title: Lack of cross-desensitization between leptin and prolactin signaling pathways despite the induction of suppressor of cytokine signaling 3 and PTP-1B.
abstract: Hyperprolactinemia and hyperleptinemia occur during gestation and lactation with marked hyperphagia associated with leptin resistance. Prolactin (PRL) induces the expression of orexigenic neuropeptide Y (NPY) through the activation of JAK-2/STAT-3 signaling pathway in hypothalamic paraventricular nucleus (PVN) leading to hyperphagia. PRL may also act through the inhibition of anorexigenic effect of leptin via induction of suppressor of cytokine signaling 3 (SOCS-3). This paper aimed to co-localize PRL (PRL-R) and leptin (ObRb) receptors in the hypothalamus of female rats and investigate the possible cross-desensitization between PRL-R and ObRb. We showed that: 1) PRL-R and ObRb are expressed in the PVN and co-localized in the same neurons; 2) in lactating females leptin failed to activate JAK-2/STAT-3 signaling pathway; 3) in Chinese Hamster Ovary (CHO) stably co-expressing PRL-R and ObRb, overexposure to PRL did not affect leptin signaling but totally abolished PRL-dependent STAT-5 phosphorylation. The overexposure to leptin produces similar results with strong alteration of leptin-dependent STAT-3 phosphorylation, whereas PRL-dependent STAT-5 was not affected; and 4) CHO-ObRb/PRL-R cells overexposure to leptin or PRL induces the expression of negative regulators SOCS-3 and PTP-1B. Thus, we conclude that these negative regulators affect specifically the inducer signaling pathway; for instance, SOCS-3 induced by PRL will affect PRL-R signaling but not ObRb signaling and vice versa. Finally, the lack of cross-desensitization between PURL-R and ObRb suggests that hyperphagia observed during gestation and lactation may be attributed to a direct effect of PRL on NPYexpression, and is most likely exacerbated by the physiological leptin resistance state.
authors.affiliation: Neuroendocrinologie Moléculaire de la Prise Alimentaire, UMR 1197 INRA/Université Paris XI, IBAIC Bât. 447, Orsay 91405, France.
authors.forename: A F
authors.initials: AF
authors.lastname: Roy
authors.forename: Y
authors.initials: Y
authors.lastname: Benomar
authors.forename: V
authors.initials: V
authors.lastname: Bailleux
authors.forename: C M
authors.initials: CM
authors.lastname: Vacher
authors.forename: A
authors.initials: A
authors.lastname: Aubourg
authors.forename: A
authors.initials: A
authors.lastname: Gertler
authors.forename: J
authors.initials: J
authors.lastname: Djiane
authors.forename: M
authors.initials: M
authors.lastname: Taouis
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004334:Drug Administration Schedule; D004351:Drug Resistance; D005260:Female; D053614:Janus Kinase 2 / Q000378:metabolism; D007774:Lactation / Q000502:physiology; D020738:Leptin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011388:Prolactin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000096:biosynthesis*; D051381:Rats; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis*; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D020738:Leptin; D054411:Receptors, Leptin; D011981:Receptors, Prolactin; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011388:Prolactin; D053614:Janus Kinase 2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516610:Ptpn1 protein, rat