Is Required for Leptin-Mediated Depolarization of POMC Neurons in the Hypothalamic Arcuate Nucleus in Mice

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Prader-Willi Syndrome is the most common syndromic form of human obesity and is caused by the loss of function of several genes, including MAGEL2. Mice lacking Magel2 display increased weight gain with excess adiposity and other defects suggestive of hypothalamic deficiency. We demonstrate Magel2-null mice are insensitive to the anorexic effect of peripherally administered leptin. Although their excessive adiposity and hyperleptinemia likely contribute to this physiological leptin resistance, we hypothesized that Magel2 may also have an essential role in intracellular leptin responses in hypothalamic neurons. We therefore measured neuronal activation by immunohistochemistry on brain sections from leptin-injected mice and found a reduced number of arcuate nucleus neurons activated after leptin injection in the Magel2-null animals, suggesting that most but not all leptin receptor–expressing neurons retain leptin sensitivity despite hyperleptinemia. Electrophysiological measurements of arcuate nucleus neurons expressing the leptin receptor demonstrated that although neurons exhibiting hyperpolarizing responses to leptin are present in normal numbers, there were no neurons exhibiting depolarizing responses to leptin in the mutant mice. Additional studies demonstrate that arcuate nucleus pro-opiomelanocortin (POMC) expressing neurons are unresponsive to leptin. Interestingly, Magel2-null mice are hypersensitive to the anorexigenic effects of the melanocortin receptor agonist MT-II. In Prader-Willi Syndrome, loss of MAGEL2 may likewise abolish leptin responses in POMC hypothalamic neurons. This neural defect, together with increased fat mass, blunted circadian rhythm, and growth hormone response pathway defects that are also linked to loss of MAGEL2, could contribute to the hyperphagia and obesity that are hallmarks of this disorder.

Vyšlo v časopise: Is Required for Leptin-Mediated Depolarization of POMC Neurons in the Hypothalamic Arcuate Nucleus in Mice. PLoS Genet 9(1): e32767. doi:10.1371/journal.pgen.1003207
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003207

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Zdroje

1. AhimaRS, LazarMA (2008) Adipokines and the peripheral and neural control of energy balance. Mol Endocrinol 22 : 1023–1031.

2. GrahamM, ShutterJR, SarmientoU, SarosiI, StarkKL (1997) Overexpression of Agrt leads to obesity in transgenic mice. Nat Genet 17 : 273–274.

3. OllmannMM, WilsonBD, YangYK, KernsJA, ChenY, et al. (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278 : 135–138.

4. TiesjemaB, la FleurSE, LuijendijkMC, AdanRA (2009) Sustained NPY overexpression in the PVN results in obesity via temporarily increasing food intake. Obesity 17 : 1448–1450.

5. MortonGJ, CummingsDE, BaskinDG, BarshGS, SchwartzMW (2006) Central nervous system control of food intake and body weight. Nature 443 : 289–295.

6. YaswenL, DiehlN, BrennanMB, HochgeschwenderU (1999) Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med 5 : 1066–1070.

7. KrudeH, BiebermannH, SchnabelD, TansekMZ, TheunissenP, et al. (2003) Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10. J Clin Endocrinol Metab 88 : 4633–4640.

8. FarooqiIS, DropS, ClementsA, KeoghJM, BiernackaJ, et al. (2006) Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes 55 : 2549–2553.

9. MontagueCT, FarooqiIS, WhiteheadJP, SoosMA, RauH, et al. (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387 : 903–908.

10. ClementK, VaisseC, LahlouN, CabrolS, PellouxV, et al. (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392 : 398–401.

11. FarooqiIS, KeoghJM, YeoGS, LankEJ, CheethamT, et al. (2003) Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348 : 1085–1095.

12. SeoS, GuoDF, BuggeK, MorganDA, RahmouniK, et al. (2009) Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet 18 : 1323–1331.

13. CassidySB, DriscollDJ (2009) Prader-Willi syndrome. Eur J Hum Genet 17 : 3–13.

14. LeeS, KozlovS, HernandezL, ChamberlainSJ, BrannanCI, et al. (2000) Expression and imprinting of MAGEL2 suggest a role in Prader-Willi syndrome and the homologous murine imprinting phenotype. Hum Mol Genet 9 : 1813–1819.

15. DoyleJM, GaoJ, WangJ, YangM, PottsPR (2010) MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Mol Cell 39 : 963–974.

16. LeeS, WalkerCL, WevrickR (2003) Prader-Willi syndrome transcripts are expressed in phenotypically significant regions of the developing mouse brain. Gene Expr Patterns 3 : 599–609.

17. MercerRE, KwolekEM, BischofJM, van EedeM, HenkelmanRM, et al. (2009) Regionally reduced brain volume, altered serotonin neurochemistry, and abnormal behavior in mice null for the circadian rhythm output gene Magel2. Am J Med Genet B Neuropsychiatr Genet 150B: 1085–1099.

18. BischofJM, StewartCL, WevrickR (2007) Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader-Willi syndrome. Hum Mol Genet 16 : 2713–2719.

19. MercerRE, WevrickR (2009) Loss of Magel2, a candidate gene for features of prader-willi syndrome, impairs reproductive function in mice. PLoS ONE 4: e4291 doi:10.1371/journal.pone.0004291.

20. IsraelD, ChuaSJr (2010) Leptin receptor modulation of adiposity and fertility. Trends Endocrinol. Metab 21 : 10–16.

21. BecskeiC, LutzTA, RiedigerT (2009) Blunted fasting-induced hypothalamic activation and refeeding hyperphagia in late-onset obesity. Neuroendocrinology 90 : 371–382.

22. XuAW, KaelinCB, MortonGJ, OgimotoK, StanhopeK, et al. (2005) Effects of hypothalamic neurodegeneration on energy balance. PLoS Biol 3: e415 doi:10.1371/journal.pbio.0030415.

23. XuAW, Ste-MarieL, KaelinCB, BarshGS (2007) Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding. Endocrinology 148 : 72–80.

24. Segal-LiebermanG, TromblyDJ, JuthaniV, WangX, Maratos-FlierE (2003) NPY ablation in C57BL/6 mice leads to mild obesity and to an impaired refeeding response to fasting. Am J Physiol Endocrinol Metab 284: E1131–1139.

25. PatelHR, QiY, HawkinsEJ, HilemanSM, ElmquistJK, et al. (2006) Neuropeptide Y deficiency attenuates responses to fasting and high-fat diet in obesity-prone mice. Diabetes 55 : 3091–3098.

26. Van HeekM, ComptonDS, FranceCF, TedescoRP, FawziAB, et al. (1997) Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest 99 : 385–390.

27. MunzbergH, FlierJS, BjorbaekC (2004) Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology 145 : 4880–4889.

28. MunzbergH, HuoL, NillniEA, HollenbergAN, BjorbaekC (2003) Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin. Endocrinology 144 : 2121–2131.

29. PiperML, UngerEK, MyersMGJr, XuAW (2008) Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons. Mol Endocrinol 22 : 751–759.

30. DragunowM, FaullR (1989) The use of c-fos as a metabolic marker in neuronal pathway tracing. J. Neurosci. Methods 29 : 261–265.

31. EliasCF, AschkenasiC, LeeC, KellyJ, AhimaRS, et al. (1999) Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23 : 775–786.

32. WilliamsKW, MargathoLO, LeeCE, ChoiM, LeeS, et al. (2010) Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J Neurosci 30 : 2472–2479.

33. CowleyMA, SmartJL, RubinsteinM, CerdanMG, DianoS, et al. (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411 : 480–484.

34. Acuna-GoycoleaC, van den PolAN (2005) Peptide YY(3–36) inhibits both anorexigenic proopiomelanocortin and orexigenic neuropeptide Y neurons: implications for hypothalamic regulation of energy homeostasis. J Neurosci 25 : 10510–10519.

35. van den TopM, LeeK, WhymentAD, BlanksAM, SpanswickD (2004) Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat Neurosci 7 : 493–494.

36. ElmquistJK, AhimaRS, Maratos-FlierE, FlierJS, SaperCB (1997) Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology 138 : 839–842.

37. EliasCF, KellyJF, LeeCE, AhimaRS, DruckerDJ, et al. (2000) Chemical characterization of leptin-activated neurons in the rat brain. J Comp Neurol 423 : 261–281.

38. IraniBG, Le FollC, Dunn-MeynellA, LevinBE (2008) Effects of leptin on rat ventromedial hypothalamic neurons. Endocrinology 149 : 5146–5154.

39. CheeMJ, PriceCJ, StatnickMA, ColmersWF (2011) Nociceptin/orphanin FQ suppresses the excitability of neurons in the ventromedial nucleus of the hypothalamus. J Physiol 589 : 3103–3114.

40. HansenMJ, BallMJ, MorrisMJ (2001) Enhanced inhibitory feeding response to alpha-melanocyte stimulating hormone in the diet-induced obese rat. Brain research 892 : 130–137.

41. ScarpacePJ, MathenyM, ZolotukhinS, TumerN, ZhangY (2003) Leptin-induced leptin resistant rats exhibit enhanced responses to the melanocortin agonist MT II. Neuropharmacology 45 : 211–219.

42. LiG, ZhangY, WilseyJT, ScarpacePJ (2004) Unabated anorexic and enhanced thermogenic responses to melanotan II in diet-induced obese rats despite reduced melanocortin 3 and 4 receptor expression. J Endocrinol 182 : 123–132.

43. KozlovSV, BogenpohlJW, HowellMP, WevrickR, PandaS, et al. (2007) The imprinted gene Magel2 regulates normal circadian output. Nat Genet 39 : 1266–1272.

44. El-HaschimiK, PierrozDD, HilemanSM, BjorbaekC, FlierJS (2000) Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 105 : 1827–1832.

45. RahmouniK, FathMA, SeoS, ThedensDR, BerryCJ, et al. (2008) Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome. J Clin Invest 118 : 1458–1467.

46. PrpicV, WatsonPM, FramptonIC, SabolMA, JezekGE, et al. (2003) Differential mechanisms and development of leptin resistance in A/J versus C57BL/6J mice during diet-induced obesity. Endocrinology 144 : 1155–1163.

47. LinS, ThomasTC, StorlienLH, HuangXF (2000) Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice. Int J Obes Relat Metab Disord 24 : 639–646.

48. van de WallE, LeshanR, XuAW, BalthasarN, CoppariR, et al. (2008) Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 149 : 1773–1785.

49. BalthasarN, CoppariR, McMinnJ, LiuSM, LeeCE, et al. (2004) Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42 : 983–991.

50. CollinM, BackbergM, OvesjoML, FisoneG, EdwardsRH, et al. (2003) Plasma membrane and vesicular glutamate transporter mRNAs/proteins in hypothalamic neurons that regulate body weight. Eur J Neurosci 18 : 1265–1278.

51. XuAW, KaelinCB, TakedaK, AkiraS, SchwartzMW, et al. (2005) PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest 115 : 951–958.

52. MorrisonCD, MortonGJ, NiswenderKD, GellingRW, SchwartzMW (2005) Leptin inhibits hypothalamic Npy and Agrp gene expression via a mechanism that requires phosphatidylinositol 3-OH-kinase signaling. Am J Physiol Endocrinol Metab 289: E1051–1057.

53. HillJW, WilliamsKW, YeC, LuoJ, BalthasarN, et al. (2008) Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J Clin Invest 118 : 1796–1805.

54. HillJW, XuY, PreitnerF, FukudaM, ChoYR, et al. (2009) Phosphatidyl inositol 3-kinase signaling in hypothalamic proopiomelanocortin neurons contributes to the regulation of glucose homeostasis. Endocrinology 150 : 4874–4882.

55. QiuJ, FangY, RonnekleivOK, KellyMJ (2010) Leptin excites proopiomelanocortin neurons via activation of TRPC channels. J Neurosci 30 : 1560–1565.

56. ShiraishiT, OomuraY, SasakiK, WaynerMJ (2000) Effects of leptin and orexin-A on food intake and feeding related hypothalamic neurons. Physiol Behav 71 : 251–261.

57. DhillonH, ZigmanJM, YeC, LeeCE, McGovernRA, et al. (2006) Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49 : 191–203.

58. AhimaRS, PrabakaranD, MantzorosC, QuD, LowellB, et al. (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382 : 250–252.

59. FrederichRC, LollmannB, HamannA, Napolitano-RosenA, KahnBB, et al. (1995) Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. J Clin Invest 96 : 1658–1663.

60. MuroyaS, FunahashiH, YamanakaA, KohnoD, UramuraK, et al. (2004) Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca 2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. Eur J Neurosci 19 : 1524–1534.

61. YamanakaA, BeuckmannCT, WillieJT, HaraJ, TsujinoN, et al. (2003) Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38 : 701–713.

62. SchallerF, WatrinF, SturnyR, MassacrierA, SzepetowskiP, et al. (2010) A single postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse newborns deficient for the imprinted Magel2 gene. Hum Mol Genet 19 : 4895–4905.

63. LeshanRL, LouisGW, JoYH, RhodesCJ, MunzbergH, et al. (2009) Direct innervation of GnRH neurons by metabolic -⁠ and sexual odorant-sensing leptin receptor neurons in the hypothalamic ventral premammillary nucleus. J Neurosci 29 : 3138–3147.

64. HrubyVJ, LuD, SharmaSD, CastrucciAL, KestersonRA, et al. (1995) Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4–10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J Med Chem 38 : 3454–3461.