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A missense mutation in the non-neural G-protein α-subunit isoforms modulates susceptibility to obesity

Abstract

Objective:

The Gnas transcription unit located within an imprinting region encodes several proteins, including the G-protein α-subunit, Gsα, its isoform XLαs and their variant truncated neural forms GsαN1 and XLN1. Gsα and GsαN1 are expressed predominantly from the maternally derived allele in some tissues, whereas XLαs and XLN1 are expressed exclusively from the paternally derived allele. The relative contribution of full-length Gsα and XLαs, and truncated forms GsαN1 and XLN1 to phenotype is unknown. The edematous-small point mutation (Oed-Sml) in exon 6 of Gnas lies downstream of GsαN1 and XLN1, but affects full-length Gsα and XLαs, allowing us to address the role of full-length Gsα and XLαs. 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.

Conclusion:

Adult Oed and Sml mice have opposite metabolic phenotypes. On maternal inheritance, the obese Oed phenotype can be attributed to non-functional full-length Gsα. 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 XLαs. Thus, the neural isoforms, GsαN1 and XLN1, do not appear to play a role in these metabolic phenotypes.

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Acknowledgements

The authors thank the Medical Research Council and EC FP6 (Contract LSHM-CT-2003-503041) for support for this work. We also thank Swedish Research Council (No 09894). We thank the staff of the Mary Lyon Centre for their technical support; we also thank the Clinical Chemistry Department for all their help. We thank Mr Colin Beechey for providing Figure 1. QMA is a Medical Research Council-funded Clinical Research Fellow and Imperial College BRC Investigator.

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Correspondence to R D Cox.

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Kelly, M., Moir, L., Jones, L. et al. A missense mutation in the non-neural G-protein α-subunit isoforms modulates susceptibility to obesity. Int J Obes 33, 507–518 (2009). https://doi.org/10.1038/ijo.2009.30

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  • DOI: https://doi.org/10.1038/ijo.2009.30

Keywords

  • mouse
  • genetics
  • Gnas
  • metabolism
  • camp

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