Differential induction of genes in liver and brown adipose tissue regulated by peroxisome proliferator-activated receptor-α during fasting and cold exposure in acyl-CoA dehydrogenase-deficient mice

Mice deficient for either long-chain acyl-CoA dehydrogenase (LCAD−/−) or very-long-chain acyl-CoA dehydrogenase (VLCAD−/−) develop hepatic steatosis upon fasting, due to disrupted mitochondrial fatty acid oxidation. Moreover, neither mouse model can maintain core body temperature when exposed to cold. We investigated the effects of fasting and cold exposure on gene expression in these mice. Non-fasted LCAD−/− mice showed gene expression changes indicative of fatty liver, including elevated mRNA levels for peroxisome proliferator-activated receptor-γ (PPARγ) and genes involved in lipogenesis. In LCAD−/− and VLCAD−/− mice challenged with fasting and cold exposure, expression of fatty acid oxidation genes was elevated in liver, consistent with increased PPARα activity. This effect was not seen in brown adipose tissue, suggesting that expression of these genes may be regulated differently than in liver. The effect of acute cold exposure on expression of fatty acid oxidation genes was measured in peroxisome proliferator-activated receptor (PPAR)-α-deficient mice (PPARα−/−) and controls. In PPARα−/− mice, basal expression of the acyl-CoA dehydrogenases was reduced in liver but was not altered in brown adipose tissue. While cold altered the expression of PPARγ, sterol-regulatory element binding protein-1 (SREBP-1), ATP citrate lyase, and the uncoupling proteins in brown adipose tissue from both PPARα−/− and control mice, fatty acid oxidation genes were unaffected. Thus, while fatty acid oxidation appears critical for non-shivering thermogenesis, expression of the acyl-CoA dehydrogenases is not influenced by cold exposure. Moreover, mitochondrial fatty acid oxidation genes are not regulated by PPARα in brown adipose tissue as they are in liver.