Gsα Deficiency in the Paraventricular Nucleus of the Hypothalamus Partially Contributes to Obesity Associated with Gsα Mutations

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.

Conditional Knock-out Reveals a Requirement for O-Linked N-Acetylglucosaminase (O-GlcNAcase) in Metabolic Homeostasis

“…Body weight and body composition were measured every other week. Energy expenditure, RER, food intake, and activity were measured by indirect calorimetry at 22°C using a 12-chamber CLAMS system (Columbus Instruments, Columbus, OH) as described previously (66). Mice were acclimated for 2 days in the metabolic chamber before measurements were taken.…”

An Essential Role for the K+-dependent Na+/Ca2+-exchanger, NCKX4, in Melanocortin-4-receptor-dependent Satiety

“…However, a causative role for cAMP in MC4R signaling that leads to satiety has not to our knowledge been demonstrated. Indeed, loss of G␣ s function in PVN does not influence feeding behavior (23,24). Thus, the mechanism that links MC4R signaling to changes in neuronal firing, and particularly to the control of feeding behavior, remains unknown.…”

Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations

“…Several hypothalamic nuclei, including the paraventricular nucleus (PVN), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), are involved in regulation of energy and glucose metabolism. However, G s mutations within the PVN (9) or VMH (10) do not produce the metabolic phenotype seen in E1 m-or mBrGsKO mice. Therefore, the CNS site or sites where G s α is imprinted that accounts for the metabolic phenotype seen in AHO patients and mice with maternal G s α mutations remain unknown.…”

“…mBrGsKO mice have impaired stimulation of energy expenditure in response to the melanocortin agonist melanotan II (MTII), while the ability of MTII to inhibit food intake in these mice is unaffected (8). It therefore appears that melanocortins stimulate energy expenditure by signaling through G s α at a CNS site other than the PVN (9,12). In this study, we show that G s α is imprinted in the DMH, that the metabolic phenotype associated with maternal G s α mutations is due to G s α deficiency in the DMH, and that loss of MC4R in the DMH leads to a similar metabolic phenotype.…”