title: Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation.
abstract: OBJECTIVE
  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 MΦs (CAM), which contribute to adipose inflammation and insulin resistance. In contrast, MΦs that primarily metabolize fatty acids are alternatively activated MΦs (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 MΦ fatty acid transport and metabolism to limit inflammation and contribute to the maintenance of adipose tissue homeostasis.
  
  
  METHODS
  Bone marrow derived MΦs (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 MΦ 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 MΦs. Fatp1 (-/-) BMDMs and FATP1-OE RAW 264.7 MΦs 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 MΦs and modulated lipid mediator metabolism in MΦs.
  
  
  CONCLUSIONS
  Our findings provide evidence that FATP1 is a novel regulator of MΦ 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 MΦs 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.
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Johnson
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Alyssa J
authors.initials: AJ
authors.lastname: Cozzo
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Freemerman
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Huang
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Liyang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Brante P
authors.initials: BP
authors.lastname: Sampey
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: J Justin
authors.initials: JJ
authors.lastname: Milner
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Nutrition, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Nutrition Obesity Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Beck
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Blossom
authors.initials: B
authors.lastname: Damania
authors.affiliation: Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Naim
authors.initials: N
authors.lastname: Rashid
authors.affiliation: Department of Nutrition, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Nutrition Obesity Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Galanko
authors.affiliation: Omic Insight, Inc., Durham, NC 27713, USA.
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Lee
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Departments of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Fueger
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA 94720, USA.
authors.forename: Brittney
authors.initials: B
authors.lastname: Dietz
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA 94720, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mohlke
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Nutrition, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Nutrition Obesity Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: liza.makowski@unc.edu.
authors.forename: Liza
authors.initials: L
authors.lastname: Makowski
keywords: Adipose tissue macrophage; Crown-like structures; Glycolysis; M2 macrophage; Mitochondria; Obesity