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

Triggering receptor expressed on myeloid cells 2 (TREM2) is highly expressed by innate immune cells and has been implicated in a variety of diseases, including Alzheimer disease, cancer, and diabetes. TREM2 binds a wide array of ligands signaling tissue damage (1), including pathogenic lipids, which can elicit highly variable effects (both in terms of magnitude and direction) on downstream signaling pathways in a ligand-specific manner (2). Given the importance of pathogenic lipids and myeloid cells in obesity and diabetes, there has been considerable interest in elucidating the role of TREM2 in disease progression. Metabolic studies in mice globally overexpressing TREM2 (3) or in mice with global TREM2 knockout ( Trem2 −/−) (4,5) both reported increased body weight gain and exacerbated insulin resistance. Thus, the relationship between TREM2 and insulin resistance has proven complicated, and the mechanism(s) underlying its effects on metabolic disease require further elucidation to help develop a therapeutic approach. 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). Using a metabolomics approach, the authors demonstrate elevated serum ceramide levels in Trem2 −/− mice at baseline and during diet-induced obesity (DIO) relative to wild-type …