Lipoxins reduce obesity-induced adipose tissue inflammation in 3D-cultured human adipocytes and explant cultures

Matúš Soták; Meenu Rohini Rajan; Madison Clark; Matthew Harms; Alankrita Rani; Jamie D Kraft; David Tandio; Tong Shen; Kamil Borkowski; Oliver Fiehn; John W Newman; Marianne Quiding-Järbrink; Christina Biörserud; Peter Apelgren; Trude Staalesen; Carolina E Hagberg; Jeremie Boucher; Ville Wallenius; Stephan Lange; Emma Börgeson

doi:10.1016/j.isci.2022.104602

Lipoxins reduce obesity-induced adipose tissue inflammation in 3D-cultured human adipocytes and explant cultures

iScience. 2022 Jun 11;25(7):104602. doi: 10.1016/j.isci.2022.104602. eCollection 2022 Jul 15.

Authors

Matúš Soták^{1

2

3}, Meenu Rohini Rajan^{1

2

3}, Madison Clark^{1

2}, Matthew Harms⁴, Alankrita Rani^{1

2

3}, Jamie D Kraft^{1

2}, David Tandio^{1

2}, Tong Shen⁵, Kamil Borkowski⁵, Oliver Fiehn⁵, John W Newman^{5

6

7}, Marianne Quiding-Järbrink⁸, Christina Biörserud⁹, Peter Apelgren^{9

10}, Trude Staalesen^{9

10}, Carolina E Hagberg^{11

12}, Jeremie Boucher^{2

13

4}, Ville Wallenius⁹, Stephan Lange^{1

14}, Emma Börgeson^{1

2

3}

Affiliations

¹ Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
² Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 40530 Gothenburg, Sweden.
³ Region Vaestra Goetaland, Sahlgrenska University Hospital, Department of Clinical Physiology, 41345 Gothenburg, Sweden.
⁴ Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
⁵ NIH West Coast Metabolomics Center, Genome Center, University of California Davis, Davis, CA 95616, USA.
⁶ Department of Nutrition, University of California Davis, Davis, CA 95616, USA.
⁷ USDA, ARS, Western Human Nutrition Research Center, Davis, USA.
⁸ Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
⁹ Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁰ Region Vaestra Goetaland, Sahlgrenska University Hospital, Department of Plastic Surgery, Gothenburg, Sweden.
¹¹ Division of Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
¹² Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
¹³ The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁴ Division of Cardiology, School of Medicine, University of California San Diego, San Diego, CA, USA.

Abstract

Adipose tissue inflammation drives obesity-related cardiometabolic diseases. Enhancing endogenous resolution mechanisms through administration of lipoxin A₄, a specialized pro-resolving lipid mediator, was shown to reduce adipose inflammation and subsequently protects against obesity-induced systemic disease in mice. Here, we demonstrate that lipoxins reduce inflammation in 3D-cultured human adipocytes and adipose tissue explants from obese patients. Approximately 50% of patients responded particularly well to lipoxins by reducing inflammatory cytokines and promoting an anti-inflammatory M2 macrophage phenotype. Responding patients were characterized by elevated systemic levels of C-reactive protein, which causes inflammation in cultured human adipocytes. Responders appeared more prone to producing anti-inflammatory oxylipins and displayed elevated prostaglandin D2 levels, which has been interlinked with transcription of lipoxin-generating enzymes. Using explant cultures, this study provides the first proof-of-concept evidence supporting the therapeutic potential of lipoxins in reducing human adipose tissue inflammation. Our data further indicate that lipoxin treatment may require a tailored personalized-medicine approach.

Keywords: Biological sciences; Cell biology; Human metabolism; Physiology; Precision medicine.

Abstract

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