TY - JOUR
T1 - Beneficial Metabolic Effects of TREM2 in Obesity Are Uncoupled From Its Expression on Macrophages
AU - Sharif, Omar
AU - Brunner, Julia Stefanie
AU - Korosec, Ana
AU - Martins, Rui
AU - Jais, Alexander
AU - Snijder, Berend
AU - Vogel, Andrea
AU - Caldera, Michael
AU - Hladik, Anastasiya
AU - Lakovits, Karin
AU - Saluzzo, Simona
AU - Boehm, Benedikta
AU - Gorki, Anna-Dorothea
AU - Mesteri, Ildiko
AU - Lindroos-Christensen, Josefine
AU - Tillmann, Katharina
AU - Stoiber, Dagmar
AU - Menche, Jörg
AU - Schabbauer, Gernot
AU - Bilban, Martin
AU - Superti-Furga, Giulio
AU - Esterbauer, Harald
AU - Knapp, Sylvia
N1 - Funding Information:
Acknowledgments. The authors thank the staff of the animal facility at the Medical University of Vienna. Funding. This work was funded by the Austrian Science Fund (FWF P25801 and FWF P31568 to O.S.) and the special research program Immuno-thrombosis of the Austrian Science Fund (F5410-B21 to S.K.). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. O.S. designed the study and overall research plan and performed and analyzed data for the majority of the experiments. O.S. and S.K. conceived the project. J.S.B., A.K., A.V., A.H., K.L., S.S., B.B., A.D.-G., J.L.-C., D.S., G.S., and M.B. helped with the experiments. R.M. analyzed adipocyte cell size and performed experiments. A.J. and H.E. collected and analyzed human data, helped with metabolic cages, and contributed to the project design. B.S., M.C., J.M., and G.S.-F. analyzed lipidomics data. I.M. analyzed liver steatosis. K.T. contributed to mouse husbandry/veterinary care. O.S. and S.K. wrote the manuscript and all authors read, revised and approved the final manuscript. O.S. and S.K. are guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Publisher Copyright:
© 2021 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https:// www.diabetesjournals.org/content/license.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass, and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated that ATM-expressed TREM2 promoted health. Here, we identified that in mice, TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation, or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. Bone marrow transplantation experiments revealed unremarkable influences of immune cell-expressed TREM2 on health, instead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in the systemic protective effects of TREM2 on metabolic health.
AB - Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass, and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated that ATM-expressed TREM2 promoted health. Here, we identified that in mice, TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation, or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. Bone marrow transplantation experiments revealed unremarkable influences of immune cell-expressed TREM2 on health, instead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in the systemic protective effects of TREM2 on metabolic health.
KW - Adipose Tissue/metabolism
KW - Animals
KW - Diet, High-Fat
KW - Inflammation/metabolism
KW - Insulin Resistance/physiology
KW - Lipid Metabolism/physiology
KW - Macrophages/metabolism
KW - Membrane Glycoproteins/metabolism
KW - Mice
KW - Obesity/metabolism
KW - Receptors, Immunologic/metabolism
KW - Up-Regulation
UR - http://www.scopus.com/inward/record.url?scp=85107286475&partnerID=8YFLogxK
U2 - 10.2337/db20-0572
DO - 10.2337/db20-0572
M3 - Journal article
C2 - 33627323
SN - 0012-1797
VL - 70
SP - 2042
EP - 2057
JO - Diabetes
JF - Diabetes
IS - 9
ER -