TY - JOUR
T1 - Type 2 diabetes is associated with increased circulating levels of 3-hydroxydecanoate activating GPR84 and neutrophil migration
AU - Mikkelsen, Randi Bonke
AU - Arora, Tulika
AU - Trošt, Kajetan
AU - Dmytriyeva, Oksana
AU - Jensen, Sune Kjærsgaard
AU - Meijnikman, Abraham Stijn
AU - Olofsson, Louise Elisabeth
AU - Lappa, Dimitra
AU - Aydin, Ömrüm
AU - Nielsen, Jens
AU - Gerdes, Victor
AU - Moritz, Thomas
AU - van de Laar, Arnold
AU - de Brauw, Maurits
AU - Nieuwdorp, Max
AU - Hjorth, Siv Annegrethe
AU - Schwartz, Thue Walter
AU - Bäckhed, Fredrik
N1 - Funding Information:
M.N. is in the SAB of Caelus Health and Kaleido Biosciences; however, none of these are relevant for the current manuscript. F.B. is founder and holds equity of Implexion Pharma AB and receives research funding from Biogaia AB, both of which are unrelated to this study.
Funding Information:
We thank Marianne Gregers Johansen and Nataliia Tiutcheva for technical assistance and Carina Onuczak Rosenberg for excellent mouse husbandry. We also thank Anna Hallén for making the graphical abstract. The BARIA study is funded by the Novo Nordisk Foundation ( NNF15OC0016798 ). Analyses was in part supported by the Transatlantic Networks of Excellence Award from the Leducq Foundation (17CVD01). M.N. is supported by a personal ZONMW-VICI grant 2020 [ 09150182010020 ] and F.B. is Torsten Söderberg Professor in Medicine and Wallenberg Scholar .
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/12/22
Y1 - 2022/12/22
N2 - 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.
AB - 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.
KW - Cell biology
KW - Immunology
KW - Pathophysiology
UR - https://www.scopus.com/pages/publications/85143727985
U2 - 10.1016/j.isci.2022.105683
DO - 10.1016/j.isci.2022.105683
M3 - Article
C2 - 36561890
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 12
M1 - 105683
ER -
SDG 3 Good Health and Well-being