Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation

• DOI: 10.1016/j.molmet.2016.04.005
• Publication Date: 2016-04-30T10:57:18Z
• Authors: Amy R. Johnson; Yuanyuan Qin; Alyssa J. Cozzo; Alex J. Freemerman; Megan J. Huang; Liyang Zhao; Brante P. Sampey; J. Justin Milner; Melinda A. Beck; Blossom Damania; Naim Rashid; Joseph A. Galanko; Douglas P. Lee; Matthew L. Edin; Darryl C. Zeldin; Patrick T. Fueger; Brittney Dietz; Andreas Stahl; Ying Wu; Karen L. Mohlke; Liza Makowski
• Keywords: Adipose tissue macrophage; 0303 health sciences; 03 medical and health sciences; Crown-like structures; Original Article; Obesity; Glycolysis; Internal medicine; RC31-1245; M2 macrophage; Mitochondria

A novel approach to regulate obesity-associated adipose inflammation may be through metabolic reprogramming of macrophages (MΦs). Broadly speaking, MΦs dependent on glucose are pro-inflammatory, classically activated (CAM), which contribute and insulin resistance. In contrast, that primarily metabolize fatty acids alternatively (AAM) maintain tissue sensitivity. actuality, there is much flexibility overlap in the CAM-AAM spectrum vivo upon various stimuli microenvironment. We hypothesized specific lipid trafficking proteins, e.g. acid transport protein 1 (FATP1), would direct MΦ metabolism limit maintenance homeostasis. Bone marrow derived (BMDMs) from Fatp1 −/− +/+ mice were used investigate FATP1-dependent substrate metabolism, bioenergetics, metabolomics, inflammatory responses. also generated C57BL/6J chimeric by bone transplant specifically lacking hematopoetic FATP1 ( B ) controls . Mice challenged high fat diet (HFD) or low (LFD) analyses including MRI, tolerance tests, flow cytometric, histologic, quantification assays conducted. Finally, an FATP1-overexpressing RAW 264.7 cell line (FATP1-OE) empty vector control (FATP1-EV) developed as a gain function model test effects downregulated with pro-inflammatory stimulation MΦs. BMDMs FATP1-OE demonstrated reciprocally controled flexibility, i.e. was associated response. Supporting our previous work demonstrating positive relationship between inflammation, loss enhanced exaggerated CAM phenotype. B−/− chimeras fed HFD gained more epididymal white mass, inflamed oxidatively stressed, compared HFD-fed B+/+ controls. Adipose displayed CAM-like phenotype absence Conversely, functional overexpression decreased many aspects diminished CAM-stimulated vitro acyl-CoA synthetase activity for long chain modulated mediator Our findings provide evidence regulator activation metabolism. Absence exacerbated increased local systemic components syndrome mice. suggested -mediated acids, switch glucose, oxidative stress, synthesis potential mechanisms. demonstrate first time provides unique mechanism tone regulated. • FATP1-mediated inflammation. deficiency primed activation. Lack led greater HFD-induced activated.