1. Academic Validation
  2. Growth arrest-specific protein 6 receptor antagonism impairs adipocyte differentiation and adipose tissue development in mice

Growth arrest-specific protein 6 receptor antagonism impairs adipocyte differentiation and adipose tissue development in mice

  • J Pharmacol Exp Ther. 2011 May;337(2):457-64. doi: 10.1124/jpet.110.178046.
H Roger Lijnen 1 Valerie Christiaens Llse Scroyen
Affiliations

Affiliation

  • 1 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
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.

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