Supplemental_Diabetes_revised_clean_copy.pdf (2.14 MB)
Beneficial Metabolic Effects of TREM2 in Obesity are Uncoupled from its Expression on Macrophages
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posted on 2021-02-24, 20:08 authored 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 KnappObesity-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.