its role are unclear in age-related AT dysfunction. Here, we show that ATMs (a) acquire a senescence-like phenotype during chronological aging; (b) display a global decline of basic macrophage functions such as efferocytosis, an essential process to preserve AT homeostasis by clearing dysfunctional or apoptotic cells; and (c) promote AT remodeling and dysfunction. Importantly, we uncover a major role for the age-associated accumulation of osteopontin (OPN) in these processes in visceral AT. Consistently, loss or pharmacologic inhibition of OPN and bone marrow transplantation of OPN–/– mice attenuate the ATM senescence-like phenotype, preserve efferocytosis, and finally restore healthy AT homeostasis in the context of aging. Collectively, our findings implicate pharmacologic OPN inhibition as a viable treatment modality to counter ATM senescence-mediated AT remodeling and dysfunction during aging.

Authors

Daigo Sawaki, Yanyan Zhang, Amel Mohamadi, Maria Pini, Zaineb Mezdari, Larissa Lipskaia, Suzain Naushad, Lucille Lamendour, Dogus Murat Altintas, Marielle Breau, Hao Liang, Maissa Halfaoui, Thaïs Delmont, Mathieu Surenaud, Déborah Rousseau, Takehiko Yoshimitsu, Fawzia Louache, Serge Adnot, Corneliu Henegar, Philippe Gual, Gabor Czibik, Geneviève Derumeaux

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Figure 5

Transplantation of OPN-/- bone marrow rejuvenates VAT and improves metabolic function during aging.

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Transplantation of OPN-/- bone marrow rejuvenates VAT and improves metab...
(A) Protocol of BMT from WT or OPN–/– donor to WT recipient to evaluate the effect of OPN-deficient BMDMs in vivo. (B) qRT-PCR analysis of Spp1 (OPN) in VAT of WT recipients with WT or OPN–/– BMT (n = 4–5 mice/group). (C) Representative OPN immunofluorescence of VAT of WT recipients with WT or OPN–/– BMT and quantification of positive cells in percentage of total cell number (n = 5–7 mice/group). Arrowheads, OPN+ cells. (D) Representative SA-β-Gal staining in VAT of WT recipients with WT or OPN–/– BMT. (E) Representative p16/CD68 immunofluorescence of VAT from WT recipients with WT or OPN–/– BMT. Arrowheads, double-positive cells. (F and G) Quantification of p16+ cells in percentage of total cell number (F; n = 4 mice/group) or CD68+ cell number (G; n = 4 mice/group). (H) Distribution and difference of adipocyte size in VAT from WT or OPN–/– BMT mice. (I) qRT-PCR analysis of adipokine gene expression (leptin, Lep; adiponectin, Adipoq) in VAT of WT or OPN–/– BMT mice (n = 7–8 mice/group). (J) Glucose tolerance test, temporal plot, and area under curve (AUC) analysis (n = 7–9 mice/group). (K) Representative TUNEL/CD45 immunofluorescence of VAT from WT or OPN–/– BMT mice and quantification of TUNEL+ cells (green arrowheads) in percentage of total cell number (n = 4 mice/group). (L) Representative cleaved caspase-3/CD45 immunofluorescence and quantification in VAT of the same animals as above. Arrowheads, double-positive cells (n = 4 mice/group). (M) qRT-PCR analysis of Mertk in VAT of WT and OPN–/– BMT mice (n = 5–8 mice/group). All scale bars: 50 μm. Data are presented as original images (C–E, K, and L) or individual values with mean ± SEM and analyzed with 2-tailed, unpaired Student’s t test (B, C, and F–M); ns, nonsignificant; *P < 0.05, **P < 0.01, ***P < 0.001.