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 3

Adipose tissue macrophages promote age-dependent VAT and metabolic abnormalities.

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Adipose tissue macrophages promote age-dependent VAT and metabolic abnor...
(A) Immune cell and monocyte/macrophage subpopulations in VAT of 3- and 12-month-old WT mice by FACS (n = 3–5/group). (B) Immune cell and macrophage subpopulations in VAT of 12-month-old WT and OPN–/– mice by FACS (n = 4–5/group). (C) Schematic protocol of liposome-clodronate (CLO-lip) treatment. (D) Representative CD68 immunofluorescence of VAT of 12-month-old WT mice treated with PBS or CLO (CD68, green; WGA, red; DAPI, blue), and quantification of positive cells (green) in the percentage of total cell number (DAPI; n = 4 mice/group). Arrowheads indicate CD68+ cells; scale bar: 50 μm. (E) Representative OPN Western blot analysis (with β-actin as loading control) and densitometric quantification (n = 3–4 mice/group) using protein lysates from VAT in 12-month-old WT mice treated with PBS or CLO. (F) Representative p16 immunofluorescence of VAT from 12-month-old WT mice treated with PBS or CLO (p16, green; WGA, red; DAPI, blue) and quantification of p16+ cells (green; n = 4 mice/group) in the percentage of total cells (DAPI); arrowheads indicate p16+ cells, scale bar = 50 μm. (G) Distribution and difference of adipocyte size in VAT derived from PBS- or CLO-treated 12-month-old WT mice. (H) Plasma adipokine levels by ELISA in PBS- or CLO-treated 12-month-old WT mice (n = 4–6 mice/group). (I and J) Glucose tolerance test (GTT) (I) and insulin tolerance test (ITT) (J), temporal plot and area under curve (AUC) analysis (n = 5–7 mice/group). Data are presented as original images (D–F) or individual values with mean ± SEM and analyzed with 2-tailed, unpaired Student’s t test (A, B, and D–J); ns, nonsignificant; *P < 0.05, **P < 0.01, ***P < 0.001.