Lack of cross-desensitization between leptin and prolactin signaling pathways despite the induction of suppressor of cytokine signaling 3 and PTP-1B

• Published in: Journal of endocrinology Vol. 195; no. 2; pp. 341 - 350
• Main Authors: Roy, A F, Benomar, Y, Bailleux, V, Vacher, C M, Aubourg, A, Gertler, A, Djiane, J, Taouis, M
• Format: Journal Article
• Language: English
• Published: Colchester BioScientifica 01.11.2007; Portland Press
• Subjects: Animals; Biological and medical sciences; CHO Cells; Cricetinae; Cricetulus; Drug Administration Schedule; Drug Resistance; Endocrinology and metabolism; Female; Fundamental and applied biological sciences. Psychology; Hormones and neuropeptides. Regulation; Human health and pathology; Hypothalamus. Hypophysis. Epiphysis. Urophysis; Janus Kinase 2 - metabolism; Lactation - physiology; Leptin - administration & dosage; Leptin - metabolism; Leptin - pharmacology; Life Sciences; Mice; Paraventricular Hypothalamic Nucleus - metabolism; Phosphorylation - drug effects; Prolactin - administration & dosage; Prolactin - metabolism; Prolactin - pharmacology; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - biosynthesis; Rats; Receptors, Leptin - genetics; Receptors, Leptin - metabolism; Receptors, Prolactin - genetics; Receptors, Prolactin - metabolism; Regular papers; Signal Transduction - physiology; STAT3 Transcription Factor - metabolism; STAT5 Transcription Factor - metabolism; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - biosynthesis; Tissue Distribution; Transfection; Vertebrates: endocrinology; Rat; Rodentia; Central nervous system; Cytokine; Hypothalamus; Gene expression; Encephalon; Signal transduction; Vertebrata; Mammalia; Adenohypophyseal hormone; Prolactin; Leptin; Adult animal; Female; Localization; STAT3 TRANSCRIPTION FACTOR; PROTEIN TYROSINE PHOSPHATASE; RAT; TRANSFECTION; DRUG RESISTANCE; NON RECEPTOR TYPE; RECEPTOR; PROLACTIN; CRICETULUS; PARAVENTRICULAR HYPOTHALAMIC NUCLEUS; STAT5 TRANSCRIPTION FACTOR; TISSUE DISTRIBUTION; SUPPRESSOR OF CYTOKINE SIGNALING PROTEINS; CHO CELL; CRICETINAE; DRUG ADMINISTRATION SCHEDULE; JANUS KINASE; SIGNAL TRANSDUCTION
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1677/JOE-07-0321

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.