Type 2 diabetes is associated with increased circulating levels of 3-hydroxydecanoate activating GPR84 and neutrophil migration
Randi Bonke Mikkelsen,
Tulika Arora,
Kajetan Trošt,
Oksana Dmytriyeva,
Sune Kjærsgaard Jensen,
Abraham Stijn Meijnikman,
Louise Elisabeth Olofsson,
Dimitra Lappa,
Ömrüm Aydin,
Jens Nielsen,
Victor Gerdes,
Thomas Moritz,
Arnold van de Laar,
Maurits de Brauw,
Max Nieuwdorp,
Siv Annegrethe Hjorth,
Thue Walter Schwartz,
Fredrik Bäckhed
Affiliations
Randi Bonke Mikkelsen
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Tulika Arora
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Kajetan Trošt
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Oksana Dmytriyeva
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Sune Kjærsgaard Jensen
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Abraham Stijn Meijnikman
Department of Internal and Vascular Medicine, Amsterdam University Medical Centre, Amsterdam, the Netherlands
Louise Elisabeth Olofsson
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Dimitra Lappa
Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
Ömrüm Aydin
Department of Internal and Vascular Medicine, Amsterdam University Medical Centre, Amsterdam, the Netherlands
Jens Nielsen
Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
Victor Gerdes
Department of Internal and Vascular Medicine, Amsterdam University Medical Centre, Amsterdam, the Netherlands
Thomas Moritz
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Arnold van de Laar
Department of Surgery, Spaarne Hospital, Hoofddorp, the Netherlands
Maurits de Brauw
Department of Surgery, Spaarne Hospital, Hoofddorp, the Netherlands
Max Nieuwdorp
Department of Internal and Vascular Medicine, Amsterdam University Medical Centre, Amsterdam, the Netherlands
Siv Annegrethe Hjorth
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Thue Walter Schwartz
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Fredrik Bäckhed
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg, Sweden; Corresponding author
Summary: Obesity and diabetes are associated with inflammation and altered plasma levels of several metabolites, which may be involved in disease progression. Some metabolites can activate G protein-coupled receptors (GPCRs) expressed on immune cells where they can modulate metabolic inflammation. Here, we find that 3-hydroxydecanoate is enriched in the circulation of obese individuals with type 2 diabetes (T2D) compared with nondiabetic controls. Administration of 3-hydroxydecanoate to mice promotes immune cell recruitment to adipose tissue, which was associated with adipose inflammation and increased fasting insulin levels. Furthermore, we demonstrate that 3-hydroxydecanoate stimulates migration of primary human and mouse neutrophils, but not monocytes, through GPR84 and Gαi signaling in vitro. Our findings indicate that 3-hydroxydecanoate is a T2D-associated metabolite that increases inflammatory responses and may contribute to the chronic inflammation observed in diabetes.
