These findings identify a gene regulatory pathway involved in the control of cardiac energy production during the development of HF.

No abstract

The peroxisome proliferator-activated receptor ␣ (PPAR ␣ ) is a nuclear receptor implicated in the control of cellular lipid utilization. To test the hypothesis that PPAR ␣ is activated as a component of the cellular lipid homeostatic response, the expression of PPAR ␣ target genes was characterized in response to a perturbation in cellular lipid oxidative flux caused by pharmacologic inhibition of mitochondrial fatty acid import. Inhibition of fatty acid oxidative flux caused a feedback induction of PPAR ␣ target genes encoding fatty acid oxidation enzymes in liver and heart. In mice lacking PPAR ␣ (PPAR ␣Ϫ / Ϫ ), inhibition of cellular fatty acid flux caused massive hepatic and cardiac lipid accumulation, hypoglycemia, and death in 100% of male, but only 25% of female PPAR ␣Ϫ / Ϫ mice. The metabolic phenotype of male PPAR ␣Ϫ / Ϫ mice was rescued by a 2-wk pretreatment with ␤ -estradiol. These results demonstrate a pivotal role for PPAR ␣ in lipid and glucose homeostasis in vivo and implicate estrogen signaling pathways in the regulation of cardiac and hepatic lipid metabolism. ( J.

S6 kinase (S6K) deletion in metazoans causes small cell size, insulin hypersensitivity, and metabolic adaptations; however, the underlying molecular mechanisms are unclear. Here we show that S6K-deficient skeletal muscle cells have increased AMP and inorganic phosphate levels relative to ATP and phosphocreatine, causing AMP-activated protein kinase (AMPK) upregulation. Energy stress and muscle cell atrophy are specifically triggered by the S6K1 deletion, independent of S6K2 activity. Two known AMPK-dependent functions, mitochondrial biogenesis and fatty acid beta-oxidation, are upregulated in S6K-deficient muscle cells, leading to a sharp depletion of lipid content, while glycogen stores are spared. Strikingly, AMPK inhibition in S6K-deficient cells restores cell growth and sensitivity to nutrient signals. These data indicate that S6K1 controls the energy state of the cell and the AMPK-dependent metabolic program, providing a mechanism for cell mass accumulation under high-calorie diet.