Neuropoietin activates STAT3 independent of LIFR activation in adipocytes

Neuropoietin (NP) is a member of the gp130 cytokine family that is closely related to cardiotrophin-1(CT-1) and shares functional and structural features with other family members, including ciliary neurotrophic factor (CNTF) and cardiotrophin-like cytokine (CLC). Studies have shown that NPcan play a role in the development of the nervous system, as well as affect adipogenesis and fat cell function. However, the signaling mechanisms utilized by NP in adipocytes have not been examined. In our present studies, we demonstrate that NP-induced activation of STAT3 tyrosine phosphorylation is independent of leukemia inhibitory factor receptor (LIFR) phosphorylation and degradation. Although it is widely accepted thatNPsignals via the LIFR, our studies reveal that NP results in phosphorylation of gp130, but not LIFR. These observations suggest that the profound effects that NP has on adipocytes are not mediated via LIFR signaling. © 2010 Elsevier Inc

Transcriptional factors that promote formation of white adipose tissue

Adipocytes are highly specialized cells that play a major role in energy homeostasis in vertebrate organisms. Excess adipocyte size or number is a hallmark of obesity, which is currently a global epidemic. Obesity is a major risk factor for the development of type II diabetes (T2DM), cardiovascular disease, and hypertension. Obesity and its related disorders result in dysregulation of the mechanisms that control the expression of metabolic and endocrine related genes in adipocytes. Therefore, understanding adipocyte differentiation is relevant not only for gaining insight into the pathogenesis of metabolic diseases, but also for identifying proteins or pathways which might be appropriate targets for pharmacological interventions. Significant advances towards an understanding of the regulatory processes involved in adipocyte differentiation have largely been made by the identification of transcription factors that contribute to the adipogenic process. It is important to note that the developmental origin of white and brown fat is distinct and different precursor cells are involved in the generation of these different types of adipose tissue (reviewed in Lefterova and Lazar, 2009; Seale et al., 2009). Several transcription factors, notably PPARγ, several members of the C/EBP and KLF families, STAT5, and SREBP-1c, have been shown to have significant roles in promoting adipogenesis. More comprehensive reviews on negative and positive regulators of adipogenesis have been published in the past year (reviewed in Christodoulides et al., 2009; Lefterova and Lazar, 2009). Though many proteins are known to negatively regulate adipogenesis, including Wnts, KLFs, the E2F family of transcription factors, CHOP, Delta-interacting protein A, ETO/MTG8, and members of the GATA and forkhead transcription factor families, this review will focus on transcription factors that positively impact the development of white adipose tissue. © 2009 Elsevier Ireland Ltd. All rights reserved

The gp130 receptor cytokine family: Regulators of adipocyte development and function

Gp130 cytokines are involved in the regulation of numerous biological processes, including hematopoiesis, immune response, inflammation, cardiovascular action, and neuronal survival. These cytokines share glycoprotein 130 as a common signal transducer in their receptor complex and typically activate STAT3. Most gp130 cytokines have paracrine or endocrine actions, and their levels can be measured in circulation in rodents and humans. In recent years, various laboratories have conducted studies to demonstrate that gp130 cytokines can modulate adipocyte development and function. Therefore, these studies suggest that some gp130 cytokines may be viable anti obesity therapeutics. In this review, we will summarize the reported effects of gp130 cytokines on adipocyte differentiation and adipocyte function. In addition, the modulation of gp130 cytokines in conditions of obesity, insulin resistance, and Type 2 diabetes will be presented. © 2011 Bentham Science Publishers Ltd

Gp130 cytokines exert differential patterns of crosstalk in adipocytes both in vitro and in vivo

Glycoprotein 130 (Gp130) cytokines are involved in the regulation of numerous biological processes, including hematopoiesis, immune response, inflammation, cardiovascular action, and neuronal survival. These cytokines share gp130 as a common signal transducer in their receptor complex and typically activate signal transducer and activator of transcription (STAT) 3. Studies have shown that several gp130 cytokines have differential effects on both adipogenesis and insulin-stimulated glucose uptake. Yet, the complex interactions of these cytokines in adipose tissue have not been studied. Gp130 cytokines are differentially regulated in multiple tissues due to the presence of additional receptor components that are required for signaling, including the leukemia inhibitory factor receptor (LIFR). Previous studies from our laboratory highlighted the ability of specific gp130 cytokines to crosstalk in adipocytes that correlated with LIFR degradation. Crosstalk is defined as the ability of one cytokine to modulate the signaling of another cytokine. Our novel studies reveal that white adipose tissue is highly responsive to gp130 cytokines, and we provide the first evidence that these cytokines can exert inhibitory crosstalk in adipose tissue in vivo. Moreover, several gp130 cytokines that use the LIFR, including cardiotrophin-1 (CT-1), LIF, and human oncostatin M (hOSM), can alter the subsequent signaling of other family members in adipocytes both in vitro and in vivo. Our data also show that murine OSM and neuropoietin do not crosstalk in the same manner as other gp130 cytokines, which likely results from their inability to activate the LIFR. Overall, we have observed distinctive patterns of crosstalk signaling by gp130 cytokines in adipocytes in vitro and in vivo and demonstrate the crosstalk is not dependent on new protein synthesis or extracellular-signal-regulated kinase activation. © 2011 The Obesity Society

The STAT5A-mediated induction of pyruvate dehydrogenase kinase 4 expression by prolactin or growth hormone in adipocytes

The purpose of this study was to determine whether pyruvate dehydrogenase kinase (PDK)4 was expressed in adipocytes and whether PDK4 expression was hormonally regulated in fat cells. Both Northern blot and Western blot analyses were conducted on samples isolated from 3T3-L1 adipocytes after various treatments with prolactin (PRL), growth hormone (GH), and/or insulin. Transfection of PDK4 promoter reporter constructs was performed. In addition, glucose uptake measurements were conducted. Our studies demonstrate that PRL and porcine GH can induce the expression of PDK4 in 3T3-L1 adipocytes. Our studies also show that insulin pretreatment can attenuate the ability of these hormones to induce PDK4 mRNA expression. In addition, we identified a hormone-responsive region in the murine PDK4 promoter and characterized a STAT5 binding site in this region that mediates the PRL (sheep) and GH (porcine) induction in PDK4 expression in 3T3-L1 adipocytes. PDK4 is a STAT5A target gene. PRL is a potent inducer of PDK4 protein levels, results in an inhibition of insulin-stimulated glucose transport in fat cells, and likely contributes to PRL-induced insulin resistance. © 2007 by the American Diabetes Association

AND/R: Advanced neutron diffractometer/reflectometer for investigation of thin films and multilayers for the life sciences

An elastic neutron scattering instrument, the advanced neutron diffractometer/reflectometer (AND/R), has recently been commissioned at the National Institute of Standards and Technology Center for Neutron Research. The AND/R is the centerpiece of the Cold Neutrons for Biology and Technology partnership, which is dedicated to the structural characterization of thin films and multilayers of biological interest. The instrument is capable of measuring both specular and nonspecular reflectivity, as well as crystalline or semicrystalline diffraction at wave-vector transfers up to approximately 2.20 Å(-1). A detailed description of this flexible instrument and its performance characteristics in various operating modes are given.D. J. M. is supported through a NSF NIRT grant Contract No. 0304062

Racial variations in appetite-related hormones, appetite, and laboratory-based energy intake from the E-MECHANIC randomized clinical trial

African Americans (AAs) have a higher obesity risk than Whites; however, it is unclear if appetite-related hormones and food intake are implicated. We examined differences in appetite-related hormones, appetite, and food intake between AAs (n = 53) and Whites (n = 111) with overweight or obesity. Participants were randomized into a control group or into supervised, controlled exercise groups at 8 kcal/kg of body weight/week (KKW) or 20 KKW. Participants consumed lunch and dinner at baseline and follow-up, with appetite and hormones measured before and after meals (except leptin). At baseline, AAs had lower peptide YY (PYY; p < 0.01) and a blunted elevation in PYY after lunch (p = 0.01), as well as lower ghrelin (p = 0.02) and higher leptin (p < 0.01) compared to Whites. Despite desire to eat being lower and satisfaction being higher in AAs relative to Whites (p ≤ 0.03), no racial differences in food intake were observed. Compared to Whites, leptin increased in the 8 KKW group in AAs (p = 0.01), yet no other race-by-group interactions were evident. Differences in appetite-related hormones between AAs and Whites exist; however, their influence on racial disparities in appetite, food intake, and obesity within this trial was limited

Oncostatin m is produced in adipose tissue and is regulated in conditions of obesity and type 2 diabetes

CONTEXT: Adipose tissue is a highly active endocrine organ that secretes many factors that affect other tissues and whole-body metabolism. Adipocytes are responsive to several glycoprotein 130 (gp130) cytokines, some of which have been targeted as potential antiobesity therapeutics. OBJECTIVE: Oncostatin M (OSM) is a gp130 family member known to inhibit adipocyte differentiation in vitro, but its effects on other adipocyte properties are not characterized. The expression of OSM in white adipose tissue (WAT) has not been evaluated in the context of obesity. Thus, our objective was to examine the expression of adipose tissue OSM in obese animals and humans. DESIGN: OSM expression was examined in adipose tissues from mice with diet-induced and genetic obesity and in obese humans as well as in fractionated adipose tissue from mice. Murine adipocytes were used to examine OSM receptor expression and the effects of OSM on adipocytes, including the secretion of factors such as plasminogen activator inhibitor 1 and IL-6, which are implicated in metabolic diseases. RESULTS: OSM expression is increased in rodent and human obesity/type 2 diabetes mellitus. In humans, OSM levels correlate with body weight and insulin and are inversely correlated with glucose disposal rate as measured by hyperinsulinemic-euglycemic clamp. OSM is not produced from the adipocytes in WAT but derives from cells in the stromovascular fraction, including F4/80(+) macrophages. The specific receptor of OSM, OSM receptor-β, is expressed in adipocytes and adipose tissue and increased in both rodent models of obesity examined. OSM acts on adipocytes to induce the expression and secretion of plasminogen activator inhibitor 1 and IL-6. CONCLUSIONS: These data indicate that WAT macrophages are a source of OSM and that OSM levels are significantly induced in murine and human obesity/type 2 diabetes mellitus. These studies suggest that OSM produced from immune cells in WAT acts in a paracrine manner on adipocytes to promote a proinflammatory phenotype in adipose tissue

IGF2 stimulates fetal growth in a sex- and organ-dependent manner

BackgroundInsulin-like growth factor 2 (IGF2) is a key determinant of fetal growth, and the altered expression of IGF2 is implicated in fetal growth disorders and maternal metabolic derangements including gestational diabetes. Here we studied how increased levels of IGF2 in late pregnancy affect fetal growth.MethodsWe employed a rat model of repeated intrafetal IGF2 administration in late pregnancy, i.e., during GD19-GD21, and measured the consequences on fetal organ weight and expression of insulin/IGF-axis components.ResultsIGF2 treatment tended to increase fetal weight, but only weight increase of the fetal stomach reached significance (+33±9%; P<0.01). Sex-dependent data analysis revealed a sexual dimorphism of IGF2 action. In male fetuses, IGF2 administration significantly increased fetal weight (+13±3%; P<0.05) and weight of fetal stomach (+42±10%; P<0.01), intestine (+26±5%; P<0.05), liver (+13±4%; P<0.05), and pancreas (+25±8%; P<0.05). Weights of heart, lungs, and kidneys were unchanged. In female fetuses, IGF2 increased only stomach weight (+26±9%; P<0.05). Furthermore, gene expression of insulin/IGF axis in the heart, lungs, liver, and stomach was more sensitive toward IGF2 treatment in male than in female fetuses.ConclusionData suggest that elevated circulating IGF2 in late pregnancy predominantly stimulates organ growth of the digestive system, and male fetuses are more susceptible toward the IGF2 effects than female fetuses.Fil: White, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Jawerbaum, Alicia Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Mazzucco, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Gauster, Martin. Medizinische Universität Graz; AustriaFil: Desoye, Gernot. Medizinische Universität Graz; AustriaFil: Hiden, Ursula. Medizinische Universität Graz; Austri