JCI Insight (Apr 2023)

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

Journal volume & issue
Vol. 8, no. 8

Abstract

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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.

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