Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic disorders, occurring in approximately 1 in every 1000 live births (Wilson, 2004). About 50% of people who inherit the mutation will develop chronic kidney disease (CKD), characterized by the development of multiple large cysts in both kidneys followed by functional decline and end-stage renal disease. While the genetic mutations in polycystin 1 and polycystin 2 (PKD1 and PKD2, respectively)(Rangan et al., 2015) were identified more than 30 years ago, the mechanism of disease development remains largely unknown (Reeders et al., 1985). Menezes et al. took an unbiased systemsbiology approach to study Pkd1 gene function and report their results in the current issue of EBioMedicine (Menezes et al., 2016). The authors performed genome wide transcript profiling on mice with conditional deletion of Pkd1, a model of ADPKD. They noted that disease severity was much milder in female mice when compared to their male counterparts. Metabolic genes represented the largest differentially expressed gene cluster, which correlated with disease development. Specifically, they identified differences in expression levels of several important regulators of lipid metabolism, which they probed further with unbiased metabolomics and lipidomics studies. Lipidomics studies highlighted several significant differences between control and Pkd1 knockout animals, including significantly lower diacylglycerol levels in mutant kidneys. Diacylglycerol is a byproduct of triglyceride metabolism. This prompted the authors to take a closer look at fatty acid oxidation. Cell culture studies showed that renal epithelial cells lacking Pkd1 have a cell autonomous defect in fatty acid oxidation, as these cells not oxidize palmitate as efficiently as control cells. Even though previous studies indicated changes in glucose metabolism in ADPKD, specifically an increased reliance on glucose as an energy source (Rowe et al., 2013), Menezes et al. were unable to detect changes in the glycolytic capacities of ADPKD cells. Throughout the body, specific tissues and cells have evolved individualized metabolic patterns. Tubular epithelial cells in the kidney require large amounts of energy, mostly to reabsorb filtered electrolytes and to eliminate potential toxins. This process has a high energy demand. Although constituting only 0.5% of body mass, kidneys consume 10% of the oxygen. To fuel this high energy consumption, tubule epithelial cells preferentially take up and oxidize fatty acids as their energy source and have a very high mitochondrial density (Meyer et al., 1997). Gene expression studies performed on microdissected tubule samples obtained from patients with (diabetic and hypertensive) chronic kidney disease (CKD) compared to healthy subjects highlighted that fatty acid metabolism is altered in human CKD samples (Kang et al., 2015). In addition, cell culture studies indicate that CKD tubule cells are unable to switch to alternative fuel source such as glucose to efficiently generate energy. When lacking in energy, tubule cells are left dedifferentiated, unable to perform energy-demanding transport functions. Results of the present study indicate that the defect in lipid metabolism is not specific for a CKD type and most likely can be seen in all forms CKD. Future studies should aim to understand molecular alterations observed in the metabolism of CKD kidneys. Are these problems caused by a defect in a single step in fatty acid oxidation, or multiple steps are altered due to transcriptional regulatory defect? Current observations hint that the defect is upstream at the transcriptional regulation of rate …