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

doi:10.1016/j.isci.2022.105683

Type 2 diabetes is associated with increased circulating levels of 3-hydroxydecanoate activating GPR84 and neutrophil migration

iScience. 2022 Nov 26;25(12):105683. doi: 10.1016/j.isci.2022.105683. eCollection 2022 Dec 22.

Authors

Randi Bonke Mikkelsen¹, Tulika Arora¹, Kajetan Trošt¹, Oksana Dmytriyeva¹, Sune Kjærsgaard Jensen¹, Abraham Stijn Meijnikman², Louise Elisabeth Olofsson³, Dimitra Lappa⁴, Ömrüm Aydin², Jens Nielsen⁴, Victor Gerdes², Thomas Moritz¹, Arnold van de Laar⁵, Maurits de Brauw⁵, Max Nieuwdorp², Siv Annegrethe Hjorth¹, Thue Walter Schwartz¹, Fredrik Bäckhed^{1

3

6}

Affiliations

¹ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
² Department of Internal and Vascular Medicine, Amsterdam University Medical Centre, Amsterdam, the Netherlands.
³ Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁴ Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
⁵ Department of Surgery, Spaarne Hospital, Hoofddorp, the Netherlands.
⁶ Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg, Sweden.

Abstract

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 Gα_i 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.

Keywords: Cell biology; Immunology; Pathophysiology.