title: Cross down-regulation of leptin and insulin receptor expression and signalling in a human neuronal cell line.
abstract: Leptin and insulin are major signals to the hypothalamus to regulate energy homoeostasis and body adiposity. IR (insulin receptors) and leptin receptors (long isoform, ObRb) share a number of signalling cascades, such as JAK2/STAT-3 (Janus kinase 2/signal transduction and activator of transcription 3) and PI3K (phosphoinositide 3-kinase); the cross-talk between IR and ObRb have been described previously in non-neuronal cells. Differentiated human neuroblastoma (SH-SY5Y) cells express endogenous ObR and IR, and respond to leptin and insulin with stimulation of STAT-3 and MAPK (mitogen-activated protein kinase) phosphorylation, and PI3K activity. Insulin or leptin pre-treatment of SH-SY5Y cells increased basal STAT-3 phosphorylation, but abolished the acute effect of these hormones, and, interestingly, leptin pre-treatment abolished insulin effect and vice versa. Similar results were obtained for MAPK phosphorylation, but leptin or insulin pre-treatment did not completely abolish the acute effect of insulin or leptin. We have also showed that insulin and leptin are able to activate PI3K through IRS-1 (insulin receptor substrate 1) and IRS-2 respectively. Furthermore, leptin or insulin pre-treatment increased basal PI3K activity and IRS-1 or IRS-2 association with p85 and abolished acute insulin or leptin effect, in addition to the down-regulation of IRS-1 and IRS-2. Finally, insulin pre-treatment reduced leptin binding by approx. 60%, and leptin pre-treatment reduced the expression of insulin receptor by 40% in SH-SY5Y cells, which most likely accounts for the cross down-regulation of leptin and insulin receptors. These results provide evidence to suggest cross down-regulation of leptin and insulin receptors at both receptor and downstream signalling levels. This finding may contribute to the understanding of the complex relationship between leptin resistance and insulin resistance at the neuronal level.
authors.affiliation: Neuroendocrinologie Moléculaire de la Prise Alimentaire, Laboratoire d'Endocrinologie de la Nutrition, INRA, Université Paris XI, IBAIC Bat. 447, Orsay 91405, France.
authors.forename: Yacir
authors.initials: Y
authors.lastname: Benomar
authors.forename: Anne-France
authors.initials: AF
authors.lastname: Roy
authors.forename: Alain
authors.initials: A
authors.lastname: Aubourg
authors.forename: Jean
authors.initials: J
authors.lastname: Djiane
authors.forename: Mohammed
authors.initials: M
authors.lastname: Taouis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D047468:Immunoprecipitation; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits; D011972:Receptor, Insulin / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D054411:Receptors, Leptin; D012756:Sheep; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D021122:Protein Subunits; D011972:Receptor, Insulin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D014212:Tretinoin; C526292:IRS1 protein, human; C526297:IRS2 protein, human; C515448:LEPR protein, human
references.citation: Diabetologia. 2000 Jan;43(1):3-12
references.pmid: 10663211
references.citation: Endocrinology. 1997 Aug;138(8):3395-401
references.pmid: 9231793
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2355-60
references.pmid: 10688912
references.citation: Domest Anim Endocrinol. 2000 Apr;18(3):325-35
references.pmid: 10793271
references.citation: J Biol Chem. 2000 May 12;275(19):14563-72
references.pmid: 10799542
references.citation: Biochem Biophys Res Commun. 2000 May 19;271(3):703-9
references.pmid: 10814526
references.citation: Nat Neurosci. 2000 Aug;3(8):757-8
references.pmid: 10903566
references.citation: J Clin Invest. 2000 Aug;106(4):473-81
references.pmid: 10953022
references.citation: J Biol Chem. 2000 Dec 22;275(51):40649-57
references.pmid: 11018044
references.citation: FEBS Lett. 2001 Jul 6;500(3):119-24
references.pmid: 11445068
references.citation: J Clin Invest. 2001 Oct;108(7):1079-85
references.pmid: 11581309
references.citation: Endocrinology. 2001 Nov;142(11):4806-12
references.pmid: 11606447
references.citation: Nature. 2001 Oct 25;413(6858):794-5
references.pmid: 11677594
references.citation: Eur J Clin Invest. 2001 Nov;31(11):966-77
references.pmid: 11737239
references.citation: Am J Physiol Endocrinol Metab. 2002 Mar;282(3):E664-71
references.pmid: 11832371
references.citation: Trends Cell Biol. 2002 Feb;12(2):65-71
references.pmid: 11849969
references.citation: Nat Neurosci. 2002 Jun;5(6):566-72
references.pmid: 12021765
references.citation: Mol Endocrinol. 2002 Jul;16(7):1612-28
references.pmid: 12089355
references.citation: J Biol Chem. 2002 Jul 12;277(28):25297-304
references.pmid: 12000752
references.citation: J Biol Chem. 2002 Nov 1;277(44):41547-55
references.pmid: 12196522
references.citation: Nutr Rev. 2002 Oct;60(10 Pt 2):S20-9; discussion S68-84, 85-7
references.pmid: 12403080
references.citation: J Biol Chem. 2002 Nov 29;277(48):46304-9
references.pmid: 12226096
references.citation: J Histochem Cytochem. 2003 Mar;51(3):275-83
references.pmid: 12588955
references.citation: Nature. 2003 Feb 20;421(6925):856-9
references.pmid: 12594516
references.citation: Biol Chem. 2003 Jan;384(1):151-9
references.pmid: 12674509
references.citation: Cell. 1995 Dec 29;83(7):1263-71
references.pmid: 8548812
references.citation: Nature. 1997 Sep 25;389(6649):374-7
references.pmid: 9311777
references.citation: Nature. 1997 Nov 27;390(6658):349
references.pmid: 9389472
references.citation: Nature. 1997 Dec 4;390(6659):521-5
references.pmid: 9394003
references.citation: Brain Res. 1997 Nov 28;777(1-2):231-6
references.pmid: 9449434
references.citation: Science. 1998 May 29;280(5368):1378-83
references.pmid: 9603721
references.citation: Endocrinology. 1998 Aug;139(8):3485-91
references.pmid: 9681499
references.citation: Biochem J. 1998 Oct 15;335 ( Pt 2):293-300
references.pmid: 9761726
references.citation: Nature. 1998 Oct 22;395(6704):763-70
references.pmid: 9796811
references.citation: J Biol Chem. 1998 Nov 20;273(47):31160-7
references.pmid: 9813020
references.citation: Endocrinology. 1999 May;140(5):2117-24
references.pmid: 10218962
references.citation: Diabetes. 1999 Feb;48(2):287-91
references.pmid: 10334303
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9677-82
references.pmid: 10449753
references.citation: Mol Cell Endocrinol. 2003 Jul 31;205(1-2):115-20
references.pmid: 12890573
references.citation: J Biol Chem. 2003 Oct 24;278(43):41677-84
references.pmid: 12923167
references.citation: Recent Prog Horm Res. 2004;59:287-304
references.pmid: 14749507
references.citation: Am J Physiol. 1994 Jan;266(1 Pt 2):R59-64
references.pmid: 8304556
references.citation: J Biol Chem. 1994 Nov 4;269(44):27762-6
references.pmid: 7525562
references.citation: Diabetes. 1995 Feb;44(2):147-51
references.pmid: 7859932
references.citation: Science. 1995 Jul 28;269(5223):540-3
references.pmid: 7624776
references.citation: J Biol Chem. 1996 May 24;271(21):12121-4
references.pmid: 8647800
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8374-8
references.pmid: 8710878
references.citation: Science. 1996 Nov 15;274(5290):1185-8
references.pmid: 8895466
references.citation: J Biol Chem. 1997 Feb 14;272(7):4065-71
references.pmid: 9020115
references.citation: Mol Endocrinol. 1997 Apr;11(4):393-9
references.pmid: 9092791
references.citation: J Biol Chem. 1997 Mar 7;272(10):6093-6
references.pmid: 9102398
references.citation: Diabetologia. 1997 May;40(5):606-9
references.pmid: 9165231
references.citation: J Biol Chem. 2000 Feb 18;275(7):4660-9
references.pmid: 10671495