Transcriptional coactivator PGC-1α and its splice variant NT-PGC-1α regulate a number of genes involved in metabolic pathways in a tissue-specific manner. We previously showed that FL-PGC-1α-/- mice lacking full-length PGC-1α (aa 1-797) are resistant to high-fat diet (HFD)-induced obesity because of increased energy expenditure resulting from enhanced brown adipose tissue thermogenesis. The aim of the preset study was to investigate the effect of NT-PGC-1α deficiency on HFD-induced obesity.
NT-PGC-1α-/- mice and wild type littermates (n=12 per group) were fed a regular chow or a 60% HFD for 16 weeks at 28C.
On the chow diet WT and NT-PGC-1α-/- mice exhibited comparable weight gain and similar body composition. However, when placed on HFD, NT-PGC-1α-/- mice displayed a significant reduction in weight gain and adiposity compared with WT mice. Decreased adiposity was also associated with improved glucose tolerance. The observed reduction in weight gain in NT-PGC-1α-/- mice was in part due to decreased food intake and increased fecal energy excretion. Energy expenditure did not differ between WT and NT-PGC-1α-/- mice. NT-PGC-1α-/- inguinal and gonadal adipose tissue had a greater frequency of small adipocytes and a lower frequency of mid- to large-sized adipocytes. While NT-PGC-1α deficiency had no discernable effect on lipolysis and fatty acid oxidation enzyme gene expression in inguinal and gonadal adipose tissue, it led to downregulation of key genes involved in fatty acid uptake and lipid synthesis. Consistent with transcriptional changes, NT-PGC-1α-/- inguinal and gonadal adipose tissue showed a decrease in [14C]-palmitate uptake.
The results indicate that decreased food intake and increased fecal energy excretion contribute to the attenuation of HFD-induced obesity in NT-PGC-1α-/- mice. Moreover, the decreased ability of NT-PGC-1α-/- adipose tissue to take up fatty acids further contribute to a reduction in fat storage in adipose tissue.