Prolactin Receptor Signaling Is Essential for Perinatal Brown Adipocyte Function: A Role for Insulin-like Growth Factor-2

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

Prolactin Release by Adipose Explants, Primary Adipocytes, and LS14 Adipocytes

Background: Prolactin (PRL) is a multifunctional hormone produced in humans by both pituitary and extrapituitary sites, including adipose tissue

Decreased expression of adipogenic genes in obese subjects with type 2 diabetes

OBJECTIVE: Our objective was to delineate the potential role of adipogenesis in insulin resistance and type 2 diabetes. Obesity is characterized by an increase in adipose tissue mass resulting from enlargement of existing fat cells (hypertrophy) and/or from increased number of adipocytes (hyperplasia). The inability of the adipose tissue to recruit new fat cells may cause ectopic fat deposition and insulin resistance. RESEARCH METHODS AND PROCEDURES: We examined the expression of candidate genes involved in adipocyte proliferation and/or differentiation [ CCAAT/enhancer-binding protein (C/EBP) , C/EBP , GATA domain-binding protein 3 (GATA3), C/EBP , peroxisome proliferator-activated receptor (PPAR) 2, signal transducer and activator of transcription 5A (STAT5A), Wnt-10b, tumor necrosis factor , sterol regulatory element-binding protein 1c (SREBP1c), 11 beta-hydroxysteroid dehydrogenase, PPARG angiopoietin-related protein (PGAR), insulin-like growth factor 1, PPAR coactivator 1 , PPAR coactivator 1 , and PPAR ] in subcutaneous adipose tissue from 42 obese individuals with type 2 diabetes and 25 non-diabetic subjects matched for age and obesity. RESULTS: Insulin sensitivity was measured by a 3-hour 80 mU/m2 per minute hyperinsulinemic glucose clamp (100 mg/dL). As expected, subjects with type 2 diabetes had lower glucose disposal (4.9 1.9 vs. 7.5 2.8 mg/min per kilogram fat-free mass; p < 0.001) and larger fat cells (0.90 0.26 vs. 0.78 0.17 m; p = 0.04) as compared with obese control subjects. Three genes (SREBP1c, p < 0.01; STAT5A, p = 0.02; and PPAR 2, p = 0.02) had significantly lower expression in obese type 2 diabetics, whereas C/EBP only tended to be lower (p = 0.07). DISCUSSION: This cross-sectional study supports the hypothesis that impaired expression of adipogenic genes may result in impaired adipogenesis, potentially leading to larger fat cells in subcutaneous adipose tissue and insulin resistance.Severine G. Dubois, Leonie K. Heilbronn, Steven R. Smith, Jeanine B. Albu, David E. Kelley, Eric Ravussin and the Look AHEAD Adipose Research Grou