Prolactin receptor signaling is essential for perinatal brown adipocyte function: a role for insulin-like growth factor-2.

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2008-02-06

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BACKGROUND: The lactogenic hormones prolactin (PRL) and placental lactogens (PL) play central roles in reproduction and mammary development. Their actions are mediated via binding to PRL receptor (PRLR), highly expressed in brown adipose tissue (BAT), yet their impact on adipocyte function and metabolism remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: PRLR knockout (KO) newborn mice were phenotypically characterized in terms of thermoregulation and their BAT differentiation assayed for gene expression studies. Derived brown preadipocyte cell lines were established to evaluate the molecular mechanisms involved in PRL signaling on BAT function. Here, we report that newborn mice lacking PRLR have hypotrophic BAT depots that express low levels of adipocyte nuclear receptor PPARgamma2, its coactivator PGC-1alpha, uncoupling protein 1 (UCP1) and the beta3 adrenoceptor, reducing mouse viability during cold challenge. Immortalized PRLR KO preadipocytes fail to undergo differentiation into mature adipocytes, a defect reversed by reintroduction of PRLR. That the effects of the lactogens in BAT are at least partly mediated by Insulin-like Growth Factor-2 (IGF-2) is supported by: i) a striking reduction in BAT IGF-2 expression in PRLR KO mice and in PRLR-deficient preadipocytes; ii) induction of cellular IGF-2 expression by PRL through JAK2/STAT5 pathway activation; and iii) reversal of defective differentiation in PRLR KO cells by exogenous IGF-2. CONCLUSIONS: Our findings demonstrate that the lactogens act in concert with IGF-2 to control brown adipocyte differentiation and growth. Given the prominent role of brown adipose tissue during the perinatal period, our results identified prolactin receptor signaling as a major player and a potential therapeutic target in protecting newborn mammals against hypothermia.

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10.1371/journal.pone.0001535

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Viengchareun, Say, Nathalie Servel, Bruno Fève, Michael Freemark, Marc Lombès and Nadine Binart (2008). Prolactin receptor signaling is essential for perinatal brown adipocyte function: a role for insulin-like growth factor-2. PLoS One, 3(2). p. e1535. 10.1371/journal.pone.0001535 Retrieved from https://hdl.handle.net/10161/4483.

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Freemark

Michael Scott Freemark

Robert C. Atkins, M.D. and Veronica Atkins Distinguished Professor of Pediatrics, in the School of Medicine

The primary objective of my basic research has been to elucidate the roles of placental and fetal hormones in the regulation of maternal metabolism and fetal growth. My work has focused on the lactogenic hormones produced by the pituitary gland and placenta. To that end we used targeted knockout mice to explore the molecular mechanisms by which prolactin and placental lactogen regulate pancreatic beta cell mass and insulin production during pregnancy and postnatal life.

I also have a longstanding clinical research interest in the pathogenesis and treatment of obesity and hyperlipidemia and the prevention of type 2 diabetes. In previous studies we showed that the drug metformin reduces fat stores and blood glucose and insulin levels in obese adolescents and may reduce the risk of progression to diabetes in selected patients. We have also examined the unique metabolic characteristics of Prader Willi syndrome, a genetic obesity disorder.

Finally, my colleagues and I have performed detailed studies of hormone production and intermediary metabolism in malnourished children in Uganda, Bangladesh, Liberia, and Burkina Faso and characterized the effects of concurrent HIV infection on nutritional recovery.  We showed that the adipocyte hormone leptin is a major determinant of morbidity and mortality in children with moderate and severe acute malnutrition. 


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