| First Author | Johnson AR | Year | 2016 |
| Journal | Mol Metab | Volume | 5 |
| Issue | 7 | Pages | 506-526 |
| PubMed ID | 27408776 | Mgi Jnum | J:327202 |
| Mgi Id | MGI:7328870 | Doi | 10.1016/j.molmet.2016.04.005 |
| Citation | Johnson AR, et al. (2016) Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation. Mol Metab 5(7):506-526 |
| abstractText | OBJECTIVE: A novel approach to regulate obesity-associated adipose inflammation may be through metabolic reprogramming of macrophages (MPhis). Broadly speaking, MPhis dependent on glucose are pro-inflammatory, classically activated MPhis (CAM), which contribute to adipose inflammation and insulin resistance. In contrast, MPhis that primarily metabolize fatty acids are alternatively activated MPhis (AAM) and maintain tissue insulin sensitivity. In actuality, there is much flexibility and overlap in the CAM-AAM spectrum in vivo dependent upon various stimuli in the microenvironment. We hypothesized that specific lipid trafficking proteins, e.g. fatty acid transport protein 1 (FATP1), would direct MPhi fatty acid transport and metabolism to limit inflammation and contribute to the maintenance of adipose tissue homeostasis. METHODS: Bone marrow derived MPhis (BMDMs) from Fatp1 (-/-) and Fatp1 (+/+) mice were used to investigate FATP1-dependent substrate metabolism, bioenergetics, metabolomics, and inflammatory responses. We also generated C57BL/6J chimeric mice by bone marrow transplant specifically lacking hematopoetic FATP1 (Fatp1 (B-/-)) and controls Fatp1 (B+/+). Mice were challenged by high fat diet (HFD) or low fat diet (LFD) and analyses including MRI, glucose and insulin tolerance tests, flow cytometric, histologic, and protein quantification assays were conducted. Finally, an FATP1-overexpressing RAW 264.7 MPhi cell line (FATP1-OE) and empty vector control (FATP1-EV) were developed as a gain of function model to test effects on substrate metabolism, bioenergetics, metabolomics, and inflammatory responses. RESULTS: Fatp1 is downregulated with pro-inflammatory stimulation of MPhis. Fatp1 (-/-) BMDMs and FATP1-OE RAW 264.7 MPhis demonstrated that FATP1 reciprocally controled metabolic flexibility, i.e. lipid and glucose metabolism, which was associated with inflammatory response. Supporting our previous work demonstrating the positive relationship between glucose metabolism and inflammation, loss of FATP1 enhanced glucose metabolism and exaggerated the pro-inflammatory CAM phenotype. Fatp1 (B-/-) chimeras fed a HFD gained more epididymal white adipose mass, which was inflamed and oxidatively stressed, compared to HFD-fed Fatp1 (B+/+) controls. Adipose tissue macrophages displayed a CAM-like phenotype in the absence of Fatp1. Conversely, functional overexpression of FATP1 decreased many aspects of glucose metabolism and diminished CAM-stimulated inflammation in vitro. FATP1 displayed acyl-CoA synthetase activity for long chain fatty acids in MPhis and modulated lipid mediator metabolism in MPhis. CONCLUSION: Our findings provide evidence that FATP1 is a novel regulator of MPhi activation through control of substrate metabolism. Absence of FATP1 exacerbated pro-inflammatory activation in vitro and increased local and systemic components of the metabolic syndrome in HFD-fed Fatp1 (B-/-) mice. In contrast, gain of FATP1 activity in MPhis suggested that Fatp1-mediated activation of fatty acids, substrate switch to glucose, oxidative stress, and lipid mediator synthesis are potential mechanisms. We demonstrate for the first time that FATP1 provides a unique mechanism by which the inflammatory tone of adipose and systemic metabolism may be regulated. |
