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Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice

Author

Listed:
  • Vissarion Efthymiou

    (Nutrition and Health
    Harvard Medical School)

  • Lianggong Ding

    (Nutrition and Health)

  • Miroslav Balaz

    (Nutrition and Health
    Slovak Academy of Sciences)

  • Wenfei Sun

    (Nutrition and Health
    Stanford University
    Stanford University School of Medicine)

  • Lucia Balazova

    (Nutrition and Health
    Slovak Academy of Sciences)

  • Leon G. Straub

    (Nutrition and Health
    Federal Research Institute of Nutrition and Food)

  • Hua Dong

    (Nutrition and Health
    Stanford University School of Medicine)

  • Eric Simon

    (Boehringer Ingelheim Pharma GmbH & Co. KG)

  • Adhideb Ghosh

    (Nutrition and Health)

  • Aliki Perdikari

    (Nutrition and Health)

  • Svenja Keller

    (Nutrition and Health
    University of Zurich)

  • Umesh Ghoshdastider

    (Nutrition and Health)

  • Carla Horvath

    (Nutrition and Health)

  • Caroline Moser

    (Nutrition and Health)

  • Bradford Hamilton

    (Boehringer Ingelheim Pharma GmbH & Co. KG)

  • Heike Neubauer

    (Boehringer Ingelheim Pharma GmbH & Co. KG)

  • Christian Wolfrum

    (Nutrition and Health)

Abstract

The current obesity epidemic and high prevalence of metabolic diseases necessitate efficacious and safe treatments. Brown adipose tissue in this context is a promising target with the potential to increase energy expenditure, however no pharmacological treatments activating brown adipose tissue are currently available. Here, we identify AXL receptor tyrosine kinase as a regulator of adipose function. Pharmacological and genetic inhibition of AXL enhance thermogenic capacity of brown and white adipocytes, in vitro and in vivo. Mechanistically, these effects are mediated through inhibition of PI3K/AKT/PDE signaling pathway, resulting in induction of nuclear FOXO1 localization and increased intracellular cAMP levels via PDE3/4 inhibition and subsequent stimulation of the PKA-ATF2 pathway. In line with this, both constitutive Axl deletion as well as inducible adipocyte-specific Axl deletion protect animals from diet-induced obesity concomitant with increases in energy expenditure. Based on these data, we propose AXL receptor as a target for the treatment of obesity.

Suggested Citation

  • Vissarion Efthymiou & Lianggong Ding & Miroslav Balaz & Wenfei Sun & Lucia Balazova & Leon G. Straub & Hua Dong & Eric Simon & Adhideb Ghosh & Aliki Perdikari & Svenja Keller & Umesh Ghoshdastider & C, 2023. "Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39715-8
    DOI: 10.1038/s41467-023-39715-8
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    References listed on IDEAS

    as
    1. Thomas S. Morley & Jonathan Y. Xia & Philipp E. Scherer, 2015. "Selective enhancement of insulin sensitivity in the mature adipocyte is sufficient for systemic metabolic improvements," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    2. Caroline Araiz & Anqi Yan & Lucia Bettedi & Isabella Samuelson & Sam Virtue & Anne K. McGavigan & Christian Dani & Antonio Vidal-Puig & Lazaros C. Foukas, 2019. "Enhanced β-adrenergic signalling underlies an age-dependent beneficial metabolic effect of PI3K p110α inactivation in adipose tissue," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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