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      Growth Hormone and Prolactin Receptors in Adipogenesis: STAT-5 Activation, Suppressors of Cytokine Signaling, and Regulation of Insulin-Like Growth Factor I

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          Growth hormone (GH) stimulates lipolysis in mature adipocytes and primary preadipocytes but promotes adipogenesis in preadipocyte cell lines. The lactogenic hormones (prolactin [PRL] and placental lactogen) also stimulate adipogenesis in preadipocyte cell lines but have variable lipolytic and lipogenic effects in mature adipose tissue. We hypothesized that differences in expression of GH receptors (GHR) and PRL receptors (PRLR) during adipocyte development might explain some of the differential effects of the somatogens and lactogens on fat metabolism. To that end, we compared: (a) the expression of GHR and PRLR mRNAs in 3T3-L1 preadipocytes during the course of adipocyte differentiation; (b) the induction of STAT-5 activity by GH and PRL during adipogenesis; and (c) the acute effects of GH and PRL on the suppressors of cytokine signaling (SOCS-1–3 and cytokine-inducible SH2-domain-containing protein [CIS]) and IGF-I. In confluent, undifferentiated 3T3-L1 cells, the levels of GHR mRNA were ∼250-fold higher than the levels of PRLR mRNA. Following induction of adipocyte differentiation the levels of PRLR mRNA rose 90-fold but GHR mRNA increased only 0.8-fold. Expression of both full-length (long) and truncated (short) isoforms of the PRLR increased during differentiation but the long isoform predominated at all time points. Mouse GH (mGH) stimulated increases in STAT-5a and 5b activity in undifferentiated as well as differentiating 3T3-L1 cells; mouse PRL (mPRL) had little or no effect on STAT-5 activity in undifferentiated cells but stimulated increases in STAT-5a and 5b activity in differentiating cells. mGH stimulated increases in SOCS-2 and SOCS-3 mRNAs in undifferentiated cells and SOCS-1–3 and CIS mRNAs in differentiating cells; mPRL induced CIS in differentiating cells but had no effect on SOCS-1–3. mPRL and mGH stimulated increases in IGF-I mRNA in differentiating cells but not in undifferentiated cells; the potency of mGH (3–6-fold increase, p < 0.01) exceeded that of mPRL (40–90% increase, p < 0.05). Our findings reveal disparities in the expression of PRLR and GHR during adipocyte development and differential effects of the hormones on STAT-5, the SOCS proteins, CIS, and IGF-I. These observations suggest that somatogens and lactogens regulate adipocyte development and fat metabolism through distinct but overlapping cellular mechanisms.

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          Most cited references 20

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          Identification of functional prolactin (PRL) receptor gene expression: PRL inhibits lipoprotein lipase activity in human white adipose tissue.

          During lactation serum levels of prolactin (PRL) are elevated, and the activity of lipoprotein lipase (LPL) is decreased in the adipose tissue and increased in the mammary gland. However, PRL has been suggested to affect the adipose tissue in an indirect fashion during lactation. In the present study, we demonstrated expression of four PRL receptor (PRLR) mRNA isoforms (L, I, S1(a), and S1(b)) in human sc abdominal adipose tissue and breast adipose tissue using RT-PCR/Southern blot analysis. In addition, L-PRLR [relative molecular mass (M(r)) 90,000] and I-PRLR (M(r) 50,000) protein expression was detected in human sc abdominal adipose tissue and breast adipose tissue using immunoblot analysis. Two additional protein bands with the molecular weight M(r) 40-35,000 were also detected. The direct effect of PRL on the regulation of LPL activity in human abdominal adipose tissue cultured in vitro was investigated. PRL (500 ng/ml) reduced the LPL activity in human adipose tissue to 31 +/- 7.7%, compared with control. GH (100 ng/ml) also reduced the LPL activity, to 45 +/- 8.6%, compared with control. In agreement with previous studies, cortisol increased the LPL activity and GH inhibited cortisol-induced LPL activity. Furthermore, we found that PRL also inhibited the cortisol-induced LPL activity. Taken together, these results demonstrate a direct effect of PRL, via functional PRLRs, in reducing the LPL activity in human adipose tissue, and these results suggest that LPL might also be regulated in this fashion during lactation.
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            Inhibition and restoration of prolactin signal transduction by suppressors of cytokine signaling.

            Prolactin (PRL) has been shown to activate the cytoplasmic tyrosine kinase Janus kinase 2 (Jak2) and the subsequent recruitment of various signaling molecules including members of the signal transducer and activator of transcription family of transcription factors. Recently, an expanding family of cytokine-inducible inhibitors of signaling has been identified that initially included four members: suppressor of cytokine signaling (SOCS)-1, SOCS-2, SOCS-3, and cytokine-inducible src homology domain 2 (SH-2) proteins. The present study analyzes the role of these members in PRL signaling. Constitutive expression of SOCS-1 and SOCS-3 suppressed PRL-induced signal transducer and activator of transcription 5-dependent gene transcription, and Jak2 tyrosine kinase activity was greatly reduced in the presence of SOCS-1 or SOCS-3. SOCS-1 was shown to associate with Jak2, whereas SOCS-2 was associated with the prolactin receptor. Co-transfection studies were conducted to further analyze the interactions of SOCS proteins. SOCS-2 was shown to suppress the inhibitory effect of SOCS-1 by restoring Jak2 kinase activity but did not affect the inhibitory effect of SOCS-3 on PRL signaling. Northern blot analysis revealed that SOCS-3 and SOCS-1 genes were transiently expressed in response to PRL, both in vivo and in vitro, whereas the expression of SOCS-2 and CIS genes was still elevated 24 h after hormonal stimulation. We thus propose that the early expressed SOCS genes (SOCS-1 and SOCS-3) switch off PRL signaling and that the later expressed SOCS-2 gene can restore the sensitivity of cells to PRL, partly by suppressing the SOCS-1 inhibitory effect.
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              Regulation of Maternal Metabolism by Pituitary and Placental Hormones: Roles in Fetal Development and Metabolic Programming

               M Freemark (2006)
              This review outlines the regulation of maternal metabolism by hormones, cytokines and growth factors, highlighting recent studies that implicate disordered somatolactogen signalling in the pathogenesis of perinatal growth failure and the development of the metabolic syndrome.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                August 2006
                11 August 2006
                : 66
                : 3
                : 101-110
                Departments of Pediatrics and Cell Biology, Duke University Medical Center, Durham, N.C., USA
                93667 Horm Res 2006;66:101–110
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 7, Tables: 1, References: 36, Pages: 10
                Original Paper


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