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PMID: 10712433 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism.

The Journal of clinical investigation ·Vol. 105 ·No. 5 ·2000-03-00 ·Pages 615-23

Yu S, Gavrilova O, Chen H, Lee R, Liu J, Pacak K, Parlow AF, Quon MJ, Reitman ML, Weinstein LS

Abstract

Heterozygous disruption of Gnas, the gene encoding the stimulatory G-protein alpha subunit (G(s)alpha), leads to distinct phenotypes depending on whether the maternal (m-/+) or paternal (+/p-) allele is disrupted. G(s)alpha is imprinted, with the maternal allele preferentially expressed in adipose tissue. Hence, expression is decreased in m-/+ mice but normal in +/p- mice. M-/+ mice become obese, with increased lipid per cell in white and brown adipose tissue, whereas +/p- mice are thin, with decreased lipid in adipose tissue. These effects are not due to abnormalities in thyroid hormone status, food intake, or leptin secretion. +/p- mice are hypermetabolic at both ambient temperature (21 degrees C) and thermoneutrality (30 degrees C). In contrast, m-/+ mice are hypometabolic at ambient temperature and eumetabolic at thermoneutrality M-/+ and wild-type mice have similar dose-response curves for metabolic response to a beta(3)-adrenergic agonist, CL316243, indicating normal sensitivity of adipose tissue to sympathetic stimulation. Measurement of urinary catecholamines suggests that +/p- and m-/+ mice have increased and decreased activation of the sympathetic nervous system, respectively. This is to our knowledge the first animal model in which a single genetic defect leads to opposite effects on energy metabolism depending on parental inheritance. This probably results from deficiency of maternal- and paternal-specific Gnas gene products, respectively.

MeSH Terms
Adrenergic beta-Agonists/pharmacology Alleles Animals Body Weight Dioxoles/pharmacology Energy Metabolism Female GTP-Binding Protein alpha Subunits, Gs/deficiency,genetics Genomic Imprinting Histocytochemistry Leptin/blood Lipids/blood Male Mice Mice, Knockout Obesity/blood,genetics Phenotype Thyroid Hormones/blood Thyrotropin/blood
Chemicals
Adrenergic beta-Agonists Dioxoles Leptin Lipids Thyroid Hormones disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate Thyrotropin GTP-Binding Protein alpha Subunits, Gs
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Yu S
Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.
Gavrilova O
Chen H
Lee R
Liu J
Pacak K
Parlow A F
Quon M J
Reitman M L
Weinstein L S
References (56)
56 references, click to expand
  1. Serum immunoreactive-leptin concentrations in normal-weight and obese humans.
    N Engl J Med. 1996 Feb 1;334(5):292-5 PMID: 8532024
  2. XL alpha s is a new type of G protein.
    Nature. 1994 Dec 22-29;372(6508):804-9 PMID: 7997272
  3. Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds.
    Dev Biol. 1996 Aug 1;177(2):517-35 PMID: 8806828
  4. Transgenic mice overexpressing the beta 1-adrenergic receptor in adipose tissue are resistant to obesity.
    Mol Endocrinol. 1997 Jan;11(1):27-38 PMID: 8994185
  5. Targeted disruption of the melanocortin-4 receptor results in obesity in mice.
    Cell. 1997 Jan 10;88(1):131-41 PMID: 9019399
  6. Role of the beta3-adrenoceptor in the control of leptin expression.
    Horm Metab Res. 1996 Dec;28(12):633-7 PMID: 9013732
  7. Regulation of the uncoupling protein gene expression.
    Eur J Endocrinol. 1997 Mar;136(3):251-64 PMID: 9100546
  8. Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity.
    J Biol Chem. 1997 Apr 25;272(17):11657-62 PMID: 9111083
  9. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese.
    Nature. 1997 May 1;387(6628):90-4 PMID: 9139827
  10. Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline.
    Nature. 1997 May 1;387(6628):94-7 PMID: 9139828
  11. Raising at thermoneutrality prevents obesity and hyperphagia in BAT-ablated transgenic mice.
    Am J Physiol. 1997 Apr;272(4 Pt 2):R1088-93 PMID: 9140006
  12. Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta3-adrenergic agonists, and leptin.
    J Biol Chem. 1997 Sep 26;272(39):24129-32 PMID: 9305858
  13. A novel mutation adjacent to the switch III domain of G(S alpha) in a patient with pseudohypoparathyroidism.
    Mol Endocrinol. 1997 Oct;11(11):1718-27 PMID: 9328353
  14. Growth effects of uniparental disomies and the conflict theory of genomic imprinting.
    Trends Genet. 1997 Nov;13(11):436-43 PMID: 9385840
  15. Genomic imprinting in mammals.
    Annu Rev Genet. 1997;31:493-525 PMID: 9442905
  16. Temperature-dependent feeding: lack of role for leptin and defect in brown adipose tissue-ablated obese mice.
    Am J Physiol. 1998 Apr;274(4 Pt 2):R1131-5 PMID: 9575979
  17. Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha-subunit (Gsalpha) knockout mice is due to tissue-specific imprinting of the gsalpha gene.
    Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8715-20 PMID: 9671744
  18. The conflict theory of genomic imprinting: how much can be explained?
    Curr Top Dev Biol. 1998;40:255-93 PMID: 9673853
  19. The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins.
    Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10038-43 PMID: 9707596
  20. Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality.
    Genes Dev. 1994 Dec 15;8(24):2953-63 PMID: 8001817
  21. Parental origin of transcription from the human GNAS1 gene.
    J Med Genet. 1994 Aug;31(8):607-14 PMID: 7815417
  22. Imprinting mechanisms.
    Genome Res. 1998 Sep;8(9):881-900 PMID: 9750189
  23. Leptin and the regulation of body weight in mammals.
    Nature. 1998 Oct 22;395(6704):763-70 PMID: 9796811
  24. Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins.
    Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15475-80 PMID: 9860993
  25. The sins of the fathers and mothers: genomic imprinting in mammalian development.
    Cell. 1999 Jan 22;96(2):185-93 PMID: 9988214
  26. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors.
    Nature. 1995 Apr 6;374(6522):542-6 PMID: 7700379
  27. Oxytocin as an antidiuretic hormone. II. Role of V2 vasopressin receptor.
    Am J Physiol. 1995 Jul;269(1 Pt 2):F78-85 PMID: 7631834
  28. Genomic organization and regulation by dietary fat of the uncoupling protein 3 and 2 genes.
    Biochem Biophys Res Commun. 1999 Mar 5;256(1):27-32 PMID: 10066417
  29. A cluster of oppositely imprinted transcripts at the Gnas locus in the distal imprinting region of mouse chromosome 2.
    Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3830-5 PMID: 10097123
  30. The new chromogranin-like protein NESP55 is preferentially localized in adrenaline-synthesizing cells of the bovine and rat adrenal medulla.
    Neurosci Lett. 1999 Mar 19;263(1):13-6 PMID: 10218899
  31. Size and form in efficient transportation networks.
    Nature. 1999 May 13;399(6732):130-2 PMID: 10335841
  32. Relative amounts and molecular forms of NESP55 in various bovine tissues.
    Brain Res. 1999 May 22;829(1-2):99-106 PMID: 10350534
  33. The fourth dimension of life: fractal geometry and allometric scaling of organisms.
    Science. 1999 Jun 4;284(5420):1677-9 PMID: 10356399
  34. Localization of neuroendocrine secretory protein 55 messenger RNA in the rat brain.
    Neuroscience. 1999;91(2):685-94 PMID: 10366025
  35. Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1.
    Nature. 1999 Jul 15;400(6741):261-5 PMID: 10421367
  36. Molecular characterization of the melanin-concentrating-hormone receptor.
    Nature. 1999 Jul 15;400(6741):265-9 PMID: 10421368
  37. A comparison of the effects of a variety of factors on the metabolic rate of the mouse.
    Aust J Exp Biol Med Sci. 1967 Aug;45(4):331-46 PMID: 6053582
  38. Analysis for urinary catecholamines by liquid chromatography with amperometric detection: methodology and clinical interpretation of results.
    Clin Chem. 1979 Feb;25(2):256-63 PMID: 759019
  39. A role for brown adipose tissue in diet-induced thermogenesis.
    Nature. 1979 Sep 6;281(5726):31-5 PMID: 551265
  40. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein.
    Am J Med. 1983 Apr;74(4):545-56 PMID: 6301273
  41. Cold-stimulated sympathetic activity in brown adipose tissue of obese (ob/ob) mice.
    Am J Physiol. 1983 Apr;244(4):E361-6 PMID: 6837731
  42. Blunted plasma cyclic adenosine monophosphate response to isoproterenol in pseudohypoparathyroidism.
    J Clin Endocrinol Metab. 1983 Jun;56(6):1323-6 PMID: 6302127
  43. Thermogenic mechanisms in brown fat.
    Physiol Rev. 1984 Jan;64(1):1-64 PMID: 6320232
  44. Differential activity of maternally and paternally derived chromosome regions in mice.
    Nature. 1985 Jun 6-12;315(6019):496-8 PMID: 4000278
  45. Inhibitory and stimulatory G proteins of adenylate cyclase: cDNA and amino acid sequences of the alpha chains.
    Proc Natl Acad Sci U S A. 1986 Sep;83(18):6687-91 PMID: 3092218
  46. Responses to glucagon infusion in pseudohypoparathyroidism.
    J Clin Endocrinol Metab. 1986 Dec;63(6):1354-60 PMID: 3023420
  47. Parental imprinting of the mouse insulin-like growth factor II gene.
    Cell. 1991 Feb 22;64(4):849-59 PMID: 1997210
  48. Autosomal and X-chromosome imprinting.
    Dev Suppl. 1990;:63-72 PMID: 2090432
  49. Genomic imprinting in mammalian development: a parental tug-of-war.
    Trends Genet. 1991 Feb;7(2):45-9 PMID: 2035190
  50. Genetic mapping of the Gs-alpha subunit gene (GNAS1) to the distal long arm of chromosome 20 using a polymorphism detected by denaturing gradient gel electrophoresis.
    Genomics. 1991 Apr;9(4):782-3 PMID: 1674732
  51. Disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino] propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316,243). A potent beta-adrenergic agonist virtually specific for beta 3 receptors. A promising antidiabetic and antiobesity agent.
    J Med Chem. 1992 Aug 7;35(16):3081-4 PMID: 1354264
  52. Receptor-effector coupling by G proteins: implications for normal and abnormal signal transduction.
    Endocr Rev. 1992 Aug;13(3):536-65 PMID: 1425488
  53. Imprinting in Albright's hereditary osteodystrophy.
    J Med Genet. 1993 Feb;30(2):101-3 PMID: 8383205
  54. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue.
    Nature. 1993 Dec 23-30;366(6457):740-2 PMID: 8264795
  55. Defective stimulation of adipocyte adenylate cyclase, blunted lipolysis, and obesity in pseudohypoparathyroidism 1a.
    Pediatr Res. 1994 May;35(5):594-7 PMID: 8065843
  56. Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A.
    Nature. 1996 Aug 15;382(6592):622-6 PMID: 8757131
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI8437
Published
2000-03-00
Pages
615-23
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC289181
Subset
IM
Grants
NIDDK NIH HHS · DK-9-2246 · United States
External Links
PubMed source DOI: 10.1172/JCI8437 PMC Full Text View journal details
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