Hyperphagia-mediated obesity in transgenic mice misexpressing the RNA-editing enzyme ADAR2.
ADAR2 is a double-stranded RNA-specific adenosine deaminase involved in the editing of mammalian RNAs by the site-specific conversion of adenosine to inosine. To examine the physiologic consequences resulting from ADAR2 misexpression, we have generated mutant mice expressing either wild-type or deaminase-deficient ADAR2 transgenes under the control of the human cytomegalovirus promoter. Transgenic mice expressing either wild-type or inactive ADAR2 isoforms demonstrated adult onset obesity characterized by hyperglycemia, hyperleptinemia, and increased adiposity. Paired feeding analysis revealed that mutant mice on caloric restriction had a growth rate and body composition indistinguishable from wild-type littermates, indicating that the observed obesity predominantly results from hyperphagia rather than a metabolic derangement. The observation that expression of catalytically inactive ADAR2 also is capable of producing an obese phenotype in mutant animals suggests that ADAR2 may possess additional biological activities beyond those required for the site-selective deamination of adenosine or may interfere with the actions of other double-stranded RNA-specific binding proteins in the cell.
Singh
Minati
M
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Kesterson
Robert A
RA
Jacobs
Michelle M
MM
Joers
James M
JM
Gore
John C
JC
Emeson
Ronald B
RB
D000241:Adenosine / Q000737:chemistry; D000243:Adenosine Deaminase / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D031204:Caloric Restriction; D003587:Cytomegalovirus / Q000235:genetics; D005260:Female; D007288:Inosine / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009154:Mutation; D009765:Obesity / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins; D051381:Rats
D016601:RNA-Binding Proteins; D007288:Inosine; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; D000241:Adenosine