title: A gain-of-function mutation in adenylate cyclase 3 protects mice from diet-induced obesity.
abstract: In a screen for genes that affect the metabolic response to high-fat diet (HFD), we selected one line of N-ethyl-N-nitrosourea (ENU)-mutagenized mice, Jll, with dominantly inherited resistance to diet-induced obesity (DIO). Mutant animals had dramatically reduced body weight and fat mass, and low basal insulin and glucose levels relative to unaffected controls. Both white adipose tissue (WAT) and brown adipose tissue (BAT) depots were smaller in mutant animals. Mutant animals fed a HFD gained only slightly more weight than animals fed regular chow, and were protected from hepatic lipid accumulation. The phenotype was genetically linked to a 5.7-Mb interval on chromosome 12, and sequencing of the entire interval identified a single coding mutation, predicted to cause a methionine-to-isoleucine substitution at position 279 of the Adcy3 protein (Adcy3M279I, henceforth referred to as Adcy3Jll). The mutant protein is hyperactive, possibly constitutively so, producing elevated levels of cyclic AMP in a cell-based assay. These mice demonstrate that increased Adcy3 activity robustly protect animals from diet-induced metabolic derangements.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA, United States of America.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Pitman
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA, United States of America.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Wheeler
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lloyd
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA, United States of America.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Glynne
authors.affiliation: Donald P. Shiley BioScience Center, San Diego State University, San Diego, CA, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Gekakis
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000187:drug effects; D052436:Adipose Tissue, White / Q000187:drug effects; D000483:Alleles; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D009154:Mutation; D009765:Obesity / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D005576:Colforsin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C421784:adenylate cyclase 3