Beneficial Metabolic Effects of TREM2 in Obesity are Uncoupled from its Expression on Macrophages

Abstract

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.

A lipid-associated macrophage lineage rewires the spatial landscape of adipose tissue in early obesity

“…Examining these data, we found increased Ptprc (CD45), which is broadly expressed in immune cells, and increased ATM-associated CD68. Notably, we observed increased pro-inflammatory ATM marker Itgax (CD11c), resident ATMassociated marker Mrc1, and Trem2, which is expressed in lipid-associated ATMs and has proposed functions in protective lipid homeostasis and adipose tissue remodeling in obesity (Jaitin et al, 2019;Liu et al, 2019;Sharif et al, 2021) (Figure 1I,J). (1) First, adipose tissue sections from our three dietary conditions are evaluated for distribution of relevant marker genes.…”

Surplus Ceramides: An Added Twist in the Tale of TREM2 and Insulin Resistance

“…Second, while Sharif et al (6) suggest that TREM2's effects on metabolism are macrophage independent, recent studies by Jaitin et al (4) suggest the opposite. These discordant findings may be explained in part by the utilization of bone marrow transplantation (BMT) to discern the importance of hematopoietic cells.…”

“…Sharif et al (6) instead propose that TREM2's role in insulin resistance may be intrinsic to WAT itself. They detect adipose tissue expression of TREM2 not only in ATMs but also in adipocytes, suggesting that insulin resistance may be impacted by TREM2 expression by both cell types.…”

“…In this issue of Diabetes, Sharif et al (6) identify ceramides, a class of sphingolipids, as an important link between TREM2 and insulin resistance (measured by the insulin tolerance test). Ceramides play a role in membrane integrity, cellular stress responses, inflammation, and apoptotic signaling, and elevated ceramide levels have been implicated in numerous metabolic pathologies (7).…”

“…A major advance of the work by Sharif et al (6) is the demonstration that elevated ceramides contribute to insulin resistance in obese Trem2 À/À mice. Interestingly, the authors' metabolomics approach also uncovered an increase in serum ceramides in lean Trem2 À/À mice, suggesting a predisposition of these animals to poor metabolic outcomes in response to HFD and providing a glimpse into TREM2's potential mechanism of action in maintaining insulin sensitivity.…”