Mutation of SLC35D3 Causes Metabolic Syndrome by Impairing Dopamine Signaling in Striatal D1 Neurons


Obesity is one of the largest health problems facing the world today. Although twin and family studies suggest about two-thirds of obesity is caused by genetic factors, only a small fraction of this variance has been unraveled. There are still large numbers of genes to be identified that cause variations in body fatness and the associated diseases encompassed in the metabolic syndrome (MetS). A locus near a sequence tagged site (STS) marker D6S1009 has been linked to obesity or body mass index (BMI). However, its genetic entity is unknown. D6S1009 is located in the intergenic region between SLC35D3 and NHEG1. Here we report that the ros mutant mice harboring a recessive mutation in the Slc35d3 gene show obesity and MetS and reduced membrane dopamine receptor D1 (D1R) with impaired dopamine signaling in striatal neurons. SLC35D3 is localized to both endoplasmic reticulum (ER) and early endosomes and interacts with D1R. In ros striatal D1 neurons, lack of SLC35D3 causes the accumulation of D1R on the ER to impair its ER exit. The MetS phenotype is reversible by the administration of D1R agonist to the ros mutant. In addition, we identified two mutations in the SLC35D3 gene in patients with MetS, which alter the subcellular localization of SLC35D3. Our results suggest that the SLC35D3 gene, close to the D6S1009 locus, is a candidate gene for MetS, which is involved in metabolic control in the central nervous system by regulating dopamine signaling.


Vyšlo v časopise: Mutation of SLC35D3 Causes Metabolic Syndrome by Impairing Dopamine Signaling in Striatal D1 Neurons. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1004124
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004124

Souhrn

Obesity is one of the largest health problems facing the world today. Although twin and family studies suggest about two-thirds of obesity is caused by genetic factors, only a small fraction of this variance has been unraveled. There are still large numbers of genes to be identified that cause variations in body fatness and the associated diseases encompassed in the metabolic syndrome (MetS). A locus near a sequence tagged site (STS) marker D6S1009 has been linked to obesity or body mass index (BMI). However, its genetic entity is unknown. D6S1009 is located in the intergenic region between SLC35D3 and NHEG1. Here we report that the ros mutant mice harboring a recessive mutation in the Slc35d3 gene show obesity and MetS and reduced membrane dopamine receptor D1 (D1R) with impaired dopamine signaling in striatal neurons. SLC35D3 is localized to both endoplasmic reticulum (ER) and early endosomes and interacts with D1R. In ros striatal D1 neurons, lack of SLC35D3 causes the accumulation of D1R on the ER to impair its ER exit. The MetS phenotype is reversible by the administration of D1R agonist to the ros mutant. In addition, we identified two mutations in the SLC35D3 gene in patients with MetS, which alter the subcellular localization of SLC35D3. Our results suggest that the SLC35D3 gene, close to the D6S1009 locus, is a candidate gene for MetS, which is involved in metabolic control in the central nervous system by regulating dopamine signaling.


Zdroje

1. KopelmanPG (2000) Obesity as a medical problem. Nature 404: 635–643.

2. MaesHH, NealeMC, EavesLJ (1997) Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 27: 325–351.

3. DrongAW, LindgrenCM, McCarthyMI (2012) The genetic and epigenetic basis of type 2 diabetes and obesity. Clin Pharmacol Ther 92: 707–715.

4. MutchDM, ClementK (2006) Unraveling the genetics of human obesity. PLoS Genet 2: e188.

5. RankinenT, ZuberiA, ChagnonYC, WeisnagelSJ, ArgyropoulosG, et al. (2006) The human obesity gene map: the 2005 update. Obesity (Silver Spring) 14: 529–644.

6. FischerJ, KochL, EmmerlingC, VierkottenJ, PetersT, et al. (2009) Inactivation of the Fto gene protects from obesity. Nature 458: 894–898.

7. FoxCS, Heard-CostaNL, WilsonPW, LevyD, D'AgostinoRBSr, et al. (2004) Genome-wide linkage to chromosome 6 for waist circumference in the Framingham Heart Study. Diabetes 53: 1399–1402.

8. AryaR, LehmanD, HuntKJ, SchneiderJ, AlmasyL, et al. (2003) Evidence for bivariate linkage of obesity and HDL-C levels in the Framingham Heart Study. BMC Genet 4(Suppl 1): S52.

9. AtwoodLD, Heard-CostaNL, CupplesLA, JaquishCE, WilsonPW, et al. (2002) Genomewide linkage analysis of body mass index across 28 years of the Framingham Heart Study. Am J Hum Genet 71: 1044–1050.

10. ChintalaS, TanJ, GautamR, RusiniakME, GuoX, et al. (2007) The Slc35d3 gene, encoding an orphan nucleotide sugar transporter, regulates platelet-dense granules. Blood 109: 1533–1540.

11. MengR, WangY, YaoY, ZhangZ, HarperDC, et al. (2012) SLC35D3 delivery from megakaryocyte early endosomes is required for platelet dense granule biogenesis and is differentially defective in Hermansky-Pudlak syndrome models. Blood 120: 404–414.

12. LoboMK, KarstenSL, GrayM, GeschwindDH, YangXW (2006) FACS-array profiling of striatal projection neuron subtypes in juvenile and adult mouse brains. Nat Neurosci 9: 443–452.

13. TschopMH, SpeakmanJR, ArchJR, AuwerxJ, BruningJC, et al. (2011) A guide to analysis of mouse energy metabolism. Nat Methods 9: 57–63.

14. DumartinB, CailleI, GononF, BlochB (1998) Internalization of D1 dopamine receptor in striatal neurons in vivo as evidence of activation by dopamine agonists. J Neurosci 18: 1650–1661.

15. AlbertiKG, ZimmetP, ShawJ (2006) Metabolic syndrome–a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 23: 469–480.

16. BaoY, LuJ, WangC, YangM, LiH, et al. (2008) Optimal waist circumference cutoffs for abdominal obesity in Chinese. Atherosclerosis 201: 378–384.

17. WoodsSC, SeeleyRJ, PorteDJr, SchwartzMW (1998) Signals that regulate food intake and energy homeostasis. Science 280: 1378–1383.

18. SchwartzMW, WoodsSC, PorteDJr, SeeleyRJ, BaskinDG (2000) Central nervous system control of food intake. Nature 404: 661–671.

19. GuyenetSJ, SchwartzMW (2012) Clinical review: Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity. J Clin Endocrinol Metab 97: 745–755.

20. RamosEJ, MeguidMM, CamposAC, CoelhoJC (2005) Neuropeptide Y, alpha-melanocyte-stimulating hormone, and monoamines in food intake regulation. Nutrition 21: 269–279.

21. MartelP, FantinoM (1996) Mesolimbic dopaminergic system activity as a function of food reward: a microdialysis study. Pharmacol Biochem Behav 53: 221–226.

22. MeguidMM, FetissovSO, VarmaM, SatoT, ZhangL, et al. (2000) Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition 16: 843–857.

23. SurmeierDJ, DingJ, DayM, WangZ, ShenW (2007) D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci 30: 228–235.

24. LoboMK (2009) Molecular profiling of striatonigral and striatopallidal medium spiny neurons past, present, and future. Int Rev Neurobiol 89: 1–35.

25. WangGJ, VolkowND, LoganJ, PappasNR, WongCT, et al. (2001) Brain dopamine and obesity. Lancet 357: 354–357.

26. WangGJ, VolkowND, ThanosPK, FowlerJS (2009) Imaging of brain dopamine pathways: implications for understanding obesity. J Addict Med 3: 8–18.

27. VolkowND, WangGJ, TelangF, FowlerJS, ThanosPK, et al. (2008) Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors. Neuroimage 42: 1537–1543.

28. KimOJ, GardnerBR, WilliamsDB, MarinecPS, CabreraDM, et al. (2004) The role of phosphorylation in D1 dopamine receptor desensitization: evidence for a novel mechanism of arrestin association. J Biol Chem 279: 7999–8010.

29. CorvolJC, StudlerJM, SchonnJS, GiraultJA, HerveD (2001) Galpha(olf) is necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum. J Neurochem 76: 1585–1588.

30. IwamotoT, OkumuraS, IwatsuboK, KawabeJ, OhtsuK, et al. (2003) Motor dysfunction in type 5 adenylyl cyclase-null mice. J Biol Chem 278: 16936–16940.

31. MarcheseA, ChenC, KimYM, BenovicJL (2003) The ins and outs of G protein-coupled receptor trafficking. Trends Biochem Sci 28: 369–376.

32. JiY, YangF, PapaleoF, WangHX, GaoWJ, et al. (2009) Role of dysbindin in dopamine receptor trafficking and cortical GABA function. Proc Natl Acad Sci U S A 106: 19593–19598.

33. VargasGA, Von ZastrowM (2004) Identification of a novel endocytic recycling signal in the D1 dopamine receptor. J Biol Chem 279: 37461–37469.

34. TanCM, BradyAE, NickolsHH, WangQ, LimbirdLE (2004) Membrane trafficking of G protein-coupled receptors. Annu Rev Pharmacol Toxicol 44: 559–609.

35. BermakJC, LiM, BullockC, ZhouQY (2001) Regulation of transport of the dopamine D1 receptor by a new membrane-associated ER protein. Nat Cell Biol 3: 492–498.

36. Petaja-RepoUE, HogueM, LaperriereA, WalkerP, BouvierM (2000) Export from the endoplasmic reticulum represents the limiting step in the maturation and cell surface expression of the human delta opioid receptor. J Biol Chem 275: 13727–13736.

37. WangM, LeeFJ, LiuF (2008) Dopamine receptor interacting proteins (DRIPs) of dopamine D1-like receptors in the central nervous system. Mol Cells 25: 149–157.

38. TranAH, TamuraR, UwanoT, KobayashiT, KatsukiM, et al. (2005) Dopamine D1 receptors involved in locomotor activity and accumbens neural responses to prediction of reward associated with place. Proc Natl Acad Sci U S A 102: 2117–2122.

39. KobayashiM, IaccarinoC, SaiardiA, HeidtV, BozziY, et al. (2004) Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice. Proc Natl Acad Sci U S A 101: 11465–11470.

40. IngallsAM, DickieMM, SnellGD (1950) Obese, a new mutation in the house mouse. J Hered 41: 317–318.

41. Pi-SunyerFX (2002) The obesity epidemic: pathophysiology and consequences of obesity. Obes Res 10(Suppl 2): 97S–104S.

42. GalluzziF, SaltiR, StagiS, La CauzaF, ChiarelliF (2005) Reversible weight gain and prolactin levels–long-term follow-up in childhood. J Pediatr Endocrinol Metab 18: 921–924.

43. de Vilhena e SantosDM, KatzmarzykPT, SeabraAF, MaiaJA (2012) Genetics of physical activity and physical inactivity in humans. Behav Genet 42: 559–578.

44. CasazzaK, FontaineKR, AstrupA, BirchLL, BrownAW, et al. (2013) Myths, presumptions, and facts about obesity. N Engl J Med 368: 446–454.

45. ArchJR, HislopD, WangSJ, SpeakmanJR (2006) Some mathematical and technical issues in the measurement and interpretation of open-circuit indirect calorimetry in small animals. Int J Obes (Lond) 30: 1322–1331.

46. NonogakiK, AbdallahL, GouldingEH, BonaseraSJ, TecottLH (2003) Hyperactivity and reduced energy cost of physical activity in serotonin 5-HT(2C) receptor mutant mice. Diabetes 52: 315–320.

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