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TM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction

Author

Listed:
  • Cheoljun Choi

    (Seoul National University)

  • Yujin L. Jeong

    (Pohang University of Science and Technology (POSTECH))

  • Koung-Min Park

    (Yonsei University College of Medicine)

  • Minji Kim

    (Seoul National University)

  • Sangseob Kim

    (Seoul National University)

  • Honghyun Jo

    (Seoul National University)

  • Sumin Lee

    (Seoul National University)

  • Heeseong Kim

    (Seoul National University)

  • Garam Choi

    (Seoul National University)

  • Yoon Ha Choi

    (Pohang University of Science and Technology (POSTECH))

  • Je Kyung Seong

    (Seoul National University)

  • Sik Namgoong

    (Korea University College of Medicine)

  • Yeonseok Chung

    (Seoul National University)

  • Young-Suk Jung

    (Pusan National University)

  • James G. Granneman

    (Wayne State University)

  • Young-Min Hyun

    (Yonsei University College of Medicine)

  • Jong Kyoung Kim

    (Pohang University of Science and Technology (POSTECH))

  • Yun-Hee Lee

    (Seoul National University)

Abstract

Adipose tissue (AT) adapts to overnutrition in a complex process, wherein specialized immune cells remove and replace dysfunctional and stressed adipocytes with new fat cells. Among immune cells recruited to AT, lipid-associated macrophages (LAMs) have emerged as key players in obesity and in diseases involving lipid stress and inflammation. Here, we show that LAMs selectively express transmembrane 4 L six family member 19 (TM4SF19), a lysosomal protein that represses acidification through its interaction with Vacuolar-ATPase. Inactivation of TM4SF19 elevates lysosomal acidification and accelerates the clearance of dying/dead adipocytes in vitro and in vivo. TM4SF19 deletion reduces the LAM accumulation and increases the proportion of restorative macrophages in AT of male mice fed a high-fat diet. Importantly, male mice lacking TM4SF19 adapt to high-fat feeding through adipocyte hyperplasia, rather than hypertrophy. This adaptation significantly improves local and systemic insulin sensitivity, and energy expenditure, offering a potential avenue to combat obesity-related metabolic dysfunction.

Suggested Citation

  • Cheoljun Choi & Yujin L. Jeong & Koung-Min Park & Minji Kim & Sangseob Kim & Honghyun Jo & Sumin Lee & Heeseong Kim & Garam Choi & Yoon Ha Choi & Je Kyung Seong & Sik Namgoong & Yeonseok Chung & Young, 2024. "TM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47108-8
    DOI: 10.1038/s41467-024-47108-8
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    References listed on IDEAS

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    1. Yoon Keun Cho & Young Cheol Yoon & Hyeonyeong Im & Yeonho Son & Minsu Kim & Abhirup Saha & Cheoljun Choi & Jaewon Lee & Sumin Lee & Jae Hyun Kim & Yun Pyo Kang & Young-Suk Jung & Hong Koo Ha & Je Kyun, 2022. "Adipocyte lysoplasmalogenase TMEM86A regulates plasmalogen homeostasis and protein kinase A-dependent energy metabolism," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Margo P. Emont & Christopher Jacobs & Adam L. Essene & Deepti Pant & Danielle Tenen & Georgia Colleluori & Angelica Vincenzo & Anja M. Jørgensen & Hesam Dashti & Adam Stefek & Elizabeth McGonagle & So, 2022. "A single-cell atlas of human and mouse white adipose tissue," Nature, Nature, vol. 603(7903), pages 926-933, March.
    3. Katja Luck & Dae-Kyum Kim & Luke Lambourne & Kerstin Spirohn & Bridget E. Begg & Wenting Bian & Ruth Brignall & Tiziana Cafarelli & Francisco J. Campos-Laborie & Benoit Charloteaux & Dongsic Choi & At, 2020. "A reference map of the human binary protein interactome," Nature, Nature, vol. 580(7803), pages 402-408, April.
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