Hepatic energy metabolism is highly regulated at the level of gene transcription. Previous work has suggested that the PGC-1 coactivators play important roles in transcriptionally regulating mitochondrial biogenesis and metabolism in liver. Herein, we evaluated the effects of liver-specific, postnatal PGC-1β knockout on intermediary fatty acid metabolism and mitochondrial oxidative function. The data presented are consistent with dual roles for PGC-1β in regulating intermediary fat metabolism and suggest that PGC-1β controls hepatic mitochondrial biogenesis and oxidative function as well as the capacity for lipogenesis under conditions of high lipogenic flux.
Hepatic steatosis is related to an imbalance between fatty acid influx, de novo synthesis, oxidation, and lipoprotein secretion by the liver. The present data suggest that the steatosis observed in livers of LS-PGC-1β−/−
mice is due to impaired hepatic fatty acid oxidation. Six week old LS-PGC-1β−/−
mice exhibited marked deficiencies in the expression of genes encoding mitochondrial fatty acid oxidation and electron transport chain enzymes, reduced mtDNA content, and diminished rates of fatty acid oxidation and mitochondrial respiration. Also consistent with a defect in fatty acid β-oxidation, we detected reduced concentrations of short-chain acyl-carnitine while long-chain acyl-carnitine levels were increased. Because this is a liver-specific knockout of PGC-1β, we have eliminated the potentially confounding influences that PGC-1β deficiency in peripheral tissues, such as perturbations in adipose tissue metabolism, might have on hepatic lipid accumulation 
. The finding that the expression of multiple fatty acid oxidative enzymes is downregulated in LS-PGC-1β−/−
mice differs from the phenotype of generalized and liver-specific PGC-1α-deficient mice that exhibit normal expression of these fatty acid oxidative enzymes 
. While deficits in β-oxidation flux in PGC-1α deficient mice have been observed, these defects are attributed to abnormalities in downstream enzymes involved in electron transport leading to a metabolic bottleneck 
. The finding that loss of PGC-1β strongly affected β-oxidation enzyme expression may suggest that these genes are more highly influenced by this PGC-1 family member. Studies with isolated mitochondria determined that oxidation of succinate, which enters the mitochondrial electron transport chain directly and downstream of β-oxidation, was also reduced in LS-PGC-1β−/−
mice. These data suggest that PGC-1β has broad effects on multiple mitochondrial pathways to coordinate mitochondrial oxidative metabolism.
While previous work has suggested a great deal of overlap between PGC-1α and PGC-1β in the regulation of mitochondrial metabolism, the ability to regulate hepatic de novo lipogenesis has been shown to be a unique feature of PGC-1β. This is likely due to lack of sequence homology between PGC-1β and PGC-1α proteins in the region that mediates the interaction with SREBP1 
. In this work, we found that the expression of genes encoding lipogenic enzymes in 6–8 week old LS-PGC-1β−/−
mice is normal at baseline, when rates of hepatic de novo lipogenesis would be predicted to be low. However, in the context of refeeding a high carbohydrate diet after a prolonged fast, which is a robust stimulus for lipogenic flux, the inducible expression of genes encoding lipogenic enzymes and rates of lipogenesis were significantly attenuated by loss of PGC-1β. The actions of PGC-1β have also been suggested to be relevant to the lipogenic activation that occurs after feeding a saturated fat-enriched or high fructrose diet 
. These data suggest that PGC-1β is a regulator of the increased capacity for lipogenesis that occurs in times of nutrient excess, but may not be important for the basal expression of these genes. However, the expression of these lipogenic enzymes was still induced significantly in LS-PGC-1β−/−
mice after refeeding, indicating that other transcription factors and/or coactivators are sufficient to mediate a large component of this response. Furthermore, liver TG content was increased, rather than decreased, in refed LS-PGC-1β−/−
mice, suggesting that hepatic TG levels in this context are influenced by the capacity to oxidize fatty acids, which is reduced in the LS-PGC-1β−/−
The present data suggest that PGC-1β plays dual roles in governing hepatic fatty acid metabolism and regulates both fatty acid oxidation and de novo fatty acid synthesis 
, which is one of the more puzzling aspects of PGC-1β biology. Why would a factor promote both fatty acid synthesis and degradation, which is in essence, a futile cycle? The process of de novo lipogenesis does require the generation of reducing equivalents that could be produced by fat oxidation. Several known targets of the lipogenic transcription factor, SREBP1, are enzymes that generate reducing equivalents required to drive lipogenesis 
. High rates of hepatic lipogenesis occur only when nutrients and insulin are in abundance and the organism can afford to spend energy to store fat. There are nutrient-replete physiologic contexts wherein both fatty acid oxidation and fatty acid synthesis would be high, including after administration of high fat diet, which is known to activate PGC-1β 
. Perhaps with time, clarity regarding the physiological reason for these dichotomous effects will be achieved.