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A Gain-of-Function Mutation in Adenylate Cyclase 3 Protects Mice from Diet-Induced Obesity

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 ba...

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Autores principales: Pitman, Jeffrey L., Wheeler, Matthew C., Lloyd, David J., Walker, John R., Glynne, Richard J., Gekakis, Nicholas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199629/
https://www.ncbi.nlm.nih.gov/pubmed/25329148
http://dx.doi.org/10.1371/journal.pone.0110226
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author Pitman, Jeffrey L.
Wheeler, Matthew C.
Lloyd, David J.
Walker, John R.
Glynne, Richard J.
Gekakis, Nicholas
author_facet Pitman, Jeffrey L.
Wheeler, Matthew C.
Lloyd, David J.
Walker, John R.
Glynne, Richard J.
Gekakis, Nicholas
author_sort Pitman, Jeffrey L.
collection PubMed
description 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 (Adcy3(M279I), henceforth referred to as Adcy3(Jll)). 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.
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spelling pubmed-41996292014-10-21 A Gain-of-Function Mutation in Adenylate Cyclase 3 Protects Mice from Diet-Induced Obesity Pitman, Jeffrey L. Wheeler, Matthew C. Lloyd, David J. Walker, John R. Glynne, Richard J. Gekakis, Nicholas PLoS One Research Article 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 (Adcy3(M279I), henceforth referred to as Adcy3(Jll)). 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. Public Library of Science 2014-10-16 /pmc/articles/PMC4199629/ /pubmed/25329148 http://dx.doi.org/10.1371/journal.pone.0110226 Text en © 2014 Pitman et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Pitman, Jeffrey L.
Wheeler, Matthew C.
Lloyd, David J.
Walker, John R.
Glynne, Richard J.
Gekakis, Nicholas
A Gain-of-Function Mutation in Adenylate Cyclase 3 Protects Mice from Diet-Induced Obesity
title A Gain-of-Function Mutation in Adenylate Cyclase 3 Protects Mice from Diet-Induced Obesity
title_full A Gain-of-Function Mutation in Adenylate Cyclase 3 Protects Mice from Diet-Induced Obesity
title_fullStr A Gain-of-Function Mutation in Adenylate Cyclase 3 Protects Mice from Diet-Induced Obesity
title_full_unstemmed A Gain-of-Function Mutation in Adenylate Cyclase 3 Protects Mice from Diet-Induced Obesity
title_short A Gain-of-Function Mutation in Adenylate Cyclase 3 Protects Mice from Diet-Induced Obesity
title_sort gain-of-function mutation in adenylate cyclase 3 protects mice from diet-induced obesity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199629/
https://www.ncbi.nlm.nih.gov/pubmed/25329148
http://dx.doi.org/10.1371/journal.pone.0110226
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