Neuronal growth regulator 1-deficient mice show increased adiposity and decreased muscle mass.

Neuronal growth regulator 1 (NEGR1) is a glycosylphosphatidylinositol-anchored membrane protein that mediates neural cell communication and synapse formation. Multiple genome-wide association studies have reported that variations in NEGR1 are associated with human body weight control. Recently, we found that NEGR1 is involved in intracellular cholesterol trafficking, suggesting that it performs a non-central nervous system (CNS) function associated with human obesity. We compared peripheral tissues such as the adipose, liver, and skeletal muscle tissues of Negr1-/- and Negr1+/+ (wild-type [WT]) C57BL/6 mice (n = 5-14). Intracellular lipid content was measured, and lipid accumulation was visualized by staining tissue cross-sections with lipid-specific stains. Muscle capacity of the WT and Negr1-/- mice was determined by performing a treadmill endurance test, and muscle fiber size was examined. Plasma glucose and insulin levels were measured, and glucose and insulin tolerance tests were performed. The Negr1-/- mice showed a significant increase in fat mass (~1.5-fold increase in the epididymal white adipose tissue, p = 0.000002), with abnormally enlarged adipose cells, compared with the WT mice. Primary adipocytes of the Negr1-/- mice contained enlarged cytosolic lipid droplets (p = 0.049). Moreover, these mice showed significant hepatic lipid accumulation (~2.3-fold increase, p = 0.043). Although the Negr1-/- mice did not show a significant change in plasma lipoprotein level, they showed a >1.3-fold increase in a serum glucose (p = 0.0002) and insulin (p = 0.016) levels. Moreover, the Negr1-/- mice showed decreased muscle capacity, as indicated by a decrease in muscle mass (p = 0.000003). These results indicate that NEGR1 deficiency induces abnormal fat deposition in various peripheral cells, especially fat and liver tissue cells, and suggest that NEGR1 is a potential molecular target for designing anti-obesity drugs to regulate body weight both centrally and peripherally.