Beneficial Metabolic Effects of TREM2 in Obesity are Uncoupled from its Expression on Macrophages
figureposted on 24.02.2021, 20:08 by Omar Sharif, Julia Stefanie Brunner, Ana Korosec, Rui Martins, Alexander Jais, Berend Snijder, Andrea Vogel, Michael Caldera, Anastasiya Hladik, Karin Lakovits, Simona Saluzzo, Benedikta Boehm, Anna-Dorothea Gorki, Ildiko Mesteri, Josefine Lindroos-Christensen, Katharina Tillmann, Dagmar Stoiber, Jörg Menche, Gernot Schabbauer, Martin Bilban, Giulio Superti-Furga, Harald Esterbauer, Sylvia Knapp
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 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 TREM2’s systemic protective effects on metabolic health.