Abstract
This study investigated the influence of three high-fat diets (HFDs), differing in the percentage of total calories from saturated fat (SF) (6%, 12%, 24%) but identical in total fat (40%), for a 16-week period in mice on a variety of tissue-specific cellular processes believed to be at the root of obesity-related diseases. Specifically, we examined ectopic lipid accumulation, oxidative capacity [peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) mRNA and protein; mtDNA; Cox IV and cytochrome C protein; citrate synthase activity; and gene expression of fission 1, mitofusin (Mfn) 1 and Mfn2], oxidative stress (4-hydroxy-2-nonenal), endoplasmic reticulum (ER) stress (binding immunoglobulin protein, activating transcription factor 6-p50, p-eukaryotic initiation factor 2 alpha and x-box binding protein 1 spliced protein), inflammatory [p-c-Jun N-terminal kinase (JNK), p-nuclear factor kappa-B, p-p38 mitogen-activated protein kinase) and insulin signaling (p-Akt), and inflammation [tumor necrosis factor-alpha, monocyte chemotactic protein-1, interleukin-6, F4/80, toll-like receptor (TLR)2 and TLR4 gene expression] in various tissues, including the adipose tissue, liver, skeletal muscle and heart. In general, adipose and hepatic tissues were the only tissues which displayed evidence of dysfunction. All HFDs down-regulated adipose, cardiac and hepatic PGC-1α mRNA and hepatic citrate synthase activity, and induced adipose tissue oxidative stress, whereas only the 6%-SF and 12%-SF diet produced hepatic steatosis. However, compared to the 6%-SF and 24%-SF diets, consumption of the 12%-SF diet resulted in the greatest degree of dysregulation (hepatic ER and oxidative stress, JNK activation, increased F4/80 gene expression and down-regulation of adipose tissue Akt signaling). These findings suggest that the saturated fatty acid composition of an HFD can greatly influence the processes responsible for obesity-related diseases - nonalcoholic fatty liver disease, in particular - as well as provide further evidence that the mechanisms at the root of these diseases are diet and tissue sensitive.