title: Growth arrest-specific protein 6 receptor antagonism impairs adipocyte differentiation and adipose tissue development in mice.
abstract: A low-molecular-weight receptor tyrosine kinase inhibitor, 1-(6,7-dihydro-5H-benzo(6,7)cyclohepta(1,2-c)pyridazin-3-yl)-N3-((7-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo(7)annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine (R428) with high affinity and selectivity for the growth arrest-specific protein 6 (GAS6) receptor Axl was used to study a potential role of GAS6 signaling in adiposity. In vitro, R428 caused a concentration-dependent inhibition of preadipocyte differentiation into mature adipocytes, as evidenced by reduced lipid uptake. Inhibition of Axl-mediated signaling was confirmed by reduced levels of phospho-Akt activity. In vivo, oral administration of R428 for 5 weeks to mice kept on a high-fat diet resulted in significantly reduced weight gain and subcutaneous and gonadal fat mass. This was associated with marked adipocyte hypotrophy, enhanced macrophage infiltration, and apoptosis. Thus, affecting GAS6 signaling through receptor antagonism using a low-molecular-weight Axl antagonist impairs adipocyte differentiation and reduces adipose tissue development in a murine model of nutritionally induced obesity.
authors.affiliation: Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Campus Gasthuisberg, O and N 1, Herestraat 49, Box 911, B-3000 Leuven, Belgium. roger.lijnen@med.kuleuven.be
authors.forename: H Roger
authors.initials: HR
authors.lastname: Lijnen
authors.forename: Valerie
authors.initials: V
authors.lastname: Christiaens
authors.forename: Llse
authors.initials: L
authors.lastname: Scroyen
mesh_terms: D017667:Adipocytes / Q000187:drug effects*; D050156:Adipogenesis / Q000187:drug effects*; D000273:Adipose Tissue / Q000187:drug effects / Q000254:growth & development*; D000818:Animals; D001567:Benzocycloheptenes / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014230:Triazoles / Q000494:pharmacology; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D001567:Benzocycloheptenes; D001786:Blood Glucose; D036341:Intercellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D014230:Triazoles; D000099255:Growth Arrest-Specific Protein 6; C548378:bemcentinib