title: Reduced Gut Acidity Induces an Obese-Like Phenotype in Drosophila melanogaster and in Mice.
abstract: In order to identify genes involved in stress and metabolic regulation, we carried out a Drosophila P-element-mediated mutagenesis screen for starvation resistance. We isolated a mutant, m2, that showed a 23% increase in survival time under starvation conditions. The P-element insertion was mapped to the region upstream of the vha16-1 gene, which encodes the c subunit of the vacuolar-type H+-ATPase. We found that vha16-1 is highly expressed in the fly midgut, and that m2 mutant flies are hypomorphic for vha16-1 and also exhibit reduced midgut acidity. This deficit is likely to induce altered metabolism and contribute to accelerated aging, since vha16-1 mutant flies are short-lived and display increases in body weight and lipid accumulation. Similar phenotypes were also induced by pharmacological treatment, through feeding normal flies and mice with a carbonic anhydrase inhibitor (acetazolamide) or proton pump inhibitor (PPI, lansoprazole) to suppress gut acid production. Our study may thus provide a useful model for investigating chronic acid suppression in patients.
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pediatrics, National Taiwan University Hospital Yun-Lin branch, Yun-Lin, Taiwan.
authors.forename: Wei-Sheng
authors.initials: WS
authors.lastname: Lin
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan; Institute of Biotechnology, National Tsing Hua University, HsinChu, Taiwan.
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Huang
authors.affiliation: Institute of Neuroscience, National Chengchi University, Taipei, Taiwan.
authors.forename: You-Sheng
authors.initials: YS
authors.lastname: Song
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, Indiana, United States of America.
authors.forename: Jui-Hung
authors.initials: JH
authors.lastname: Yen
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, Indiana, United States of America.
authors.forename: Ping-Chang
authors.initials: PC
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Sheng-Rong
authors.initials: SR
authors.lastname: Yeh
authors.affiliation: Institute of Biotechnology, National Tsing Hua University, HsinChu, Taiwan.
authors.forename: Hung-Yu
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Applied Chemistry, National Chinan University, Nantou, Taiwan.
authors.forename: Tsai-Feng
authors.initials: TF
authors.lastname: Fu
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
authors.forename: Ming-Shiang
authors.initials: MS
authors.lastname: Wu
authors.affiliation: Institute of Biotechnology, National Tsing Hua University, HsinChu, Taiwan; Institute of Systems Neuroscience, National Tsing Hua University, HsinChu, Taiwan; Department of Life Science, National Tsing Hua University, HsinChu, Taiwan.
authors.forename: Horng-Dar
authors.initials: HD
authors.lastname: Wang
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Wang
mesh_terms: D000086:Acetazolamide / Q000494:pharmacology; D000136:Acid-Base Equilibrium / Q000235:genetics*; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster; D005745:Gastric Acidity Determination; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism*; D064747:Lansoprazole / Q000494:pharmacology; D051379:Mice; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D029721:Drosophila Proteins; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D025262:Vacuolar Proton-Translocating ATPases; D000086:Acetazolamide