RESUMEN
Adipogenesis is spatiotemporally coupled to angiogenesis throughout adult life, and the interplay between these two processes is communicated by multiple factors. Here we show that in a transgenic mouse model, increased expression of forkhead box C2 (FOXC2) in the adipose tissue affects angiogenesis, vascular patterning, and functions. White and brown adipose tissues contain a considerably high density of microvessels appearing as vascular plexuses, which show redistribution of vascular smooth muscle cells and pericytes. Dysfunction of these primitive vessels is reflected by impairment of skin wound healing. We further provide a mechanistic insight of the vascular phenotype by showing that FOXC2 controls Ang-2 expression by direct activation of its promoter in adipocytes. Remarkably, an Ang-2-specific antagonist almost completely reverses this vascular phenotype. Thus, the FOXC2-Ang-2 signaling system is crucial for controlling adipose vascular function, which is part of an adaptation to increased adipose tissue metabolism.
Asunto(s)
Tejido Adiposo/irrigación sanguínea , Tejido Adiposo/fisiología , Angiopoyetina 2/genética , Factores de Transcripción Forkhead/fisiología , Adipocitos/metabolismo , Adipogénesis/genética , Adipogénesis/fisiología , Tejido Adiposo Pardo/irrigación sanguínea , Tejido Adiposo Pardo/fisiología , Angiopoyetina 2/antagonistas & inhibidores , Angiopoyetina 2/fisiología , Animales , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica , Ratones , Ratones Transgénicos , Neovascularización Fisiológica/genética , Fenotipo , Regiones Promotoras Genéticas , Transducción de SeñalRESUMEN
Small molecule inhibitors of adipocyte fatty-acid binding protein (A-FABP) have gained renewed interest following the recent publication of pharmacologically beneficial effects of such inhibitors. Despite the potential utility of selective A-FABP inhibitors within the fields of metabolic disease, inflammation and atherosclerosis, there are few examples of useful A-FABP inhibitors in the public domain. Herein, we describe the optimization of N-benzyl-tetrahydrocarbazole derivatives through the use of co-crystal structure guided medicinal chemistry efforts. This led to the identification of a potent and selective class of A-FABP inhibitors as illustrated by N-benzyl-hexahydrocyclohepta[b]indole 30.
Asunto(s)
Adipocitos/efectos de los fármacos , Ácidos Carboxílicos/química , Química Farmacéutica/métodos , Proteínas de Unión a Ácidos Grasos/antagonistas & inhibidores , Animales , Sitios de Unión , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Macrófagos/metabolismo , Ratones , Modelos Químicos , Estructura Molecular , Espectrometría de Fluorescencia/métodosRESUMEN
The synthesis and biological evaluation of novel human A-FABP inhibitors based on the 6-(trifluoromethyl)pyrimidine-4(1H)-one scaffold is described. Two series of compounds, bearing either an amino or carbon substituent in the 2-position of the pyrimidine ring were investigated. Modification of substituents and chain length optimization led to novel compounds with low micromolar activity and good selectivity for human A-FABP.
Asunto(s)
Adipocitos/metabolismo , Bencilaminas/química , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/metabolismo , Piridinas/química , Bencilaminas/metabolismo , Bencilaminas/farmacología , Proteínas de Unión a Ácidos Grasos , Humanos , Piridinas/metabolismo , Piridinas/farmacología , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacologíaRESUMEN
Low micromolar human A-FABP inhibitors were found by utilizing a fluorescence polarization assay, X-ray crystallography and modeling. The carbazole- and indole-based inhibitors displayed approximately 10-fold preferences over human H-FABP and E-FABP, and are highly selective against I-FABP. This communication describes the SAR for drug-like synthetic inhibitors of human A-FABP.