Significance This study characterizes the transcriptional response to fasting in adult flies in a tissue-specific manner, highlighting a central role for adult oenocytes in the regulation of lipid mobilization and supporting the proposed analogy between oenocytes and mammalian hepatocytes. A surprising and critical role for insulin signaling activity in the oenocyte fasting response is identified, and it is shown that the Drosophila insulin-like peptide 6 (dILP6), which is induced in the fat body in response to starvation, mediates this response. A new paracrine role for insulin signaling in regulating the interaction between adipose tissue and hepatocyte-like cells in the metabolic adaptation to fasting is thus identified.