Control of metabolic adaptation to fasting by dILP6-induced insulin signaling in Drosophila oenocytes

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. Metabolic adaptation to changing dietary conditions is critical to maintain homeostasis of the internal milieu. In metazoans, this adaptation is achieved by a combination of tissue-autonomous metabolic adjustments and endocrine signals that coordinate the mobilization, turnover, and storage of nutrients across tissues. To understand metabolic adaptation comprehensively, detailed insight into these tissue interactions is necessary. Here we characterize the tissue-specific response to fasting in adult flies and identify an endocrine interaction between the fat body and liver-like oenocytes that regulates the mobilization of lipid stores. Using tissue-specific expression profiling, we confirm that oenocytes in adult flies play a central role in the metabolic adaptation to fasting. Furthermore, we find that fat body-derived Drosophila insulin-like peptide 6 (dILP6) induces lipid uptake in oenocytes, promoting lipid turnover during fasting and increasing starvation tolerance of the animal. Selective activation of insulin/IGF signaling in oenocytes by a fat body-derived peptide represents a previously unidentified regulatory principle in the control of metabolic adaptation and starvation tolerance.