Effects of deficiency of the G protein Gsα on energy and glucose homeostasis

Abstract

G s α is a ubiquitously expressed G protein α-subunit that couples receptors to the generation of intracellular cyclic AMP. The G s α gene GNAS is a complex gene that undergoes genomic imprinting, an epigenetic phenomenon that leads to differential expression from the two parental alleles. G s α is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in a small number of tissues. Albright hereditary osteodystrophy is a monogenic obesity disorder caused by heterozygous G s α mutations but only when the mutations are maternally inherited. Studies in mice indicate a similar parent-of-origin effect on energy and glucose metabolism, with maternal but not paternal mutations leading to obesity, reduced sympathetic nerve activity and energy expenditure, glucose intolerance and insulin resistance, with no primary effect on food intake. These effects result from G s α imprinting leading to severe G s α deficiency in one or more regions of the central nervous system, and are associated with a specific defect in melanocortins to stimulate sympathetic nerve activity and energy expenditure.

New Mutations at the Imprinted Gnas Cluster Show Gene Dosage Effects of Gsα in Postnatal Growth and Implicate XLαs in Bone and Fat Metabolism but Not in Suckling

“…The imprinted Gnas/GNAS cluster located on chromosome 2 in mice and chromosome 20 in humans has an important role in metabolism (13,60). Genomic imprinting results in the expression of a subset of genes according to parental origin.…”

Plasticity of the myelination genomic fabric

“…Rac1 is a member of the Rho-GTPase family which has been shown to control Schwann cell migration and proliferation in vivo (Newberna and Birchmeier 2010). Gnas is a ubiquitously expressed G protein subunit that couples receptors to the generation of intracellular cyclic-AMP (Chen et al 2011), thus far unreported in oligodendrocyte physiology, and may represent an important new candidate gene for future study.…”

Molecular and Clinical Aspects of Pseudohypoparathyroidism

“…167 These parent-of-origin effects on weight are also observed in mice, and are consistent with imprinting of Gαs in specific regions of the brain. 168 Mice with disruption of the germline maternal (but not paternal) Gnas allele that leads to specific Gαs deficiency globally 168,169 or only in the central nervous system 77,170 develop obesity and insulin-resistant diabetes associated with normal food intake, likely due to an impairment of central melanocortins to stimulate sympathetic nervous system activity and energy expenditure. 77,168,170,171 Support for this hypothesis comes from the report of the successful treatment a single patient with PHP type 1c with a cannabinoid receptor type 1 (CB1) antagonist, which lowered the patient's body mass index from 40.5 to 33.5, 165 consistent with the premise that Gαs deficiency in imprinted regions of the hypothalamus impairs melanocortin-4 receptor signaling and leads to up-regulation of the CB1 receptor.…”