Beneficial Metabolic Effects of TREM2 in Obesity Are Uncoupled From Its Expression on Macrophages.
Omar SharifJulia Stefanie BrunnerAna KorosecRui MartinsAlexander JaisBerend SnijderAndrea VogelMichael CalderaAnastasiya HladikKarin LakovitsSimona SaluzzoBenedikta BoehmAnna-Dorothea GorkiIldiko MesteriJosefine Lindroos-ChristensenKatharina TillmannDagmar StoiberJörg MencheGernot SchabbauerMartin BilbanGiulio Superti-FurgaHarald EsterbauerSylvia KnappPublished in: Diabetes (2021)
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.
Keyphrases
- insulin resistance
- adipose tissue
- high fat diet induced
- high fat diet
- metabolic syndrome
- polycystic ovary syndrome
- healthcare
- type diabetes
- public health
- bone marrow
- skeletal muscle
- mental health
- glycemic control
- dna repair
- weight loss
- weight gain
- signaling pathway
- poor prognosis
- dna damage response
- mass spectrometry
- cardiovascular disease
- induced apoptosis
- human health
- coronary artery disease
- endothelial cells
- transcription factor
- immune response
- health promotion
- acute myeloid leukemia
- cardiovascular events
- physical activity
- endoplasmic reticulum stress