Home LiteratureArticle Details
PMID: 21982743 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The arrestin domain-containing 3 protein regulates body mass and energy expenditure.

Cell metabolism ·Vol. 14 ·No. 5 ·2011-11-02 ·Pages 671-83

Patwari P, Emilsson V, Schadt EE, Chutkow WA, Lee S, Marsili A, Zhang Y, Dobrin R, Cohen DE, Larsen PR, Zavacki AM, Fong LG, Young SG, Lee RT

Abstract

A human genome-wide linkage scan for obesity identified a linkage peak on chromosome 5q13-15. Positional cloning revealed an association of a rare haplotype to high body-mass index (BMI) in males but not females. The risk locus contains a single gene, "arrestin domain-containing 3" (ARRDC3), an uncharacterized α-arrestin. Inactivating Arrdc3 in mice led to a striking resistance to obesity, with greater impact on male mice. Mice with decreased ARRDC3 levels were protected from obesity due to increased energy expenditure through increased activity levels and increased thermogenesis of both brown and white adipose tissues. ARRDC3 interacted directly with β-adrenergic receptors, and loss of ARRDC3 increased the response to β-adrenergic stimulation in isolated adipose tissue. These results demonstrate that ARRDC3 is a gender-sensitive regulator of obesity and energy expenditure and reveal a surprising diversity for arrestin family protein functions.

MeSH Terms
Adipose Tissue, Brown/metabolism Adipose Tissue, White/metabolism Adrenergic beta-Agonists/pharmacology Animals Arrestins/genetics,metabolism Body Mass Index Chromosomes, Human, Pair 5 Cohort Studies Energy Metabolism/genetics Female Genetic Loci Humans Iceland/epidemiology Linkage Disequilibrium Male Mice Mice, Knockout Obesity/epidemiology,genetics,metabolism Receptors, Adrenergic, beta/metabolism Sequence Homology, Amino Acid Sex Factors Signal Transduction Thermogenesis/genetics
Chemicals
ARRDC3 protein, human ARRDC3 protein, mouse Adrenergic beta-Agonists Arrestins Receptors, Adrenergic, beta
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Patwari Parth
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. parth@alum.mit.edu
Emilsson Valur
Schadt Eric E
Chutkow William A
Lee Samuel
Marsili Alessandro
Zhang Yongzhao
Dobrin Radu
Cohen David E
Larsen P Reed
Zavacki Ann Marie
Fong Loren G
Young Stephen G
Lee Richard T
References (51)
51 references, click to expand
  1. Exercise ameliorates high-fat diet-induced metabolic and vascular dysfunction, and increases adipocyte progenitor cell population in brown adipose tissue.
    Am J Physiol Regul Integr Comp Physiol. 2011 May;300(5):R1115-25 PMID: 21368268
  2. Txnip balances metabolic and growth signaling via PTEN disulfide reduction.
    Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3921-6 PMID: 18322014
  3. Evaluating the glucose tolerance test in mice.
    Am J Physiol Endocrinol Metab. 2008 Dec;295(6):E1323-32 PMID: 18812462
  4. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis.
    Cell. 1998 Mar 20;92(6):829-39 PMID: 9529258
  5. Beta(1)/beta(2)/beta(3)-adrenoceptor knockout mice are obese and cold-sensitive but have normal lipolytic responses to fasting.
    FEBS Lett. 2002 Oct 23;530(1-3):37-40 PMID: 12387862
  6. The guanosine monophosphate reductase gene is conserved in rats and its expression increases rapidly in brown adipose tissue during cold exposure.
    J Biol Chem. 1998 Nov 20;273(47):31092-6 PMID: 9813009
  7. Optimization of quantitative real-time RT-PCR parameters for the study of lymphoid malignancies.
    Leukemia. 2003 Apr;17(4):789-95 PMID: 12682639
  8. Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline.
    Nature. 1997 May 1;387(6628):94-7 PMID: 9139828
  9. Adrenal glands of mouse and rat do not synthesize androgens.
    Life Sci. 1992;50(12):857-61 PMID: 1312193
  10. Genetics of gene expression and its effect on disease.
    Nature. 2008 Mar 27;452(7186):423-8 PMID: 18344981
  11. Effect of ketone bodies on lipolysis in adipose tissue in vitro.
    J Lipid Res. 1966 Sep;7(5):621-6 PMID: 5971044
  12. Adrenergic activation of triiodothyronine production in brown adipose tissue.
    Nature. 1983 Oct 20-26;305(5936):712-3 PMID: 6633638
  13. Thioredoxin-independent regulation of metabolism by the alpha-arrestin proteins.
    J Biol Chem. 2009 Sep 11;284(37):24996-5003 PMID: 19605364
  14. On the origins of arrestin and rhodopsin.
    BMC Evol Biol. 2008 Jul 29;8:222 PMID: 18664266
  15. Lipid homeostasis, lipotoxicity and the metabolic syndrome.
    Biochim Biophys Acta. 2010 Mar;1801(3):209-14 PMID: 19948243
  16. The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue.
    J Clin Invest. 2001 Nov;108(9):1379-85 PMID: 11696583
  17. A twin study of human obesity.
    JAMA. 1986 Jul 4;256(1):51-4 PMID: 3712713
  18. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.
    Nature. 2006 Jan 26;439(7075):484-9 PMID: 16400329
  19. Recruitment of the ESCRT machinery to a putative seven-transmembrane-domain receptor is mediated by an arrestin-related protein.
    Mol Cell Biol. 2010 Feb;30(4):897-907 PMID: 20028738
  20. Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor.
    Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3665-9 PMID: 8386380
  21. Effects of recombinant leptin therapy in a child with congenital leptin deficiency.
    N Engl J Med. 1999 Sep 16;341(12):879-84 PMID: 10486419
  22. Medicine. Beige can be slimming.
    Science. 2010 May 28;328(5982):1113-4 PMID: 20448151
  23. The arrestin fold: variations on a theme.
    Curr Genomics. 2009 Apr;10(2):133-42 PMID: 19794886
  24. TXNIP regulates peripheral glucose metabolism in humans.
    PLoS Med. 2007 May;4(5):e158 PMID: 17472435
  25. Lipodystrophy: metabolic insights from a rare disorder.
    J Endocrinol. 2010 Dec;207(3):245-55 PMID: 20870709
  26. The genetic contribution to non-syndromic human obesity.
    Nat Rev Genet. 2009 Jul;10(7):431-42 PMID: 19506576
  27. Association of variants in the PCSK1 gene with obesity in the EPIC-Norfolk study.
    Hum Mol Genet. 2009 Sep 15;18(18):3496-501 PMID: 19528091
  28. Obesity-associated improvements in metabolic profile through expansion of adipose tissue.
    J Clin Invest. 2007 Sep;117(9):2621-37 PMID: 17717599
  29. Noradrenaline controls the concentration of the uncoupling protein in brown adipose tissue.
    FEBS Lett. 1984 Jan 30;166(2):393-6 PMID: 6319201
  30. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.
    Nat Genet. 2006 Mar;38(3):320-3 PMID: 16415884
  31. Arrestin-related ubiquitin-ligase adaptors regulate endocytosis and protein turnover at the cell surface.
    Cell. 2008 Nov 14;135(4):714-25 PMID: 18976803
  32. The human beta 3-adrenergic receptor is resistant to short term agonist-promoted desensitization.
    Mol Pharmacol. 1993 Apr;43(4):548-55 PMID: 8386307
  33. A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10.
    Nat Genet. 1998 Nov;20(3):304-8 PMID: 9806554
  34. A recurring problem with the analysis of energy expenditure in genetic models expressing lean and obese phenotypes.
    Diabetes. 2010 Feb;59(2):323-9 PMID: 20103710
  35. Arrestin domain-containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of the beta2-adrenergic receptor.
    EMBO Rep. 2010 Aug;11(8):605-11 PMID: 20559325
  36. Thioredoxin-binding protein-2-like inducible membrane protein is a novel vitamin D3 and peroxisome proliferator-activated receptor (PPAR)gamma ligand target protein that regulates PPARgamma signaling.
    Endocrinology. 2006 Feb;147(2):733-43 PMID: 16269462
  37. Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome.
    Diabetes. 2005 May;54(5):1314-23 PMID: 15855315
  38. The retromer subunit Vps26 has an arrestin fold and binds Vps35 through its C-terminal domain.
    Nat Struct Mol Biol. 2006 Jun;13(6):540-8 PMID: 16732284
  39. Inactivation of UCP1 and the glycerol phosphate cycle synergistically increases energy expenditure to resist diet-induced obesity.
    J Biol Chem. 2008 Oct 10;283(41):27688-27697 PMID: 18678870
  40. Deficiency of a beta-arrestin-2 signal complex contributes to insulin resistance.
    Nature. 2009 Feb 26;457(7233):1146-9 PMID: 19122674
  41. Admixture mapping of 15,280 African Americans identifies obesity susceptibility loci on chromosomes 5 and X.
    PLoS Genet. 2009 May;5(5):e1000490 PMID: 19461885
  42. Thioredoxin-interacting protein deficiency induces Akt/Bcl-xL signaling and pancreatic beta-cell mass and protects against diabetes.
    FASEB J. 2008 Oct;22(10):3581-94 PMID: 18552236
  43. ARRDC3 suppresses breast cancer progression by negatively regulating integrin beta4.
    Oncogene. 2010 Sep 9;29(36):5032-47 PMID: 20603614
  44. Deletion of the alpha-arrestin protein Txnip in mice promotes adiposity and adipogenesis while preserving insulin sensitivity.
    Diabetes. 2010 Jun;59(6):1424-34 PMID: 20299477
  45. Human genetics illuminates the paths to metabolic disease.
    Nature. 2009 Nov 19;462(7271):307-14 PMID: 19924209
  46. Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood flow: the dominant role of brown adipose tissue in the replacement of shivering by nonshivering thermogenesis.
    Can J Physiol Pharmacol. 1979 Mar;57(3):257-70 PMID: 445227
  47. BayGenomics: a resource of insertional mutations in mouse embryonic stem cells.
    Nucleic Acids Res. 2003 Jan 1;31(1):278-81 PMID: 12520002
  48. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity.
    Nat Genet. 2009 Jan;41(1):18-24 PMID: 19079260
  49. Obesity-related derangements in metabolic regulation.
    Annu Rev Biochem. 2006;75:367-401 PMID: 16756496
  50. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization.
    J Cell Sci. 1992 Dec;103 ( Pt 4):931-42 PMID: 1362571
  51. Genome-wide linkage analysis for severe obesity in french caucasians finds significant susceptibility locus on chromosome 19q.
    Diabetes. 2004 Jul;53(7):1857-65 PMID: 15220211
Article Info
Journal
Cell metabolism
Abbr.
Cell Metab
ISSN
1932-7420
DOI
10.1016/j.cmet.2011.08.011
Email
parth@alum.mit.edu
Published
2011-11-02
Epub
2011-00-06
Pages
671-83
Language
English
Region
United States
NLM ID
101233170
PMCID
PMC3216113
Subset
IM
Grants
NHLBI NIH HHS · HL090553 · United States
NIDDK NIH HHS · R01 DK056626-12 · United States
NIDDK NIH HHS · R01 DK056626 · United States
NIDDK NIH HHS · R01 DK076117 · United States
NIDDK NIH HHS · R01 DK048873-14 · United States
NHLBI NIH HHS · P01 HL090553 · United States
NHLBI NIH HHS · K25 HL081523-04 · United States
NIDDK NIH HHS · R01 DK048873 · United States
NIDDK NIH HHS · R01 DK036256 · United States
NHLBI NIH HHS · P01 HL048743-08 · United States
NHLBI NIH HHS · R01 HL103582-01 · United States
NHLBI NIH HHS · R01 HL103582 · United States
NHLBI NIH HHS · P01 HL090553-01A1 · United States
NHLBI NIH HHS · HL103582 · United States
NHLBI NIH HHS · HL048743 · United States
NHLBI NIH HHS · K25 HL081523 · United States
NHLBI NIH HHS · P01 HL048743 · United States
NIDDK NIH HHS · R01 DK076117-04 · United States
NHLBI NIH HHS · HL081523 · United States
NIDDK NIH HHS · DK36256 · United States
NIDDK NIH HHS · R29 DK048873 · United States
NIDDK NIH HHS · R01 DK036256-20 · United States
NIDDK NIH HHS · DK076117 · United States
NIDDK NIH HHS · DK56626 · United States
NIDDK NIH HHS · DK48873 · United States
NIDDK NIH HHS · R37 DK048873 · United States
External Links
PubMed source DOI: 10.1016/j.cmet.2011.08.011 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2