Anti-FASN monoclonal antibody, clone B-6

Background: Nrg4 expression has been linked to brown adipose tissue activity and browning of white adipocytes in mice. Here, we aimed to investigate whether these observations could be translated to humans by investigating NRG4 mRNA and markers of brown/beige adipocytes in human visceral (VAT) and subcutaneous adipose tissue (SAT). We also studied the possible association of NRG4 with insulin action. Methods: SAT and VAT NRG4 and markers of brown/beige (UCP1, UCP3, and TMEM26)-related gene expression were analyzed in two independent cohorts (n = 331 and n = 59). Insulin resistance/sensitivity was measured using HOMA(IR) and glucose infusion rate during euglycemic hyperinsulinemic clamp. Results: In both cohort 1 and cohort 2, NRG4 and thermogenic/beige-related gene expression were significantly increased in VAT compared to SAT. Adipogenic-related genes followed an opposite pattern. In cohort 1, VAT NRG4 gene expression was positively correlated with BMI and expression of UCP1, UCP3, TMEM26, and negatively with adipogenic (FASN, PPARG, and SLC2A4)- and inflammatory (IL6 and IL8)-related genes. In SAT, NRG4 gene expression was negatively correlated with HOMA I R and positively with UCP1 and TMEM26 gene expression. Multiple linear regression analysis revealed that expression of TMEM26 gene was the best predictor of NRG4 gene expression in both VAT and SAT. Specifically, NRG4 and TMEM26 gene expression was significantly increased in VAT, but not in SAT stromal vascular fraction cells (p < 0.001). In cohort 2, the significant association between NRG4 and TMEM26 gene expression in both VAT and SAT was confirmed, and SAT NRG4 gene expression also was positively correlated with insulin action and the expression of UCP1. Conclusion: Current findings suggest NRG4 gene expression as a novel marker of beige adipocytes in human adipose tissue.

Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver dysfunction, is a metabolic disease that begins with steatosis. Sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate (S1P), have recently received attention for their potential roles in insulin resistance and hepatic steatosis. FTY720/fingolimod, a prodrug for the treatment of multiple sclerosis, is phosphorylated in vivo to its active phosphorylated form by sphingosine kinase 2 and has been shown to interfere with the actions of S1P and to inhibit ceramide biosynthesis. Therefore, in this study we investigated the effects of FTY720 in a diet-induced animal model of NAFLD (DIAMOND) that recapitulates the hallmarks of the human disease. The oral administration of FTY720 to these mice fed a high-fat diet and sugar water improved glucose tolerance and reduced steatosis. In addition to decreasing liver triglycerides, FTY720 also reduced hepatic sphingolipid levels, including ceramides, monohexosylceramides, and sphingomyelins, particularly the C16:0 and C24:1 species, as well as S1P and dihydro-S1P. FTY720 administration decreased diet-induced fatty acid synthase (FASN) expression in DIAMOND mice without affecting other key enzymes in lipogenesis. FTY720 had no effect on the expression of SREBP-1c, which transcriptionally activates FASN. However, in agreement with the notion that the active phosphorylated form of FTY720 is an inhibitor of histone deacetylases, FTY720-P accumulated in the liver, and histone H3K9 acetylation was markedly increased in these mice. Hence, FTY720 might be useful for attenuating FASN expression and triglyceride accumulation associated with steatosis.