Drosophila Cytokine Unpaired 2 Regulates Physiological Homeostasis by Remotely Controlling Insulin Secretion

In Drosophila, the fat body (FB), a functional analog of the vertebrate adipose tissue, is the nutrient sensor that conveys the nutrient status to the insulin-producing cells (IPCs) in the fly brain to release Drosophila insulin-like peptides (Dilps). Dilp secretion in turn regulates energy balance and promotes systemic growth. We identify Unpaired 2 (Upd2), a protein with similarities to type I cytokines, as a secreted factor produced by the FB in the fed state. When upd2 function is perturbed specifically in the FB, it results in a systemic reduction in growth and alters energy metabolism. Upd2 activates JAK/STAT signaling in a population of GABAergic neurons that project onto the IPCs. This activation relieves the inhibitory tone of the GABAergic neurons on the IPCs, resulting in the secretion of Dilps. Strikingly, we find that human Leptin can rescue the upd2 mutant phenotypes, suggesting that Upd2 is the functional homolog of Leptin.

[1]  E. Rulifson,et al.  Remote control of insulin secretion by fat cells in Drosophila. , 2009, Cell metabolism.

[2]  Stephen Brown,et al.  Identification of the first invertebrate interleukin JAK/STAT receptor, the Drosophila gene domeless , 2001, Current Biology.

[3]  D. Berrigan,et al.  Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. , 2003, Annual review of medicine.

[4]  L. Partridge,et al.  A Drosophila Insulin-like Peptide Promotes Growth during Nonfeeding States , 2009, Developmental cell.

[5]  W. Paul,et al.  Molecular phylogeny within type I cytokines and their cognate receptors. , 2003, Immunity.

[6]  Xiangzhong Zheng,et al.  Regulation of feeding and metabolism by neuronal and peripheral clocks in Drosophila. , 2008, Cell metabolism.

[7]  N. Perrimon,et al.  Drosophila unpaired encodes a secreted protein that activates the JAK signaling pathway. , 1998, Genes & development.

[8]  Dawnis M Chow,et al.  Mutation of the Drosophila vesicular GABA transporter disrupts visual figure detection , 2010, Journal of Experimental Biology.

[9]  D. Nässel,et al.  Insulin Signaling, Lifespan and Stress Resistance Are Modulated by Metabotropic GABA Receptors on Insulin Producing Cells in the Brain of Drosophila , 2010, PloS one.

[10]  N. Perrimon,et al.  GFP reporters detect the activation of the Drosophila JAK/STAT pathway in vivo. , 2007, Gene expression patterns : GEP.

[11]  R. Nusse,et al.  Ablation of Insulin-Producing Neurons in Flies: Growth and Diabetic Phenotypes , 2002, Science.

[12]  P. Shen,et al.  Regulation of hunger-driven behaviors by neural ribosomal S6 kinase in Drosophila. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[13]  C. Thummel,et al.  Drosophila HNF4 regulates lipid mobilization and beta-oxidation. , 2009, Cell metabolism.

[14]  T. Baranski,et al.  A high-sugar diet produces obesity and insulin resistance in wild-type Drosophila , 2011, Disease Models & Mechanisms.

[15]  N. Perrimon,et al.  Vector and parameters for targeted transgenic RNA interference in Drosophila melanogaster , 2008, Nature Methods.

[16]  T. P. Neufeld,et al.  TOR coordinates bulk and targeted endocytosis in the Drosophila melanogaster fat body to regulate cell growth , 2006, The Journal of cell biology.

[17]  D. Clapham,et al.  A Prokaryotic Voltage-Gated Sodium Channel , 2001, Science.

[18]  E. Hafen,et al.  Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[19]  A. Shearn,et al.  Patterns of protein synthesis in imaginal discs of drosophila melanogaster , 1977, Cell.

[20]  Xiaobo Zhou,et al.  Towards Automated Cellular Image Segmentation for RNAi Genome-Wide Screening , 2005, MICCAI.

[21]  S. Benzer,et al.  Obesity-Blocking Neurons in Drosophila , 2009, Neuron.

[22]  D. Nässel,et al.  Insulin-producing cells in the brain of adult Drosophila are regulated by the serotonin 5-HT1A receptor , 2011, Cellular and Molecular Life Sciences.

[23]  R. Schulz,et al.  Wingless signaling induces nautilus expression in the ventral mesoderm of the Drosophila embryo. , 1996, Developmental biology.

[24]  M. White,et al.  Insulin-like signaling, nutrient homeostasis, and life span. , 2008, Annual review of physiology.

[25]  M. W. Schwartz,et al.  Central nervous system control of food intake and body weight , 2006, Nature.

[26]  T. Godenschwege,et al.  Invertebrate Synapsins: A Single Gene Codes for Several Isoforms in Drosophila , 1996, The Journal of Neuroscience.

[27]  M. Nitabach,et al.  Functional Dissection of a Neuronal Network Required for Cuticle Tanning and Wing Expansion in Drosophila , 2006, The Journal of Neuroscience.

[28]  J. Kieswich,et al.  Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function , 2011, Diabetologia.

[29]  C. Mantzoros,et al.  Role of leptin in the neuroendocrine response to fasting , 1996, Nature.

[30]  N. Perrimon,et al.  Function of the ETS transcription factor Yan in border cell migration , 2005, Development.

[31]  Matthias Landgraf,et al.  Genetically encoded dendritic marker sheds light on neuronal connectivity in Drosophila , 2010, Proceedings of the National Academy of Sciences.

[32]  Linh Vong,et al.  Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons , 2011, Neuron.

[33]  Norbert Perrimon,et al.  High-throughput RNA interference screens in Drosophila tissue culture cells. , 2005, Methods in enzymology.

[34]  E. Hafen,et al.  An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control , 2001, Current Biology.

[35]  M. Pankratz,et al.  Opposing effects of dietary protein and sugar regulate a transcriptional target of Drosophila insulin-like peptide signaling. , 2008, Cell metabolism.

[36]  Mark R. Brown,et al.  Signaling and function of insulin-like peptides in insects. , 2006, Annual review of entomology.

[37]  B. Fielding,et al.  Specialized hepatocyte-like cells regulate Drosophila lipid metabolism , 2007, Nature.

[38]  N. Perrimon,et al.  The roles of the Drosophila JAK/STAT pathway , 2000, Oncogene.

[39]  Norbert Perrimon,et al.  Genome-wide RNAi analysis of JAK/STAT signaling components in Drosophila. , 2005, Genes & development.

[40]  J. Mier,et al.  Interleukins. , 1985, Annual review of medicine.

[41]  N. Perrimon,et al.  Drosophila Wnt/Fz Pathways , 2005, Science's STKE.

[42]  Norbert Perrimon,et al.  marelle Acts Downstream of the Drosophila HOP/JAK Kinase and Encodes a Protein Similar to the Mammalian STATs , 1996, Cell.

[43]  G. Rubin,et al.  Refinement of Tools for Targeted Gene Expression in Drosophila , 2010, Genetics.

[44]  N. Perrimon,et al.  Mutational analysis reveals separable DNA binding and trans-activation of Drosophila STAT92E. , 2006, Cellular signalling.

[45]  M. Pankratz,et al.  Suppression of food intake and growth by amino acids in Drosophila: the role of pumpless, a fat body expressed gene with homology to vertebrate glycine cleavage system. , 1999, Development.

[46]  D. Zachary,et al.  Drosophila immune deficiency (IMD) is a death domain protein that activates antibacterial defense and can promote apoptosis. , 2001, Developmental cell.

[47]  Stephen Brown,et al.  Characterisation of Upd2, a Drosophila JAK/STAT pathway ligand. , 2005, Developmental biology.

[48]  Gerald M. Rubin,et al.  The activities of two Ets-related transcription factors required for drosophila eye development are modulated by the Ras/MAPK pathway , 1994, Cell.

[49]  Leonard K. Kaczmarek,et al.  Targeted Attenuation of Electrical Activity in Drosophila Using a Genetically Modified K+ Channel , 2001, Neuron.

[50]  D. Smith,et al.  Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice. , 1997, The Journal of clinical investigation.

[51]  A. Shearn,et al.  In vitro growth of imaginal disks from Drosophila melanogaster. , 1977, Science.

[52]  N. Perrimon,et al.  Stripe-specific regulation of pair-rule genes by hopscotch, a putative Jak family tyrosine kinase in Drosophila. , 1994, Genes & development.

[53]  E. Joslin,et al.  Joslin's Diabetes Mellitus , 1971 .

[54]  J. Montagne,et al.  A Nutrient Sensor Mechanism Controls Drosophila Growth , 2003, Cell.

[55]  C. Rickert,et al.  The homeobox gene repo is required for the differentiation and maintenance of glia function in the embryonic nervous system of Drosophila melanogaster. , 1995, Development.

[56]  V. Hartenstein,et al.  A Hedgehog- and Antennapedia-dependent niche maintains Drosophila haematopoietic precursors , 2007, Nature.

[57]  J. S. Britton,et al.  Environmental control of the cell cycle in Drosophila: nutrition activates mitotic and endoreplicative cells by distinct mechanisms. , 1998, Development.

[58]  M P L Calus,et al.  Genetic parameters for predicted methane production and potential for reducing enteric emissions through genomic selection. , 2011, Journal of dairy science.

[59]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1995, Nature.

[60]  E. Smythe,et al.  Differential activities of the Drosophila JAK/STAT pathway ligands Upd, Upd2 and Upd3. , 2011, Cellular signalling.

[61]  S. Benzer,et al.  Prandiology of Drosophila and the CAFE assay , 2007, Proceedings of the National Academy of Sciences.

[62]  K. Nairz,et al.  Nutrient-Dependent Expression of Insulin-like Peptides from Neuroendocrine Cells in the CNS Contributes to Growth Regulation in Drosophila , 2002, Current Biology.