Studies also show that SIRT3 mRNA expression and protein content in the liver are decreased in response to nutrient excess and increased in response to fasting. Hence, given the critical roles for SIRT3 in multiple aspects of fat and energy expenditure, programming of SIRT3 may have important consequences for offspring metabolism. Utilizing SIRT3-knockout mice, Hirschey et al. performed a meticulous study demonstrating the role of SIRT3 in regulating mitochondrial fatty acid oxidation. Increased SIRT3 expression, in response to fasting, induced LCAD via deacetylation leading to increased FAO in the liver, heart, and brown fat. Moreover, overexpression of SIRT3 rescued hepatic FAO in the SIRT3 KO mice. Our results from offspring of obese dams are analogous to the phenotypic changes observed in the SIRT3 KO mice would strongly suggest that hepatic FAO may be reduced in the offspring of obese dams. Further, a recent study by Kendrick et al. showed that fatty liver is associated with decreased SIRT3 activity, hyperacetylation of key mitochondrial proteins, and impairment of the ETC. These data are again consistent with previously reported hepatic steatosis and lipid accumulation in offspring of obese dams at weaning. Deficits in FAO in offspring of obese dams are certainly not limited to lower SIRT3 and mitochondrial OXPHOS. We previously reported that carnitine palmitoyl-CoA transferase -1, the rate-limiting enzyme for fatty acid entry into the mitochondria, is reduced in the offspring of obese dams. This was associated with a coordinated down-regulation of PPAR-a regulated genes and reduced phosphorylation of AMPKThr172 in the offspring of obese dams. Phosphorylation of AMPK induces activation of catabolic processes such as glucose uptake and fatty acid oxidation and has been shown to be affected in other models of maternal overnutrition. Moreover, SIRT3 appears to regulate AMPK activation as shown in skeletal muscle and human hepatic cells. Further, Pillai et al. have recently reported that the regulatory mechanism is via SIRT3 deacetylation and activation of LKB1, an upstream kinase known to activate AMPK in mice hearts. It is likely that a reduction in hepatic fatty acid oxidation not only further reinforces mitochondrial dysfunction, but may also be contributing to the development of hepatic steatosis observed in the offspring of obese dams at weaning. Adaptation to fasting requires activation of numerous pathways that coordinate the mobilization of fatty acids. Upregulation of PPAR-a is one of the primary drivers in the liver. It has been previously reported that mice deficient in PPAR-a develop dramatic hepatic steatosis upon fasting. Increases in pyruvate and nicotinamide adenine dinucleotide + levels during fasting result in greater enzymatic activity and protein content of SIRT1 in the nucleus. Among its many actions, SIRT1 activates PGC-1a via deacetylation leading to transcriptional activation of a complement of genes associated with mitochondrial biogenesis, OXPHOS and fatty acid oxidation. Interestingly, it appears that PPAR-a acts upstream of SIRT1, although the precise mechanisms remain unknown. SIRT1 also antagonizes lipogenic gene expression, mainly via SREBP-1. Andenovirus-mediated hepatic overexpression of SIRT1 in mice during fasting significantly downregulated SREBP1c, fatty acid synthase, and elongation of very long chain fatty acids-6.
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