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

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 & 1 others Liza Makowski

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 (Fatp1B-/-) and controls Fatp1B+/+. 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. Fatp1B-/- chimeras fed a HFD gained more epididymal white adipose mass, which was inflamed and oxidatively stressed, compared to HFD-fed Fatp1B+/+ 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. Conclusion: 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 Fatp1B-/- 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.

Original languageEnglish (US)
Pages (from-to)506-526
Number of pages21
JournalMolecular Metabolism
Volume5
Issue number7
DOIs
StatePublished - Jul 1 2016

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Fatty Acid Transport Proteins
Macrophages
Inflammation
High Fat Diet
Glucose
Fatty Acids
Metabolomics
Lipid Metabolism
Energy Metabolism
Insulin Resistance
Adipose Tissue
Coenzyme A Ligases
Phenotype
Lipids
Fat-Restricted Diet
Protein Transport

Keywords

  • Adipose tissue macrophage
  • Crown-like structures
  • Glycolysis
  • M2 macrophage
  • Mitochondria
  • Obesity

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation. / Johnson, Amy R.; Qin, Yuanyuan; Cozzo, Alyssa J.; Freemerman, Alex J.; Huang, Megan J.; Zhao, Liyang; Sampey, Brante P.; Milner, J. Justin; Beck, Melinda A.; Damania, Blossom; Rashid, Naim; Galanko, Joseph A.; Lee, Douglas P.; Edin, Matthew L.; Zeldin, Darryl C.; Fueger, Patrick T.; Dietz, Brittney; Stahl, Andreas; Wu, Ying; Mohlke, Karen L.; Makowski, Liza.

In: Molecular Metabolism, Vol. 5, No. 7, 01.07.2016, p. 506-526.

Research output: Contribution to journalArticle

Johnson, AR, Qin, Y, Cozzo, AJ, Freemerman, AJ, Huang, MJ, Zhao, L, Sampey, BP, Milner, JJ, Beck, MA, Damania, B, Rashid, N, Galanko, JA, Lee, DP, Edin, ML, Zeldin, DC, Fueger, PT, Dietz, B, Stahl, A, Wu, Y, Mohlke, KL & Makowski, L 2016, 'Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation', Molecular Metabolism, vol. 5, no. 7, pp. 506-526. https://doi.org/10.1016/j.molmet.2016.04.005
Johnson, Amy R. ; Qin, Yuanyuan ; Cozzo, Alyssa J. ; Freemerman, Alex J. ; Huang, Megan J. ; Zhao, Liyang ; Sampey, Brante P. ; Milner, J. Justin ; Beck, Melinda A. ; Damania, Blossom ; Rashid, Naim ; Galanko, Joseph A. ; Lee, Douglas P. ; Edin, Matthew L. ; Zeldin, Darryl C. ; Fueger, Patrick T. ; Dietz, Brittney ; Stahl, Andreas ; Wu, Ying ; Mohlke, Karen L. ; Makowski, Liza. / Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation. In: Molecular Metabolism. 2016 ; Vol. 5, No. 7. pp. 506-526.
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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 (Fatp1B-/-) and controls Fatp1B+/+. 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. Fatp1B-/- chimeras fed a HFD gained more epididymal white adipose mass, which was inflamed and oxidatively stressed, compared to HFD-fed Fatp1B+/+ 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. Conclusion: 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 Fatp1B-/- 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.",
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author = "Johnson, {Amy R.} and Yuanyuan Qin and Cozzo, {Alyssa J.} and Freemerman, {Alex J.} and Huang, {Megan J.} and Liyang Zhao and Sampey, {Brante P.} and Milner, {J. Justin} and Beck, {Melinda A.} and Blossom Damania and Naim Rashid and Galanko, {Joseph A.} and Lee, {Douglas P.} and Edin, {Matthew L.} and Zeldin, {Darryl C.} and Fueger, {Patrick T.} and Brittney Dietz and Andreas Stahl and Ying Wu and Mohlke, {Karen L.} and Liza Makowski",
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TY - JOUR

T1 - Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation

AU - Johnson, Amy R.

AU - Qin, Yuanyuan

AU - Cozzo, Alyssa J.

AU - Freemerman, Alex J.

AU - Huang, Megan J.

AU - Zhao, Liyang

AU - Sampey, Brante P.

AU - Milner, J. Justin

AU - Beck, Melinda A.

AU - Damania, Blossom

AU - Rashid, Naim

AU - Galanko, Joseph A.

AU - Lee, Douglas P.

AU - Edin, Matthew L.

AU - Zeldin, Darryl C.

AU - Fueger, Patrick T.

AU - Dietz, Brittney

AU - Stahl, Andreas

AU - Wu, Ying

AU - Mohlke, Karen L.

AU - Makowski, Liza

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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 (Fatp1B-/-) and controls Fatp1B+/+. 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. Fatp1B-/- chimeras fed a HFD gained more epididymal white adipose mass, which was inflamed and oxidatively stressed, compared to HFD-fed Fatp1B+/+ 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. Conclusion: 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 Fatp1B-/- 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.

AB - 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 (Fatp1B-/-) and controls Fatp1B+/+. 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. Fatp1B-/- chimeras fed a HFD gained more epididymal white adipose mass, which was inflamed and oxidatively stressed, compared to HFD-fed Fatp1B+/+ 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. Conclusion: 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 Fatp1B-/- 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.

KW - Adipose tissue macrophage

KW - Crown-like structures

KW - Glycolysis

KW - M2 macrophage

KW - Mitochondria

KW - Obesity

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