A missense mutation in the non-neural G-protein α-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, Gs alpha, its isoform XL alpha s and their variant truncated neural forms Gs alpha N1 and XLN1. Gs alpha and Gs alpha N1 are expressed predominantly from the maternally derived allele in some tissues, whereas XL alpha s and XLN1 are expressed exclusively from the paternally derived allele. The relative contribution of full-length Gs alpha and XL alpha s, and truncated forms Gs alpha N1 and XLN1 to phenotype is unknown. The edematous-small point mutation (Oed-Sml) in exon 6 of Gnas lies downstream of Gs alpha N1 and XLN1, but affects full-length Gs alpha and XL alpha s, allowing us to address the role of full-length Gs alpha and XL alpha s. 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 Gs alpha. 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 XL alpha s. Thus, the neural isoforms, Gs alpha N1 and XLN1, do not appear to play a role in these metabolic phenotypes. International Journal of Obesity (2009) 33, 507-518; doi: 10.1038/ijo.2009.30; published online 24 February 2009