Loss of the acyltransferase TMEM68 leads to growth delay and dysregulation of triacylglycerol and glycerophospholipid homeostasis in the mouse brain

Abstract

Lipid droplets (LDs) are ubiquitous cellular storage organelles for triacylglycerol (TAG) that have recently been implicated in brain development and aging, and the progression of neurodegenerative diseases. However, the enzymes responsible for brain TAG synthesis are incompletely understood. Transmembrane protein 68 (TMEM68) catalyzes TAG synthesis independent of canonical diacylglycerol acyltransferase (DGAT) enzymes and is highly expressed in the brain. In the current study, we addressed the role of TMEM68 in murine brain TAG metabolism using a global Tmem68 knockout mouse model. We found that loss of TMEM68 led to decreased TAG levels in the cerebral cortex and a concomitant increase in polyunsaturated glycerophospholipid species. These changes in lipid pattern were associated with perturbed expression of genes involved in fatty acid and glycerophospholipid metabolism. While brain size and morphology were largely unaffected, TMEM68 deficiency caused reductions in white adipose tissue mass, decreased insulin-like growth factor 1 levels, and retarded weight gain. In conclusion, our study identifies TMEM68 as regulator of TAG and glycerophospholipid homeostasis in the central nervous system and discloses a requirement of the enzyme for postnatal development and energy metabolism.