The current investigation has several novel observations. First, fasting induces the expression of coactivator PGC-1α and orphan nuclear receptor ERRα and ERRγ in mouse kidney. Second, the fasting-induced expression of the PGC-1α, ERRα and ERRγ is primarily localized in the OSOM of the kidney. Third, genes involved in energy balance are upregulated at the OSOM of the kidney during short-term fasting.
It is well known tissues requiring a high level of energy for normal physiological function also contain greater levels of PGC-1α, ERRα and ERRγ (see review and references therein 
). We have examined the relative levels of PGC-1α and the ERRs in the same polyA RNA preparation of various human tissues by Northern blot analysis and found that the kidney and heart contain relatively high levels of all three mRNAs. This underscores the importance of PGC-1α, ERRα and ERRγ in maintaining the normal physiological functions in these high energy demanding tissues 
. Interestingly, these proteins are relatively low in the liver but highly inducible during fasting 
. In this study, we found that the expression characteristics of PGC-1α, ERRα and ERRγ in the mouse kidney are reminiscent of that in the liver with an increase in expression during fasting () despite already high basal levels. By using the ERRα knockout mouse model, the authors have demonstrated that several genes involved in blood pressure regulation, ion transport and electrolyte homeostasis was dysregulated. To further evaluate the participation of ERRα with the genes of the kidney that regulate the renin-angiotensin-aldosterone system, the siRNA knockdown of ERRα in the immortalized juxtaglomerular As4.1 cell line was performed and a direct repressive effect of ERRα on renin expression was confirmed 
. These findings suggested that the ERRs are not only involved in general energy production but also involved in specific kidney functions. When we examined by qPCR, the mRNAs prepared from the OSOM of the kidney during fasting for additional target genes, we found that the expression of NHE-3 was significantly increased (Data not shown). NHE-3 plays an important role in the homeostasis of Na+
-fluid volume. The NHE-3 Na+
exchanger deficiency mice showed sharp reduction in HCO3−
and fluid absorption in the proximal convoluted tubule 
. This observation is consistent with the role of proximal tubule in the ATP-dependent re-absorption function of the kidney. Whether ERRs play any role in NHE-3 expression is unclear and further experimentations are needed. However, we scanned the genomic sequence of mouse Slc9a3 (NM_001081060) plus its 20-kilobase pair upstream promoter sequence (65,841 bp in total) and found several putative ERE/ERREs. Although it is not clear if any of the predicted response elements functional and could bind ERRs, the possibility exists that NHE-3 gene could be regulated by PGC-1α/ERRs pathway.
Study on ERRγ null mice revealed the gene expression of key potassium channel subunits in the embryonic kidney were markedly reduced and the potassium homeostasis was profoundly dysregulated 
. The study highlights the important role that ERRγ plays in the control of ion homeostasis in highly oxidative renal tissue. It is not surprising that both ERRα and ERRγ carry out similar physiological roles in the kidney since they share 98% identity in their DNA binding domain, are able to form homodimers or heterodimers with each other, and bind to their target genes in a similar fashion 
implicating that these two receptors could target the same gene and carry out comparable cellular energy metabolism functions. These observations reconfirm the functional roles of ERRs when coexpressed in the kidney under normal and stressful physiological conditions.
Inducing PGC-1α expression in the liver and muscle by fasting has been well documented 
and our current study is able to add the kidney to this list. PGC-1α is a key regulator to metabolic homeostasis and it activates glycogenolysis, switches on gluconeogenesis and increases fatty acid oxidation by activating the transcriptional program of the genes involved in such programs during fasting. The functional mechanisms of PGC-1α rely on its ability to coactivate its DNA binding partners, the ERRs 
to transactivate a number of key enzymes involved in various metabolic functions. For instance, enzymes involved in the initial steps of steroidogenesis 
, enzymes that commit cholesterol to the neutral bile acid biosynthesis pathway 
and enzymes that switch the energy source from glucose to fatty acids 
. Induction of PGC-1α and its' ERR partners in the kidney during fasting strongly suggests that the energy homeostasis program in the kidney is carried out in a similar fashion as with the other tissues.
What affects the function of ERRs could also have an impact on the response and function of the kidney during fasting. Recently, it has been demonstrated that endocrine disruptors such as bisphenol A 
binds and opposes 4-OHT induced effects on ERRγ. Therefore, the effect of environmental pollutants on the function of ERRs during fasting could be an important area for further study. It has been reported that there are gender differences in lipid kinetics during the short-term fasting 
. The basal lipolytic rate in females is higher than in males. During the short term fasting, the relative increase in whole body lipolytic rate was blunted in females as compared with males whereas the decline in glucose production was similar in both genders. There are apparent differences in the metabolic profiles of males and females in response to fasting 
. Although gender differences could contribute to the levels of gonadal hormones or body fat content, the basic mechanism of gene expression in response to fasting may differ between males and females. Our current study was carried out with female mice. Future studies will be conducted to investigate the effects of fasting on the expression of PGC-1α and the ERRs in the kidney of the male mice.