Beneficial Metabolic Effects of TREM2 in Obesity Are Uncoupled From Its Expression on Macrophages

Abstract

Obesity-induced white adipose tissue (WAT) hypertro-phy is associated with elevated adipose tissue macro-phage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) report-edly increases adiposity, worsening health. Paradoxi-cally, using insulin resistance, elevated fat mass, and hypercholesterolemia as hallmarks of unhealthy obesi-ty, 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 ceram-ides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, in-flammation, 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, in-stead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in the systemic protective effects of TREM2 on metabolic health.