Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice.
Vissarion EfthymiouLianggong DingMiroslav BalazWenfei SunLucia BalazovaLeon G StraubHua DongEric SimonAdhideb GhoshAliki PerdikariSvenja KellerUmesh GhoshdastiderCarla HorvathCaroline MoserBradford HamiltonHeike NeubauerChristian WolfrumPublished in: Nature communications (2023)
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.
Keyphrases
- tyrosine kinase
- adipose tissue
- insulin resistance
- signaling pathway
- pi k akt
- high fat diet induced
- epidermal growth factor receptor
- high fat diet
- metabolic syndrome
- type diabetes
- weight loss
- skeletal muscle
- weight gain
- transcription factor
- cell proliferation
- cell cycle arrest
- induced apoptosis
- gene expression
- binding protein
- body mass index
- endoplasmic reticulum stress
- copy number
- combination therapy
- human health
- cell death
- data analysis