Cross down-regulation of leptin and insulin receptor expression and signalling in a human neuronal cell line.
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.
Benomar
Yacir
Y
Neuroendocrinologie Moléculaire de la Prise Alimentaire, Laboratoire d'Endocrinologie de la Nutrition, INRA, Université Paris XI, IBAIC Bat. 447, Orsay 91405, France.
Roy
Anne-France
AF
Aubourg
Alain
A
Djiane
Jean
J
Taouis
Mohammed
M
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
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
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