Cyp1b1 and undefined substrates play a central role in the systemic, external regulation of hepatic fatty acid metabolism. The extensive sexual dimorphism of the hepatic gene changes points towards estradiol metabolism as a contributor. Removal of Cyp1b1 activity produces an extensive suppression of endogenous PPARα signaling in males, under ad libitum feeding conditions, which becomes more selective in 36 week females. There is evidence for suppression of other lipid-controlled receptors, including CAR, PXR and LXR. ChIPseq analyses of specific epigenetic changes in responsive genes in Cyp1b1-ko hepatocytes provides the means to examine this possibility. These effects may also be developmentally determined, notably by effects of Cyp1b1 metabolism on local estradiol levels in the hypothalamus. Retention of in vivo changes in Cyp1b1-ko hepatocytes in culture or effects of non-parenchymal cells from Cyp1b1-ko mice on co-cultured WT hepatocytes may each provide insight into how Cyp1b1 is functioning. Adropin has emerged as a strong candidate for mediation of Cyp1b1-deletion effects [66]. The conserved effects of Cyp1b1-deletion on hepatic gene expression are remarkably linked to extensive anti-diabetic effects (Table 4). These beneficial effects could
