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

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, Carla Horvath, Caroline Moser, Bradford Hamilton, Heike Neubauer and Christian Wolfrum ()
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Vissarion Efthymiou: Nutrition and Health
Lianggong Ding: Nutrition and Health
Miroslav Balaz: Nutrition and Health
Wenfei Sun: Nutrition and Health
Lucia Balazova: Nutrition and Health
Leon G. Straub: Nutrition and Health
Hua Dong: Nutrition and Health
Eric Simon: Boehringer Ingelheim Pharma GmbH & Co. KG
Adhideb Ghosh: Nutrition and Health
Aliki Perdikari: Nutrition and Health
Svenja Keller: Nutrition and Health
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

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39715-8

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