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 liverlike 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 insulinlike 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.T o maintain metabolic homeostasis during fasting periods, metazoans have to coordinate the mobilization of glycogen, lipids, and protein, ensuring an adequate energy supply across tissues. In addition to tissue-autonomous metabolic adjustments, endocrine signals are therefore critical components of the fasting response (1, 2). In mammals, the liver is central to adjusting intermediary metabolism during fasting. Starvation stimulates lipid accumulation in hepatocytes, which oxidize these lipids to provide energy in the form of ketone bodies for other tissues. Hepatocytes also respond to glucagon and insulin signals to control the expression of enzymes involved in glycogenolysis and gluconeogenesis, lipolysis, fatty acid oxidation, and ketogenesis, all regulated by a battery of transcription factors that include forkhead box O (Foxo), cAMP-response element binding (CREB), peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1a), and hepatocyte nuclear factor 4a (HNF4a) (3-5). At the same time, the liver integrates a suite of endocrine signals derived from major energy storing and consuming tissues, such as the brain, the adipose tissue, and the muscle (1). Deregulation of these processes can lead to hepatic steatosis and is a major cause of metabolic diseases, including diabetes and metabolic syndrome (1,3,6).Drosophila has emerged as a productive model organism in which to characterize the endocrine regulation of metabolic adaptation (7,8). The central function of the liver in metabolic adaptation of flies is shared by the fat body and oenocytes. Whereas the fat body is an important glycogen and fat storage organ in flies, it also serves as an endocrine organ to coordinate metabolic homeostasis (9-12). Oenocytes have a critical role in lipid mobilization and turnover in larvae, accumulating lipids during s...
