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Central nervous system imprinting of the G protein G(s)alpha and its role in metabolic regulation.

ABSTRACT: In Albright hereditary osteodystrophy, a monogenic obesity disorder linked to heterozygous mutations of G(s)alpha, the G protein that mediates receptor-stimulated cAMP generation, obesity develops only when the mutation is on the maternal allele. Likewise, mice with maternal (but not paternal) germline G(s)alpha mutation develop obesity, insulin resistance, and diabetes. These parent-of-origin effects are due to G(s)alpha imprinting, with preferential expression from the maternal allele in some tissues. As G(s)alpha is ubiquitously expressed, the tissue involved in this metabolic imprinting effect is unknown. Using brain-specific G(s)alpha knockout mice, we show that G(s)alpha imprinting within the central nervous system underlies these effects and that G(s)alpha is imprinted in the paraventricular nucleus of the hypothalamus. Maternal G(s)alpha mutation impaired melanocortin stimulation of energy expenditure but did not affect melanocortin's effect on food intake, suggesting that melanocortins may regulate energy balance in the central nervous system through both G(s)alpha-dependent and -independent pathways.

SUBMITTER: Chen M

PROVIDER: S-EPMC2698878 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Central nervous system imprinting of the G protein G(s)alpha and its role in metabolic regulation.

Chen Min M Wang Jie J Dickerson Kathryn E KE Kelleher James J Xie Tao T Gupta Divakar D Lai Edwin W EW Pacak Karel K Gavrilova Oksana O Weinstein Lee S LS

Cell metabolism 20090601 6

In Albright hereditary osteodystrophy, a monogenic obesity disorder linked to heterozygous mutations of G(s)alpha, the G protein that mediates receptor-stimulated cAMP generation, obesity develops only when the mutation is on the maternal allele. Likewise, mice with maternal (but not paternal) germline G(s)alpha mutation develop obesity, insulin resistance, and diabetes. These parent-of-origin effects are due to G(s)alpha imprinting, with preferential expression from the maternal allele in some ...[more]

PMID: 19490909

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Project description:BACKGROUND:Metabolic alterations, related to cerebral glucose metabolism, brain insulin resistance, and age-induced mitochondrial dysfunction, play an important role in Alzheimer's disease (AD) on both the systemic and central nervous system level. To study the extent and significance of these alterations in AD, quantitative metabolomics was applied to plasma and cerebrospinal fluid (CSF) from clinically well-characterized AD patients and cognitively healthy control subjects. The observed metabolic alterations were associated with core pathological processes of AD to investigate their relation with amyloid pathology and tau-related neurodegeneration. METHODS:In a case-control study of clinical and biomarker-confirmed AD patients (n = 40) and cognitively healthy controls without cerebral AD pathology (n = 34) with paired plasma and CSF samples, we performed metabolic profiling, i.e., untargeted metabolomics and targeted quantification. Targeted quantification focused on identified deregulated pathways highlighted in the untargeted assay, i.e. the TCA cycle, and its anaplerotic pathways, as well as the neuroactive tryptophan and kynurenine pathway. RESULTS:Concentrations of several TCA cycle and beta-oxidation intermediates were higher in plasma of AD patients, whilst amino acid concentrations were significantly lower. Similar alterations in these energy metabolism intermediates were observed in CSF, together with higher concentrations of creatinine, which were strongly correlated with blood-brain barrier permeability. Alterations of several amino acids were associated with CSF Amyloidβ1-42. The tryptophan catabolites, kynurenic acid and quinolinic acid, showed significantly higher concentrations in CSF of AD patients, which, together with other tryptophan pathway intermediates, were correlated with either CSF Amyloidβ1-42, or tau and phosphorylated Tau-181. CONCLUSIONS:This study revealed AD-associated systemic dysregulation of nutrient sensing and oxidation and CNS-specific alterations in the neuroactive tryptophan pathway and (phospho)creatine degradation. The specific association of amino acids and tryptophan catabolites with AD CSF biomarkers suggests a close relationship with core AD pathology. Our findings warrant validation in independent, larger cohort studies as well as further investigation of factors such as gender and APOE genotype, as well as of other groups, such as preclinical AD, to identify metabolic alterations as potential intervention targets.

Dataset Information

Central nervous system imprinting of the G protein G(s)alpha and its role in metabolic regulation.

Publications

Central nervous system imprinting of the G protein G(s)alpha and its role in metabolic regulation.

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