The HLA-F Adjacent Transcript #10 (FAT10) is an ubiquitin like modifier composed of two ubiquitin related sequences arranged in tandem. We previously reported on the discovery that silencing FAT10 expression in mice extends their lifespan by 25% and reduces total body fat by 50%, for both genders. FAT10ko mice (2 months) display an increased insulin response and glucose tolerance (ITT and GTT). However, it was not clear whether this early age insulin sensitivity will be maintained to an advanced age.In addition, we notice that WAT from the leaner FAT10ko has smaller adipocytes. Thus, we hypothesized that FAT10ko has impaired adipogenesis.
FAT10ko mice and their controls were evaluated by hyperinsulinemic-hypoglycemic clamps (2-16 months). Adipogenesis was studied in vitro on 3T3-L1 cells following FAT10 knockdown. RNA-Seq was performed at several time points during adipogenesis and the data was analyzed by Ingenuity Pathway Analysis combined with TRANSFAC analysis.
Hypoglycemic clamp data indicate that FAT10ko mice kept significantly low insulin levels through 15 months of age. FAT10 expression was detected in 3T3-L1 cells throughout their adipogenic differentiation. Silencing FAT10 resulted in reduced adipogenesis and bioinformatics analysis revealed major differential gene expressions associated with adipocyte metabolic functions and growth. Finally, we identified new regulation of FAT10 by adipogenic transcription factors.
FAT10 silencing supports health-span by increasing insulin sensitivity and by maintaining this through the aging process. Similarly, the reduced adiposity is at least partially due to the impaired adipogenesis in the absence of FAT10 expression. Both obesity and diabetes have negative impact on health-span and life-span. FAT10 thus provides a potentially new insight into mechanisms of mammalian metabolism and aging and ultimately an opportunity to identify druggable targets.