Prolactin receptor signaling is essential for perinatal brown adipocyte function: a role for insulin-like growth factor-2.
Abstract
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.
Type
Journal articleSubject
Adaptation, PhysiologicalAdipocytes, Brown
Animals
Animals, Newborn
Cell Differentiation
Cold Temperature
Gene Expression Regulation
Insulin-Like Growth Factor II
Mice
Mice, Knockout
Phenotype
Receptors, Prolactin
Signal Transduction
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https://hdl.handle.net/10161/4483Published Version (Please cite this version)
10.1371/journal.pone.0001535Publication Info
Viengchareun, Say; Servel, Nathalie; Fève, Bruno; Freemark, Michael; Lombès, Marc;
& Binart, Nadine (2008). Prolactin receptor signaling is essential for perinatal brown adipocyte function:
a role for insulin-like growth factor-2. PLoS One, 3(2). pp. e1535. 10.1371/journal.pone.0001535. Retrieved from https://hdl.handle.net/10161/4483.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
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

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