title: The Nutrient-Responsive Hormone CCHamide-2 Controls Growth by Regulating Insulin-like Peptides in the Brain of Drosophila melanogaster.
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.
authors.affiliation: Department of Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Fukuoka, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Sano
authors.affiliation: Department of Germline Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Texada
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America.
authors.forename: James W
authors.initials: JW
authors.lastname: Truman
authors.affiliation: Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishimoto
authors.affiliation: Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Kamikouchi
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nibu
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kume
authors.affiliation: Division for Searching and Identification of Bioactive Peptides, Department of Bioactive Peptides, Frontier Science Research Center, University of Miyazaki, Miyazaki, Miyazaki, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Ida
authors.affiliation: Department of Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Fukuoka, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Kojima
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism; D029721:Drosophila Proteins / Q000096:biosynthesis* / Q000235:genetics*; D004331:Drosophila melanogaster; D005216:Fat Body / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D061385:Insulins / Q000096:biosynthesis* / Q000235:genetics; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics*; D018004:Receptors, Bombesin / Q000235:genetics*; D018035:Receptors, Odorant / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C555823:CCH-amide-2 neuropeptide, Drosophila; D029721:Drosophila Proteins; C570846:Ilp5 protein, Drosophila; D007328:Insulin; D061385:Insulins; D009479:Neuropeptides; D018004:Receptors, Bombesin; D018035:Receptors, Odorant; C107120:bombesin receptor subtype 3