The Nutrient-Responsive Hormone CCHamide-2 Controls Growth by Regulating Insulin-like Peptides in the Brain of Drosophila melanogaster

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Abstract
The coordination of growth with nutritional status is essential for proper development and physiology. Nutritional information is mostly perceived by peripheral organs before being relayed to the brain, which modulates physiological responses. Hormonal signaling ensures this organ-to-organ communication, and the failure of endocrine regulation in humans can cause diseases including obesity and diabetes. In Drosophila melanogaster, the fat body (adipose tissue) has been suggested to play an important role in coupling growth with nutritional status. Here, we show that the peripheral tissue-derived peptide hormone CCHamide-2 (CCHa2) acts as a nutrient-dependent regulator of Drosophila insulin-like peptides (Dilps). A BAC-based transgenic reporter revealed strong expression of CCHa2 receptor (CCHa2-R) in insulin-producing cells (IPCs) in the brain. Calcium imaging of brain explants and IPC-specific CCHa2-R knockdown demonstrated that peripheral-tissue derived CCHa2 directly activates IPCs. Interestingly, genetic disruption of either CCHa2 or CCHa2-R caused almost identical defects in larval growth and developmental timing. Consistent with these phenotypes, the expression of dilp5, and the release of both Dilp2 and Dilp5, were severely reduced. Furthermore, transcription of CCHa2 is altered in response to nutritional levels, particularly of glucose. These findings demonstrate that CCHa2 and CCHa2-R form a direct link between peripheral tissues and the brain, and that this pathway is essential for the coordination of systemic growth with nutritional availability. A mammalian homologue of CCHa2-R, Bombesin receptor subtype-3 (Brs3), is an orphan receptor that is expressed in the islet β-cells; however, the role of Brs3 in insulin regulation remains elusive. Our genetic approach in Drosophila melanogaster provides the first evidence, to our knowledge, that bombesin receptor signaling with its endogenous ligand promotes insulin production. Animals need to couple growth with nutritional availability for proper development and physiology, which leads to better survival. Nutritional information is mostly perceived by peripheral organs, particularly metabolic organs such as adipose tissue and gut, before being relayed to the brain, which modulates physiological responses. Hormonal signaling ensures this organ-to-organ communication, and defects in this endocrine regulation in humans often cause diseases including obesity and diabetes. In the fruit fly Drosophila melanogaster, adipose tissue (the “fat body”) has been suggested to play an important role in coordinating growth with metabolism. Here, we show that the Drosophila CCHamide-2 (CCHa2) gene, expressed in the fat body and gut, encodes a nutrient-sensitive peptide hormone. The CCHa2 peptide signals to neuroendocrine cells in the brain that produce Drosophila insulin-like peptides (Dilps) through its receptor (CCHa2-R) and promotes the production of Dilps. Mutants of both CCHa2 and CCHa2-R display severe growth retardation during larval stages. These results suggest that CCHa2 and CCHa2-R functionally connect peripheral tissues with the brain, and that CCHa2/CCHa2-R signaling coordinates the animal’s growth with its nutritional conditions by regulating its production of insulin-like peptides.

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