A missense mutation in the non-neural G-protein alpha-subunit isoforms modulates susceptibility to obesity.
OBJECTIVE
The Gnas transcription unit located within an imprinting region encodes several proteins, including the G-protein alpha-subunit, Gsalpha, its isoform XLalphas and their variant truncated neural forms GsalphaN1 and XLN1. Gsalpha and GsalphaN1 are expressed predominantly from the maternally derived allele in some tissues, whereas XLalphas and XLN1 are expressed exclusively from the paternally derived allele. The relative contribution of full-length Gsalpha and XLalphas, and truncated forms GsalphaN1 and XLN1 to phenotype is unknown. The edematous-small point mutation (Oed-Sml) in exon 6 of Gnas lies downstream of GsalphaN1 and XLN1, but affects full-length Gsalpha and XLalphas, allowing us to address the role of full-length Gsalpha and XLalphas. The aim of this study was therefore to determine the metabolic phenotypes of Oed and Sml mice, and to correlate phenotypes with affected transcripts.


METHODS
Mice were fed standard or high-fat diets and weighed regularly. Fat mass was determined by DEXA analysis. Indirect calorimetry was used to measure metabolic rate. Glucose was measured in tolerance tests and biochemical parameters in fasted plasma samples. Histological analysis of fat and liver was carried out post mortem.


RESULTS
Oed mice are obese on either diet and have a reduced metabolic rate. Sml mice are lean and are resistant to a high-fat diet and have an increased metabolic rate.


CONCLUSIONS
Adult Oed and Sml mice have opposite metabolic phenotypes. On maternal inheritance, the obese Oed phenotype can be attributed to non-functional full-length Gsalpha. In contrast, on paternal inheritance, Sml mice were small and resistant to the development of obesity on a high-fat diet, effects that can be attributed to mutant XLalphas. Thus, the neural isoforms, GsalphaN1 and XLN1, do not appear to play a role in these metabolic phenotypes.
Kelly
M L
ML
MRC Harwell, Metabolism and Inflammation Section, Diabetes Group, Harwell Science and Innovation Campus, Oxfordshire, UK.
Moir
L
L
Jones
L
L
Whitehill
E
E
Anstee
Q M
QM
Goldin
R D
RD
Hough
A
A
Cheeseman
M
M
Jansson
J-O
JO
Peters
J
J
Cox
R D
RD
D000818:Animals; D015415:Biomarkers / Q000097:blood; D001823:Body Composition; D002864:Chromogranins; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006943:Hyperglycemia / Q000235:genetics*; D008297:Male; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D020033:Protein Isoforms
D015415:Biomarkers; D002864:Chromogranins; D004041:Dietary Fats; D044385:GTP-Binding Protein alpha Subunits; D020033:Protein Isoforms; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs