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

Diabetes. 2021 Sep;70(9):2042-2057. doi: 10.2337/db20-0572. Epub 2021 Feb 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism*
  • Animals
  • Diet, High-Fat
  • Inflammation / metabolism
  • Insulin Resistance / physiology
  • Lipid Metabolism / physiology
  • Macrophages / metabolism*
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Obesity / metabolism*
  • Receptors, Immunologic / metabolism*
  • Up-Regulation


  • Membrane Glycoproteins
  • Receptors, Immunologic
  • TREM2 protein, human

Associated data

  • figshare/10.2337/figshare.14074550