title: The Obesity-Linked Gene Nudt3 Drosophila Homolog Aps Is Associated With Insulin Signaling.
abstract: Several genome-wide association studies have linked the Nudix hydrolase family member nucleoside diphosphate-linked moiety X motif 3 (NUDT3) to obesity. However, the manner of NUDT3 involvement in obesity is unknown, and NUDT3 expression, regulation, and signaling in the central nervous system has not been studied. We performed an extensive expression analysis in mice, as well as knocked down the Drosophila NUDT3 homolog Aps in the nervous system, to determine its effect on metabolism. Detailed in situ hybridization studies in the mouse brain revealed abundant Nudt3 mRNA and protein expression throughout the brain, including reward- and feeding-related regions of the hypothalamus and amygdala, whereas Nudt3 mRNA expression was significantly up-regulated in the hypothalamus and brainstem of food-deprived mice. Knocking down Aps in the Drosophila central nervous system, or a subset of median neurosecretory cells, known as the insulin-producing cells (IPCs), induces hyperinsulinemia-like phenotypes, including a decrease in circulating trehalose levels as well as significantly decreasing all carbohydrate levels under starvation conditions. Moreover, lowering Aps IPC expression leads to a decreased ability to recruit these lipids during starvation. Also, loss of neuronal Aps expression caused a starvation susceptibility phenotype while inducing hyperphagia. Finally, the loss of IPC Aps lowered the expression of Akh, Ilp6, and Ilp3, genes known to be inhibited by insulin signaling. These results point toward a role for this gene in the regulation of insulin signaling, which could explain the robust association with obesity in humans.
authors.affiliation: Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, 75 124 Uppsala, Sweden.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Williams
authors.affiliation: Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, 75 124 Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Eriksson
authors.affiliation: Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, 75 124 Uppsala, Sweden.
authors.forename: Muksheed
authors.initials: M
authors.lastname: Shaik
authors.affiliation: Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, 75 124 Uppsala, Sweden.
authors.forename: Sarah
authors.initials: S
authors.lastname: Voisin
authors.affiliation: Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, 75 124 Uppsala, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Yamskova
authors.affiliation: Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, 75 124 Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Paulsson
authors.affiliation: Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, 75 124 Uppsala, Sweden.
authors.forename: Ketan
authors.initials: K
authors.lastname: Thombare
authors.affiliation: Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, 75 124 Uppsala, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Fredriksson
authors.affiliation: Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, 75 124 Uppsala, Sweden.
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000679:Amygdala / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004330:Drosophila; D029721:Drosophila Proteins / Q000096:biosynthesis; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics; D006963:Hyperphagia / Q000235:genetics; D007031:Hypothalamus / Q000378:metabolism; D007301:Insect Hormones / Q000096:biosynthesis; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics*; D009842:Oligopeptides / Q000096:biosynthesis; D011755:Pyrophosphatases / Q000235:genetics*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics; D013002:Somatomedins / Q000096:biosynthesis; D013217:Starvation / Q000235:genetics*; D014199:Trehalose / Q000097:blood
chemical_list: D029721:Drosophila Proteins; C542424:ILP3 protein, Drosophila; C546576:Ilp6 protein, Drosophila; D007301:Insect Hormones; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides; D012333:RNA, Messenger; D013002:Somatomedins; C065368:DAKH peptide; D014199:Trehalose; D017766:Acid Anhydride Hydrolases; C552307:Aps protein, Drosophila; D011755:Pyrophosphatases; C116368:diphosphoinositol polyphosphate phosphohydrolase; D011761:Pyrrolidonecarboxylic Acid