Abstract |
The G protein α-subunit G(s)α mediates receptor-stimulated cAMP generation. Heterozygous inactivating G(s)α mutations on the maternal allele result in obesity primarily due to reduced energy expenditure in Albright hereditary osteodystrophy patients and in mice. We previously showed that mice with central nervous system (CNS)-specific G(s)α deletion on the maternal allele (mBrGs KO) also develop severe obesity with reduced energy expenditure and that G(s)α is primarily expressed from the maternal allele in the paraventricular nucleus (PVN) of the hypothalamus, an important site of energy balance regulation. We now generated mice with PVN-specific G(s)α deficiency by mating Single-minded 1-cre and G(s)α-floxed mice. Homozygous G(s)α deletion produced early lethality. Heterozygotes with maternal G(s)α deletion (mPVNGsKO) also developed obesity and had small reductions in energy expenditure. However, this effect was much milder than that found in mBrGsKO mice and was more prominent in males. We previously showed mBrGsKO mice to have significant reductions in melanocortin receptor agonist-stimulated energy expenditure and now show that mBrGsKO mice have impaired cold-induced brown adipose tissue stimulation. In contrast, these effects were absent in mPVNGsKO mice. mPVNGsKO mice also had minimal effects on glucose metabolism as compared with mBrGsKO mice. Consistent with the presence of G(s)α imprinting, paternal heterozygotes showed no changes in energy or glucose metabolism. These results indicate that although G(s)α deficiency in PVN partially contributes to the metabolic phenotype resulting from maternal G(s)α mutations, G(s)α imprinting in other CNS regions is also important in mediating the CNS effects of G(s)α mutations on energy and glucose metabolism.
|
Authors | Min Chen, Alta Berger, Ahmed Kablan, Jiandi Zhang, Oksana Gavrilova, Lee S Weinstein |
Journal | Endocrinology
(Endocrinology)
Vol. 153
Issue 9
Pg. 4256-65
(Sep 2012)
ISSN: 1945-7170 [Electronic] United States |
PMID | 22733970
(Publication Type: Journal Article, Research Support, N.I.H., Intramural)
|
Chemical References |
- GTP-Binding Protein alpha Subunits, Gs
|
Topics |
- Animals
- Body Composition
(genetics, physiology)
- Eating
(genetics, physiology)
- Female
- GTP-Binding Protein alpha Subunits, Gs
(deficiency, genetics)
- Hypothalamus
(metabolism)
- Male
- Mice
- Mice, Knockout
- Mutation
- Obesity
(genetics)
- Paraventricular Hypothalamic Nucleus
(metabolism)
|