Publications by authors named "Andreas Hoeflich"

97 Publications

Control of Protein and Energy Metabolism in the Pituitary Gland in Response to Three-Week Running Training in Adult Male Mice.

Cells 2021 Mar 26;10(4). Epub 2021 Mar 26.

Institute for Genome Biology, Lab Animal Facility, Institute for Genetics and Biometry, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.

It is assumed that crosstalk of central and peripheral tissues plays a role in the adaptive response to physical activity and exercise. Here, we wanted to study the effects of training and genetic predisposition in a marathon mouse model on mRNA expression in the pituitary gland. Therefore, we used a mouse model developed by phenotype selection for superior running performance (DUhTP) and non-inbred control mice (DUC). Both mouse lines underwent treadmill training for three weeks or were kept in a sedentary condition. In all groups, total RNA was isolated from the pituitary gland and sequenced. Molecular pathway analysis was performed by ingenuity pathway analysis (IPA). Training induced differential expression of 637 genes (DEGs) in DUC but only 50 DEGs in DUhTP mice. Genetic selection for enhanced running performance strongly affected gene expression in the pituitary gland and identified 1732 DEGs in sedentary DUC versus DUhTP mice. Training appeared to have an even stronger effect on gene expression in both lines and comparatively revealed 3828 DEGs in the pituitary gland. From the list of DEGs in all experimental groups, candidate genes were extracted by comparison with published genomic regions with significant effects on training responses in mice. Bioinformatic modeling revealed induction and coordinated expression of the pathways for ribosome synthesis and oxidative phosphorylation in DUC mice. By contrast, DUhTP mice were resistant to the positive effects of three-week training on protein and energy metabolism in the pituitary gland.
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http://dx.doi.org/10.3390/cells10040736DOI Listing
March 2021

Development of a Sensitive Bioassay for the Analysis of IGF-Related Activation of AKT/mTOR Signaling in Biological Matrices.

Cells 2021 Feb 24;10(3). Epub 2021 Feb 24.

Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl Allee 2, 18196 Dummerstorf, Germany.

The bioactivity of the IGF system is not a function of isolated hormone concentrations in a given biological matrix. Instead, the biological activities of IGFs are regulated by IGFBPs, IGFBP proteases, and inhibitors of IGFBP proteases. Therefore, assays based on IGF-related bioactivity may describe functions of the complete IGF system in a given biological matrix. Of particular interest are the IGF system effects on the AKT/mTOR pathway, as a dominant system for controlling growth, metabolism, and aging. In order to improve the sensitivity of IGF-dependent bioactivity, we made use of the known short-term and enhancing effects of IGFBP2 on the intracellular PI3K pathway. As a specific readout of this pathway, and further as a marker of the mTOR pathway, we assessed the phosphorylation of AKT-Ser473. Preincubation using IGFBP2 enhanced IGF1-dependent AKT-Ser473 phosphorylation in our experimental system. The assay's specificity was demonstrated by inhibition of IGF1 receptors outside or inside the cell, using antiserum or small molecule inhibitors, which reduced AKT phosphorylation in response to exogenous IGF1 ( < 0.05). The maximal response of AKT phosphorylation was recorded 15 to 60 min after the addition of IGF1 to cell monolayers ( < 0.001). In our cellular system, insulin induced AKT phosphorylation only at supra-physiological concentrations (µM). Using this novel assay, we identified the differential biological activity of the IGF system in AKT-Ser473 phosphorylation in serum (mouse, naked mole rat, and human), in cerebrospinal fluid (human), and in colostrum or mature milk samples (dairy cow). We have developed a sensitive and robust bioassay to assess the IGF-related activation of the AKT/mTOR pathway. The assay works efficiently and does not require expensive cell culture systems. By using capillary immuno-electrophoresis, the readout of IGF-related bioactivity is substantially accelerated, requiring a minimum of hands-on time. Importantly, the assay system is useful for studying IGF-related activity in the AKT/mTOR pathway in a broad range of biological matrices.
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http://dx.doi.org/10.3390/cells10030482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995968PMC
February 2021

Genetic Diversity of in Germany and Global Relations of Its Genetic Background.

Front Genet 2020 22;11:610353. Epub 2021 Jan 22.

Leibniz-Institute for Farm Animal Biology, Dummerstorf, Germany.

This is the first study to explore the genetic diversity and population structure of domestic water buffalo () in Germany and their potential relations to herds in other parts of Europe or worldwide. To this end, animals from different herds in Germany, Bulgaria, Romania, and Hungary were genotyped and compared to genotypes from other populations with worldwide distribution and open to the public. The pilot study analyzed population structure, phylogenetic tree, and inbreeding events in our samples. In buffalos from Germany, a mixed genetic make-up with contributions from Bulgaria (Murrah breed), Romania, and Italy was found. All in all, a high degree of genetic diversity was identified in European buffalos, and a novel genotype was described in Hungarian buffalos by this study. We demonstrate that European buffalos stand out from other buffalo populations worldwide, supporting the idea that buffalos have not completely disappeared from the European continent during the late Pleistocene. The high genetic diversity in European buffalos seems to be an excellent prerequisite for the establishment of local breeds characterized by unique traits and features. This study may also be considered as an initial step on the way to genome characterization for the sustainable development of the buffalo economy in Germany and other parts of Europe in the future.
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http://dx.doi.org/10.3389/fgene.2020.610353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863760PMC
January 2021

Reduced Fragmentation of IGFBP-2 and IGFBP-3 as a Potential Mechanism for Decreased Ratio of IGF-II to IGFBPs in Cerebrospinal Fluid in Response to Repeated Intrathecal Administration of Triamcinolone Acetonide in Patients With Multiple Sclerosis.

Front Endocrinol (Lausanne) 2020 5;11:565557. Epub 2021 Jan 5.

Department of Neurology, Neuroimmunological Section, University Medicine Rostock, Rostock, Germany.

Multiple sclerosis (MS) is a chronic autoimmune disease of the brain and spinal cord causing a wide range of symptoms such as impaired walking capability, spasticity, fatigue, and pain. The insulin-like growth factor (IGF) system has regulatory functions for the induction of inflammatory pathways in experimental encephalomyelitis. We have therefore assessed expression and regulation of the IGF system on the level of IGFs and IGFBPs in serum and cerebrospinal fluid (CSF) in the course of four repeated triamcinolone acetonide (TCA) administrations in two female and four male MS patients. Sample series of 20 treatment cycles were analyzed. IGF-I and IGF-II were quantified by ELISAs, and IGFBPs were analyzed by quantitative Western ligand (qWLB) and Western immunoblotting (WIB) in order to differentiate intact and fragmented IGFBPs. The ratios of fragmented to intact IGFBP-2 and -3 were calculated in serum and CSF. Finally, the ratios of IGF-I and IGF-II to the total IGF-binding activity, quantified by qWLB, were determined as an indicator of IGF-related bioactivity. After the fourth TCA administration, the average level of IGF-I was increased in serum (p < 0.001). The increase of IGF-I concentrations in serum resulted in an increased ratio of IGF-I to IGFBPs in the circulation. By contrast in CSF, fragmentation of IGFBP-2 and IGFBP-3 and the ratio of IGF-II to intact IGFBPs were decreased at the fourth TCA administration (p < 0.01). Furthermore, reduced fragmentation of IGFBP-3 in CSF was accompanied by increased concentrations of intact IGFBP-3 (p < 0.001). We conclude that reduced fragmentation of IGFBPs and concomitant reduction of IGF-II to IGFBP ratios indicate regulation of bioactivity of IGF-II in CSF during repeated intrathecal TCA administration in MS patients.
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http://dx.doi.org/10.3389/fendo.2020.565557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813808PMC
January 2021

Xenogeneic and Stem Cell-Based Therapy for Cardiovascular Diseases: Genetic Engineering of Porcine Cells and Their Applications in Heart Regeneration.

Int J Mol Sci 2020 Dec 18;21(24). Epub 2020 Dec 18.

Institute of Genome Biology, Leibniz Institute for Farm Animal Biology, 18196 Dummerstorf, Germany.

Cardiovascular diseases represent a major health concern worldwide with few therapy options for ischemic injuries due to the limited regeneration potential of affected cardiomyocytes. Innovative cell replacement approaches could facilitate efficient regenerative therapy. However, despite extensive attempts to expand primary human cells in vitro, present technological limitations and the lack of human donors have so far prevented their broad clinical use. Cell xenotransplantation might provide an ethically acceptable unlimited source for cell replacement therapies and bridge the gap between waiting recipients and available donors. Pigs are considered the most suitable candidates as a source for xenogeneic cells and tissues due to their anatomical and physiological similarities with humans. The potential of porcine cells in the field of stem cell-based therapy and regenerative medicine is under intensive investigation. This review outlines the current progress and highlights the most promising approaches in xenogeneic cell therapy with a focus on the cardiovascular system.
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http://dx.doi.org/10.3390/ijms21249686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766969PMC
December 2020

Analysis of Activity-Dependent Energy Metabolism in Mice Reveals Regulation of Mitochondrial Fission and Fusion mRNA by Voluntary Physical Exercise in Subcutaneous Fat from Male Marathon Mice (DUhTP).

Cells 2020 12 16;9(12). Epub 2020 Dec 16.

Institute for Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.

Physical inactivity is considered as one of the main causes of obesity in modern civilizations, and it has been demonstrated that resistance training programs can be used to reduce fat mass. The effects of voluntary exercise on energy metabolism are less clear in adipose tissue. Therefore, the effects of three different voluntary exercise programs on the control of energy metabolism in subcutaneous fat were tested in two different mouse lines. In a cross-over study design, male mice were kept for three or six weeks in the presence or absence of running wheels. For the experiment, mice with increased running capacity (DUhTP) were used and compared to controls (DUC). Body and organ weight, feed intake, and voluntary running wheel activity were recorded. In subcutaneous fat, gene expression of browning markers and mitochondrial energy metabolism were analyzed. Exercise increased heart weight in control mice (p < 0.05) but significantly decreased subcutaneous, epididymal, perinephric, and brown fat mass in both genetic groups (p < 0.05). Gene expression analysis revealed higher expression of browning markers and individual complex subunits present in the electron transport chain in subcutaneous fat of DUhTP mice compared to controls (DUC; p < 0.01), independent of physical activity. While in control mice, voluntary exercise had no effect on markers of mitochondrial fission or fusion, in DUhTP mice, reduced mitochondrial DNA, transcription factor Nrf1, fission- (Dnm1), and fusion-relevant transcripts (Mfn1 and 2) were observed in response to voluntary physical activity (p < 0.05). Our findings indicate that the superior running abilities in DUhTP mice, on one hand, are connected to elevated expression of genetic markers for browning and oxidative phosphorylation in subcutaneous fat. In subcutaneous fat from DUhTP but not in unselected control mice, we further demonstrate reduced expression of genes for mitochondrial fission and fusion in response to voluntary physical activity.
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http://dx.doi.org/10.3390/cells9122697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765678PMC
December 2020

Surprisingly long survival of premature conclusions about naked mole-rat biology.

Biol Rev Camb Philos Soc 2021 Apr 30;96(2):376-393. Epub 2020 Oct 30.

Department of Reproduction Management, Leibniz-Institute for Zoo and Wildlife Research, Berlin, 10315, Germany.

Naked mole-rats express many unusual traits for such a small rodent. Their morphology, social behaviour, physiology, and ageing have been well studied over the past half-century. Many early findings and speculations about this subterranean species persist in the literature, although some have been repeatedly questioned or refuted. While the popularity of this species as a natural-history curiosity, and oversimplified story-telling in science journalism, might have fuelled the perpetuation of such misconceptions, an accurate understanding of their biology is especially important for this new biomedical model organism. We review 28 of these persistent myths about naked mole-rat sensory abilities, ecophysiology, social behaviour, development and ageing, and where possible we explain how these misunderstandings came about.
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http://dx.doi.org/10.1111/brv.12660DOI Listing
April 2021

Sex-Specific Control of Muscle Mass: Elevated IGFBP Proteolysis and Reductions of IGF-1 Levels Are Associated with Substantial Loss of Carcass Weight in Male DU6PxIGFBP-2 Transgenic Mice.

Cells 2020 09 26;9(10). Epub 2020 Sep 26.

Institute of Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany.

In farmed animals, carcass weight represents an important economic trait. Since we had demonstrated that IGFBP-2 represents a potent inhibitor of muscle accretion in inbred mice, we wanted to quantify the inhibitory effects of IGFBP-2 under conditions of elevated protein mass in growth selected non-inbred mice (DU6P). Therefore, we crossed male DU6P mice with female IGFBP-2 transgenic mice. Male IGFBP-2 transgenic offspring (DU6P/IGFBP-2) were characterized by more than 20% reductions of carcass mass compared to male non-transgenic littermates. The carcass mass in males was also significantly lower ( < 0.001) than in transgenic female DU6P/IGFBP-2 mice, which showed a reduction of less than 10% ( < 0.05) compared to non-transgenic female DU6P/IGFBP-2 mice. Although transgene expression was elevated in the muscle of both sexes ( < 0.001), serum levels were normal in female, but significantly reduced in male transgenic DU6P/IGFBP-2 mice ( < 0.001). In this group, also IGFBP-3 and IGFBP-4 were significantly reduced in the circulation ( < 0.01). Particularly in male transgenic mice, we were able to identify proteolytic activity against recombinant IGFBP-2 included in diluted serum. IGFBP-proteolysis in males correlated with massive reductions of IGF-1 in serum samples and the presence of elevated levels of IGFBP-2 fragments. From our data, we conclude that elevated tissue expression of IGFBP-2 is an essential effector of muscle accretion and may block more than 20% of carcass mass. However, in the circulation, intact IGFBP-2 contained no reliable biomarker content. Notably, for the estimation of breeding values in meat-producing animal species, monitoring of IGFBP-2 expression in muscle appears to be supported by the present study in a model system.
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http://dx.doi.org/10.3390/cells9102174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600981PMC
September 2020

Systemic Effects by Intrathecal Administration of Triamcinolone Acetonide in Patients With Multiple Sclerosis.

Front Endocrinol (Lausanne) 2020 27;11:574. Epub 2020 Aug 27.

Neuroimmunological Section, Department of Neurology, Rostock University Medical Center, Rostock, Germany.

In patients suffering from multiple sclerosis (MS), intrathecal injection of triamcinolone acetonide (TCA) has been shown to improve symptoms of spasticity. Although repeated intrathecal injection of TCA has been used in a number of studies in late-stage MS patients with spinal cord involvement, no clinical-chemical data are available on the distribution of TCA in cerebrospinal fluid (CSF) or serum. Moreover, the effects of intrathecal TCA administration on the concentrations of endogenous steroids remain poorly understood. Therefore, we have quantified TCA and selected endogenous steroids in CSF and serum of TCA-treated MS patients suffering from spasticity. Concentrations of steroids were quantified by LC-MS, ELISA, or ECLIA and compared with the blood-brain barrier status, diagnosed with the Reibergram. The concentration of TCA in CSF significantly increased during each treatment cycle up to >5 μg/ml both in male and female patients ( < 0.001). Repeated TCA administration also evoked serum concentrations of TCA up to >30 ng/ml ( < 0.001) and severely depressed serum levels of cortisol and corticosterone ( < 0.001). In addition, concentrations of circulating estrogen were significantly suppressed ( < 0.001). Due to the potent suppressive effects of TCA on steroid hormone concentrations both in the brain and in the periphery, we recommend careful surveillance of adrenal function following repeated intrathecal TCA injections in MS patients.
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http://dx.doi.org/10.3389/fendo.2020.00574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481359PMC
August 2020

Overlap of Peak Growth Activity and Peak IGF-1 to IGFBP Ratio: Delayed Increase of IGFBPs versus IGF-1 in Serum as a Mechanism to Speed up and down Postnatal Weight Gain in Mice.

Cells 2020 06 22;9(6). Epub 2020 Jun 22.

Institute of Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany.

Forced expression of insulin-like growth factor binding proteins (IGFBPs) in transgenic mice has clearly revealed inhibitory effects on somatic growth. However, by this approach, it cannot be solved if or how IGFBPs rule insulin-like growth factor (IGF)-dependent growth under normal conditions. In order to address this question, we have used growth-selected mouse models (obese and lean) and studied IGF-1 and IGFBPs in serum with respect to longitudinal growth activity in males and females compared with unselected controls. In mice of both genders, body weights were recorded and daily weight gains were calculated. Between 2 and 54 weeks of age, serum IGF-1 was determined by ELISA and intact IGFBP-2, -3 and -4 were quantified by Western ligand blotting. The molar ratio of IGF-1 to the sum of IGFBP-2 to -4 was calculated for all groups and plotted against the daily weight gain curve. Growth-selected mice are characterized by higher daily weight gains and extended periods of elevated growth activity if compared to matched unselected controls. Therefore, adult mice from the obese and lean groups can achieve more than twofold increased body weight in both genders ( < 0.001). Between 2 and 11 weeks of age, in obese and lean mice of both genders, serum IGF-1 concentrations are increased more prominently if compared to unselected controls ( < 0.001). Instead, substantial decreases of IGFBPs, particularly of IGFBP-2, are observed in males and females of all groups at the age of 2 to 4 weeks ( < 0.001). Due to the strong increase of IGF-1 but not of IGFBPs between two and four weeks of age, the ratio of IGF-1 to IGFBP-2 to -4 in serum significantly increased in all groups and genders ( < 0.05). Notably, the IGF-1 to IGFBP ratio was higher in male and female obese mice if compared to unselected controls ( < 0.05).
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http://dx.doi.org/10.3390/cells9061516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348928PMC
June 2020

Integrative Cluster Analysis of Whole Hearts Reveals Proliferative Cardiomyocytes in Adult Mice.

Cells 2020 05 6;9(5). Epub 2020 May 6.

Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany.

The recent development and broad application of sequencing techniques at the single-cell level is generating an unprecedented amount of data. The different techniques have their individual limits, but the datasets also offer unexpected possibilities when utilized collectively. Here, we applied snRNA-seq in whole adult murine hearts from an inbred (C57BL/6NRj) and an outbred (Fzt:DU) mouse strain to directly compare the data with the publicly available scRNA-seq data of the tabula muris project. Explicitly choosing a single-nucleus approach allowed us to pin down the typical heart tissue-specific technical bias, coming up with novel insights on the mammalian heart cell composition. For our integrated dataset, cardiomyocytes, fibroblasts, and endothelial cells constituted the three main cell populations accounting for about 75% of all cells. However, their numbers severely differed between the individual datasets, with cardiomyocyte proportions ranging from about 9% in the tabula muris data to around 23% for our BL6 data, representing the prime example for cell capture technique related bias when using a conventional single-cell approach for these large cells. Most strikingly in our comparison was the discovery of a minor population of cardiomyocytes characterized by proliferation markers that could not be identified by analyzing the datasets individually. It is now widely accepted that the heart has an, albeit very restricted, regenerative potential. However there is still an ongoing debate where new cardiomyocytes arise from. Our findings support the idea that the renewal of the cardiomyocyte pool is driven by cytokinesis of resident cardiomyocytes rather than differentiation of progenitor cells. We thus provide data that can contribute to an understanding of heart cell regeneration, which is a prerequisite for future applications to enhance the process of heart repair.
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http://dx.doi.org/10.3390/cells9051144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291011PMC
May 2020

Single nuclei sequencing of entire mammalian hearts: strain-dependent cell-type composition and velocity.

Cardiovasc Res 2020 06;116(7):1249-1251

Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell therapy (RTC), Rostock University Medical Center, 18057 Rostock, Germany.

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http://dx.doi.org/10.1093/cvr/cvaa054DOI Listing
June 2020

Single-Nucleus Sequencing of an Entire Mammalian Heart: Cell Type Composition and Velocity.

Cells 2020 01 28;9(2). Epub 2020 Jan 28.

Reference and Translation Center for Cardiac Stem Cell therapy (RTC), Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany.

Analyses on the cellular level are indispensable to expand our understanding of complex tissues like the mammalian heart. Single-nucleus sequencing (snRNA-seq) allows for the exploration of cellular composition and cell features without major hurdles of single-cell sequencing. We used snRNA-seq to investigate for the first time an entire adult mammalian heart. Single-nucleus quantification and clustering led to an accurate representation of cell types, revealing 24 distinct clusters with endothelial cells (28.8%), fibroblasts (25.3%), and cardiomyocytes (22.8%) constituting the major cell populations. An additional RNA velocity analysis allowed us to study transcription kinetics and was utilized to visualize the transitions between mature and nascent cellular states of the cell types. We identified subgroups of cardiomyocytes with distinct marker profiles. For example, the expression of Hand2os1 distinguished immature cardiomyocytes from differentiated cardiomyocyte populations. Moreover, we found a cell population that comprises endothelial markers as well as markers clearly related to cardiomyocyte function. Our velocity data support the idea that this population is in a trans-differentiation process from an endothelial cell-like phenotype towards a cardiomyocyte-like phenotype. In summary, we present the first report of sequencing an entire adult mammalian heart, providing realistic cell-type distributions combined with RNA velocity kinetics hinting at interrelations.
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http://dx.doi.org/10.3390/cells9020318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072447PMC
January 2020

Editorial: Current Perspectives on Insulin-Like Growth Factor Binding Protein (IGFBP) Research.

Front Endocrinol (Lausanne) 2018 20;9:667. Epub 2018 Nov 20.

College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.

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http://dx.doi.org/10.3389/fendo.2018.00667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255849PMC
November 2018

Effect of adipocyte-derived IGF-I on adipose tissue mass and glucose metabolism in the Berlin Fat Mouse.

Growth Factors 2018 04;36(1-2):78-88

a Department of Crop and Animal Sciences, Humboldt-Universität zu Berlin , Berlin , Germany.

Besides liver, IGF-I is expressed in adipose tissue. However, the effects of this local IGF-I on adipose tissue and metabolism are unclear. We generated adipocyte-specific knock-out mice on the background of the Berlin Fat Mouse Inbred (BFMI) line to evaluate the contribution of adipocyte-IGF-I on glucose metabolism and adipose tissue development. BFMI mice are obese, non-diabetic with elevated plasma insulin and IGF-I concentration. The knock-out in adipocytes led to a total white adipose tissue expression of 50-60% due to unaltered Igf-1 expression in stromavascular cells. The lack of IGF-I from adipocytes did not alter plasma IGF-I concentration. BFMI-Igf-I-KO mice had reduced adipose tissue mass in most depots. During oral glucose tolerance tests, BFMI-Igf-I-KO mice showed an impaired glucose clearance (p = .03). Interestingly, insulin action was enhanced during insulin tolerance tests (p = .05). In conclusion, adipocyte-specific IGF-I ablation in obese BFMI mice results in reduced adipose tissue mass and thereby alters glucose metabolism.
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http://dx.doi.org/10.1080/08977194.2018.1497621DOI Listing
April 2018

Current IGFBP-Related Biomarker Research in Cardiovascular Disease-We Need More Structural and Functional Information in Clinical Studies.

Front Endocrinol (Lausanne) 2018 16;9:388. Epub 2018 Jul 16.

Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.

Cardiovascular diseases are the leading cause of death around the world and the insulin-like growth factor (IGF)-system has multiple functions for the pathological conditions of atherosclerosis. IGF binding proteins (IGFBPs) are widely investigated as biomarkers for pathological disorders, including those of the heart. At the tissue level, IGFBP-1 to -6 decrease bioactivity of IGF-I and -II due to their high affinity IGF-binding sites. By contrast, in the circulation, the IGFBPs increase biological half-life of the IGFs and may therefore be regarded as positive regulators of IGF-effects. The IGFBPs may also exert IGF-independent functions inside or outside the cell. Importantly, the circulating IGFBP-concentrations are regulated by trophic, metabolic, and reproductive hormones. In a multitude of studies of healthy subjects and patients with coronary heart diseases, various significant associations between circulating IGFBP-levels and defined parameters have been reported. However, the complex hormonal and conditional control of IGFBPs may explain the lack of clear associations between IGFBPs and parameters of cardiac failure in broader studies including larger populations. Furthermore, the IGFBPs are subject to posttranslational modifications and proteolytic degradation by proteases, upon which the IGFs are released. In this review, we emphasize that, with the exception of IGFBP-4 and in sharp contrast to the preclinical studies, virtually all clinical studies do not have structural or functional information on their biomarker. The use of analytical systems with no discriminatory potential toward intact vs. fragmented IGFBPs represents a major issue in IGFBP-related biomarker research and an important focus point for the future. Overall, measurements of selected IGFBPs or more complex IGFBP-signatures of the family of IGFBPs have potential to identify pathophysiological alterations in the heart or patients with high cardiovascular risk, particularly if defined cohorts are to be assessed. However, a more thorough understanding of the dynamic IGF-IGFBP system as well as its proteases and protease inhibitors in both normal physiology and in cardiovascular diseases is necessary.
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http://dx.doi.org/10.3389/fendo.2018.00388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054974PMC
July 2018

Increased Concentrations of Insulin-Like Growth Factor Binding Protein (IGFBP)-2, IGFBP-3, and IGFBP-4 Are Associated With Fetal Mortality in Pregnant Cows.

Front Endocrinol (Lausanne) 2018 12;9:310. Epub 2018 Jun 12.

Clinic for Cattle, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.

Insulin-like growth factors (IGFs) play a critical role in fetal growth, and components of the IGF system have been associated with fetal growth restriction in women. In human pregnancy, the proteolytic cleavage of insulin-like growth factor binding proteins (IGFBPs), particularly IGFBP-4, releases free IGF for respective action at the tissue level. The aim of the present study was to determine IGFBP-2, IGFBP-3, and IGFBP-4 concentrations by Western ligand blotting during pregnancy until day 100 in cows and to compare these concentrations with those of non-pregnant cows and cows undergoing embryonic/fetal mortality. Therefore, two study trials (I and II) and an study were conducted. In study I, 43 cows were not pregnant, 34 cows were pregnant, and 4 cows were undergoing fm. In study II, 500 cows were examined, and 7 cases of pregnancy loss between days 24-27 and 34-37 after artificial insemination (AI, late embryonic mortality; em) and 8 cases of pregnancy loss between days 34-37 and 54-57 after AI (late embryonic mortality and early fetal mortality; em/fm) were defined from the analyses of 30 pregnant and 20 non-pregnant cows randomly selected for insulin-like growth factor 1 and IGFBP analyses. serum from pregnant ( = 3) and non-pregnant ( = 3) cows spiked after incubation with recombinant human (rh) IGFBP-4 for 24 h, and IGFBP-4 levels were analyzed before and after incubation to detect proteolytic degradation. The IGFBP-2, -3, and -4 concentrations did not decline during early pregnancy in cows, while IGFBP-4 concentrations were comparable between pregnant and non-pregnant cows, irrespective of low proteolytic activity, which was also demonstrated in cows. Interestingly, cows with em or fm showed distinct IGFBP patterns. The IGFBP-2 and -3 concentrations were higher ( < 0.05) in cows with fm compared to pregnant. The IGFBP-4 levels were significantly higher in cows developing fm. Thus, distinct differences in the circulating IGFBP concentrations could be associated with late embryonic and early fetal losses in cattle.
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http://dx.doi.org/10.3389/fendo.2018.00310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006986PMC
June 2018

Characterization of igf1 and igf2 genes during maraena whitefish (Coregonus maraena) ontogeny and the effect of temperature on embryogenesis and igf expression.

Growth Horm IGF Res 2018 06 25;40:32-43. Epub 2018 Apr 25.

Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Fish Genetics Unit, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany. Electronic address:

The insulin-like growth factors IGF-1 and IGF-2 play important roles in the growth, development, and metabolism of teleost fish. We isolated cDNA sequences of igf1, and igf2 genes from maraena whitefish. We quantified the mRNA and protein expressions of IGFs in different tissues of marketable juvenile maraena whitefish. Moreover, we analyzed the gene expression profiles during maraena whitefish development from unfertilized egg to fingerling and examined the effect of incubation temperature on igf1, and igf2 gene expression during embryonic and early larval development. Transcripts encoding IGF-1 or IGF-2 were detected in all tested tissues, with the greatest abundance in the liver. We measured higher igf2 than igf1 copy numbers in all tissues and at all developmental stages examined, even at advanced juvenile stages. Using the Western blot technique, we demonstrated that several isoforms of IGF-1 are expressed in the liver and gills but not in muscle tissue, indicating tissue-specific protein expression of IGF-1. We observed an accelerated embryonic development with increasing temperature, resulting in shortened hatching periods. Out of the three tested temperatures, we observed the highest hatching rate, larval hatching size, and larval growth at 6 °C. At 9 °C, hatching rate, larval hatching size and larval growth were reduced compared to the values we observed at 4 °C and 6 °C, since incubation temperature might have exceeded the optimum. To our knowledge, our data show for the first time that both igf1 and igf2 expression were upregulated due to elevated incubation temperature within embryonic development of fish. Further, we found significantly higher igf expression for the best-developing larvae (6 °C group) at specific life stages of maraena whitefish.
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http://dx.doi.org/10.1016/j.ghir.2018.04.003DOI Listing
June 2018

Potential Functions of IGFBP-2 for Ovarian Folliculogenesis and Steroidogenesis.

Front Endocrinol (Lausanne) 2018 13;9:119. Epub 2018 Apr 13.

Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.

Ovarian follicles, as transient structural and functional complexes with the oocyte and the associated cells, determine the female reproductive cycle and thus fertility. Ovarian function is subject to the strict control of hormones and growth factors and thus regulated by auto-, para-, and endocrine mechanisms but influenced also by endogenous factors. During the waves of follicular growth and development, one follicle (monoovulatory) or a limited number of them (polyovulatory) are selected under hypothalamic-gonadal control for maturation until ovulation, resulting in the fertile oocyte. Subordinate follicles inevitably enter different stages of atresia. A number of studies have observed species-specific alterations of IGFBP-2 levels during the phases of growth and development or selection and atresia of follicles. IGFBP-2 is thus probably involved in the process of follicle growth, differentiation, and degeneration. This may occur on the levels of IGF-dependent and -independent growth control but also due to the control of steroidogenesis, e.g., induction of aromatase expression. In mice, IGFBP-2 delayed reproductive development most probably by IGF-independent mechanisms. Because reproductive development is closely linked to the control of life- or health-span and energy metabolism, we feel that the time is right now to resume research on the effects of IGFBP-2 in the ovarian follicular compartment.
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http://dx.doi.org/10.3389/fendo.2018.00119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908976PMC
April 2018

Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver.

Mol Metab 2018 05 15;11:113-128. Epub 2018 Mar 15.

Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Feodor-Lynen-Str. 25, 81377 Munich, Germany; Center for Innovative Medical Models (CiMM), Department of Veterinary Sciences, LMU Munich, Hackerstr. 27, 85764 Oberschleißheim, Germany; Meiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama, Kawasaki, 214-8571, Japan; German Center for Diabetes Research (DZD), Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, Feodor-Lynen-Str. 25, 81377 Munich, Germany. Electronic address:

Objective: Laron syndrome (LS) is a rare, autosomal recessive disorder in humans caused by loss-of-function mutations of the growth hormone receptor (GHR) gene. To establish a large animal model for LS, pigs with GHR knockout (KO) mutations were generated and characterized.

Methods: CRISPR/Cas9 technology was applied to mutate exon 3 of the GHR gene in porcine zygotes. Two heterozygous founder sows with a 1-bp or 7-bp insertion in GHR exon 3 were obtained, and their heterozygous F1 offspring were intercrossed to produce GHR-KO, heterozygous GHR mutant, and wild-type pigs. Since the latter two groups were not significantly different in any parameter investigated, they were pooled as the GHR expressing control group. The characterization program included body and organ growth, body composition, endocrine and clinical-chemical parameters, as well as signaling studies in liver tissue.

Results: GHR-KO pigs lacked GHR and had markedly reduced serum insulin-like growth factor 1 (IGF1) levels and reduced IGF-binding protein 3 (IGFBP3) activity but increased IGFBP2 levels. Serum GH concentrations were significantly elevated compared with control pigs. GHR-KO pigs had a normal birth weight. Growth retardation became significant at the age of five weeks. At the age of six months, the body weight of GHR-KO pigs was reduced by 60% compared with controls. Most organ weights of GHR-KO pigs were reduced proportionally to body weight. However, the weights of liver, kidneys, and heart were disproportionately reduced, while the relative brain weight was almost doubled. GHR-KO pigs had a markedly increased percentage of total body fat relative to body weight and displayed transient juvenile hypoglycemia along with decreased serum triglyceride and cholesterol levels. Analysis of insulin receptor related signaling in the liver of adult fasted pigs revealed increased phosphorylation of IRS1 and PI3K. In agreement with the loss of GHR, phosphorylation of STAT5 was significantly reduced. In contrast, phosphorylation of JAK2 was significantly increased, possibly due to the increased serum leptin levels and increased hepatic leptin receptor expression and activation in GHR-KO pigs. In addition, increased mTOR phosphorylation was observed in GHR-KO liver samples, and phosphorylation studies of downstream substrates suggested the activation of mainly mTOR complex 2.

Conclusion: GHR-KO pigs resemble the pathophysiology of LS and are an interesting model for mechanistic studies and treatment trials.
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http://dx.doi.org/10.1016/j.molmet.2018.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001387PMC
May 2018

Cytokines in milk and the role of TGF-beta.

Best Pract Res Clin Endocrinol Metab 2018 01 2;32(1):47-56. Epub 2018 Feb 2.

Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany. Electronic address:

Cytokines are required for normal growth and development of the mammary gland and TGF-β prominently represents an established effector of apoptosis, e.g., during involution of the mammary gland. By the control of intracellular signaling pathways, including JAK/STAT, MAPK, PI-3K, and NF-κB, cytokines efficiently regulate cell proliferation and inflammation in the breast. Therefore, cytokines are discussed also in a context of malignant mammary growth. As a group of tissue hormones produced by somatic cells or by cells from the immune system, cytokines are defined by their immunomodulatory potential. Over the past 40 years, multiple cytokines were identified in colostrum and milk. Importantly, cytokines derived from mammary secretions after birth are required for maturation of the immune system in the developing gastrointestinal tract from the suckling. Moreover, recent studies have further assessed the particular interactions between probiotic bacterial strains and cytokines. In light of the increasing prevalence of inflammatory diseases of the gastrointestinal system, the effects of probiotic microorganisms during milk fermentation may have immunotherapeutic potential in the future.
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http://dx.doi.org/10.1016/j.beem.2018.01.006DOI Listing
January 2018

Hormones in milk-new directions.

Best Pract Res Clin Endocrinol Metab 2018 01 3;32(1):1-3. Epub 2018 Feb 3.

Hospital for Children and Adolescents, Center of Paediatric Research, University of Leipzig, Leipzig, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.beem.2018.01.008DOI Listing
January 2018

Effects of Transport Duration and Environmental Conditions in Winter or Summer on the Concentrations of Insulin-Like Growth Factors and Insulin-Like Growth Factor-Binding Proteins in the Plasma of Market-Weight Pigs.

Front Endocrinol (Lausanne) 2018 13;9:36. Epub 2018 Feb 13.

Institute of Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.

In previous work using market-weight pigs, we had demonstrated that insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) are regulated during shipment characterized by changing conditions of stress due to loading or unloading, transportation, lairage, and slaughter. In addition, we found in a previous study that IGFBP-2 concentrations were lower in pigs transported for longer periods of time. Therefore, we performed a more detailed study on the effects of transport duration and season on the plasma concentrations of IGFs and IGFBPs in adult pigs. For the study, exsanguination blood was collected from 240 market-weight barrows that were transported for 6, 12, or 18 h in January or July. IGF-I and -II were detected using commercial ELISAs whereas IGFBPs were quantified by quantitative Western ligand blotting. In addition, established markers of stress and metabolism were studied in the animals. The results show that plasma concentrations of IGFBP-3 were significantly reduced after 18 h of transport compared to shorter transport durations (6 and 12 h;  < 0.05). The concentrations of IGF-I in plasma were higher ( < 0.001) in pigs transported 12 h compared to shorter or longer durations. Season influenced plasma concentrations of IGFBP-3 and IGF-II ( < 0.05 and  < 0.01, respectively). Neither transport duration nor differential environmental conditions of winter or summer had an effect on glucocorticoids, albumin, triglycerides, or glucose concentrations ( > 0.05). However, low-density lipoprotein concentrations decreased after 18 h compared to 6 h of transport ( < 0.05), whereas high-density lipoprotein concentrations were higher ( < 0.05) in pigs transported for 12 or 18 h compared to those transported for only 6 h. Our findings indicate differential regulation of IGF-compounds in response to longer transport duration or seasonal changes and support current evidence of IGFs and IGFBPs as innovative animal-based indicators of psycho-social or metabolic stress in pigs.
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http://dx.doi.org/10.3389/fendo.2018.00036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816936PMC
February 2018

Kynurenic Acid: The Janus-Faced Role of an Immunomodulatory Tryptophan Metabolite and Its Link to Pathological Conditions.

Front Immunol 2017 10;8:1957. Epub 2018 Jan 10.

Institute for Genome Biology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.

Tryptophan metabolites are known to participate in the regulation of many cells of the immune system and are involved in various immune-mediated diseases and disorders. Kynurenic acid (KYNA) is a product of one branch of the kynurenine pathway of tryptophan metabolism. The influence of KYNA on important neurophysiological and neuropathological processes has been comprehensively documented. In recent years, the link of KYNA to the immune system, inflammation, and cancer has become more apparent. Given this connection, the anti-inflammatory and immunosuppressive functions of KYNA are of particular interest. These characteristics might allow KYNA to act as a "double-edged sword." The metabolite contributes to both the resolution of inflammation and the establishment of an immunosuppressive environment, which, for instance, allows for tumor immune escape. Our review provides a comprehensive update of the significant biological functions of KYNA and focuses on its immunomodulatory properties by signaling G-protein-coupled receptor 35 (GPR35)- and aryl hydrocarbon receptor-mediated pathways. Furthermore, we discuss the role of KYNA-GPR35 interaction and microbiota associated KYNA metabolism for gut homeostasis.
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http://dx.doi.org/10.3389/fimmu.2017.01957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770815PMC
January 2018

Functional analysis of the IGF-system in milk.

Best Pract Res Clin Endocrinol Metab 2017 08 20;31(4):409-418. Epub 2017 Oct 20.

Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.

The development of milk during evolution is considered a more recent step to provide the neonate with adequate amounts of energy, nutrients, and specific hormonal signals thereby, granting a fast and efficient rate of postnatal growth and development. Since the insulin- or the insulin-like growth factor (IGF) systems were evolved much earlier, it can be assumed that the functionality of the IGF-system has been integrated into the novel matrix milk containing casein and whey proteins from the beginnings. In fact, IGFs and IGF-binding proteins (IGFBPs) are abundantly present in milk, which is particularly true for fore-milk or colostrum and the potential effects of milk-borne IGF-compounds on the consuming organisms have in fact been addressed by several studies. Those studies examined, if orally administered IGFs can be absorbed by the consumer's gastro-intestinal tract and thus contribute e.g. to the somatic growth of infants. A second line of studies assessed local effects of milk-borne IGFs on growth and development of the gastro-intestinal tract itself. Finally, distinct functions of isolated IGF-compounds for growth and involution of the mammary gland have also been provided in the past. While the consumption of milk seems not to represent a major source of endogenous IGFs, accumulating evidence indicates secondary effects of milk on the endogenous IGF-system, which may be mediated by micronutrients such as branched amino acids and metabolic programming. By contrast, direct effects on growth and development of oesophageal and intestinal cells have been observed if IGFs were administered orally.
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http://dx.doi.org/10.1016/j.beem.2017.10.002DOI Listing
August 2017

Hormones in milk.

Best Pract Res Clin Endocrinol Metab 2017 08;31(4):363-365

Hospital for Children and Adolescents, Center of Paediatric Research, University of Leipzig, Leipzig, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.beem.2017.11.003DOI Listing
August 2017

Partial phenotype conversion and differential trait response to conditions of husbandry in mice.

J Comp Physiol B 2018 05 6;188(3):527-539. Epub 2017 Dec 6.

Institute for Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany.

Functional genome analysis usually is performed on the level of genotype-phenotype interaction. However, phenotypes also depend on the relations between genomes and environment. In our experimental system, we observed differential response to environmental factors defined by different conditions of husbandry in a semi-barrier unit or in a SPF (specific pathogen free) barrier unit, which resulted in partial reversal of phenotypes previously observed under semi-barrier conditions. To provide an update of basic phenotypes in unselected and randomly mated controls (DUC) and long-term selected DUhTP (Dummerstorf high treadmill performance) mice in the SPF facility, we compared growth parameters, reproductive performance, the accretion of muscle and fat mass, physical activity, and running performance as well as food intake in all experimental groups. For selected parameters, the comparative analysis spans more than 30 generations. In DUC mice, under SPF conditions a more than threefold (P < 0.0001) higher subcutaneous fat mass, higher muscle mass by about 25% (P < 0.0001), but lower epididymal fat mass in DUhTP mice by about 20% (P < 0.0001) were observed. In SPF husbandry, body weight increased to a stronger extent in adult DUC mice (≈ 20%; P < 0.0001) than in DUhTP mice (≈ 8%; P = 0.001). The concentrations of IGF-1 and IGFBPs in the serum as well as the liver weights were similar in all experimental groups, indicating growth effects independent of the somatotropic axis. Under SPF conditions the litter size at birth increased in DUC mice (P < 0.001) but not in DUhTP mice. The differential effect of husbandry on body weights at day 21 and concentrations of triglycerides in the serum of our model were due to the different diets used in the semi-barrier and in the SPF facility. Our results demonstrate differential trait response to environmental factors resulting in partial phenotype conversion in our experimental system. The existence of conditional phenotypes as a result of genotype-environment interactions points to the importance of environmental factors in functional genome analysis.
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http://dx.doi.org/10.1007/s00360-017-1138-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920005PMC
May 2018

Interference of stress with the somatotropic axis in pigs - lights on new biomarkers.

Sci Rep 2017 09 21;7(1):12055. Epub 2017 Sep 21.

Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.

The acceptance of animal products is increasingly associated with standardized animal welfare, which relates to appropriate animal husbandry from birth to slaughter. In particular, shipment to the slaughterhouse is considered as a critical process exposing the animals to a number of, in part severe, stressors. New biomarkers may be useful for the assessment of animal welfare. The IGF-system has been assessed in a commercial pig transport in conjunction with established markers of stress response. Furthermore, the effect of repeated restraint as an experimental model for repeated acute stress was investigated. During shipment from farm to slaughterhouse, plasma concentrations of IGFBP-3 and IGFBP-2 were significantly reduced (p < 0.01). After shipment, the plasma concentrations of IGFBP-5, glucocorticoids and IL-2 increased but decreased after lairage (p < 0.05) whereas IGF-1 decreased after shipment (p < 0.01). Repeated acute stress increased concentrations of IGFBP-3 and IGF-1 in exsanguination blood (p < 0.05). Differential IGF- signatures can indicate altered endocrine or metabolic control and thus contain complex animal-related information. The somatotropic axis may be of particular interest when established biomarkers such as cortisol, glucose, or lactate cannot be used for the assessment of animal stress or welfare.
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http://dx.doi.org/10.1038/s41598-017-11521-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608691PMC
September 2017

Insulin-Like Growth Factor Bioactivity, Stanniocalcin-2, Pregnancy-Associated Plasma Protein-A, and IGF-Binding Protein-4 in Pleural Fluid and Serum From Patients With Pulmonary Disease.

J Clin Endocrinol Metab 2017 09;102(9):3526-3534

Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, DK-8000 Aarhus C, Denmark.

Context: Members of the insulin-like growth factor (IGF) system are primarily produced in the liver and secreted into the circulation, but they are also produced, recruited, and activated locally in tissues.

Objective: To compare activity and concentrations of IGF system components in pleural fluid and blood.

Design: Pathological pleural fluid, secondary to lung cancer or nonmalignant disease, and matching blood samples were collected from 24 patients ages 66.7 to 81.9 years.

Methods: IGF-related proteins and cytokine levels were measured by immunoassays or immunoblotting. Bioactive IGF was measured by an IGF-1 receptor phosphorylation assay.

Results: Total IGF-1 concentration did not differ between the compartments, but concentrations of free IGF-1 and bioactive IGF were more than threefold higher in pleural fluid than in corresponding serum samples (P = 0.0004), regardless of etiology. Median pregnancy-associated plasma protein-A (PAPP-A) and interleukin (IL)-6 levels were increased 47-fold and 143-fold, respectively, in pleural fluid compared with plasma (P < 0.0001). PAPP-A and IL-6 concentrations correlated positively (r = 0.46; P = 0.02). In pleural fluid, levels of PAPP-A-generated IGF binding protein-4 fragments correlated inversely with that of stanniocalcin-2 (r ≤ -0.42; P ≤ 0.05), a PAPP-A inhibitor; such correlations were absent in plasma.

Conclusion: Pathological pleural fluid is characterized by increased in vitro IGF bioactivity and elevated concentrations of PAPP-A, an IGF-activating proteinase. Thus, the tissue activity of the IGF system may differ substantially from that of the circulating IGF system. The correlation between IL-6 and PAPP-A indicates that inflammation plays a role in promoting local tissue IGF activity.
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http://dx.doi.org/10.1210/jc.2017-00033DOI Listing
September 2017

Analysis of the IGF-system in milk from farm animals - Occurrence, regulation, and biomarker potential.

Growth Horm IGF Res 2017 08 12;35:1-7. Epub 2017 May 12.

Institute of Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany. Electronic address:

IGFs and IGF-binding proteins (IGFBPs) are abundantly present in milk and in dairy products. Compared to the IGFs, the IGFBP have received less attention in milk, although truncated IGFBPs and IGFBP-glycosylation have been described in milk. Thereby, complex control of local IGF-effects can be assumed on the levels of IGFBPs, proteases, and protease inhibitors. The present review collects the current knowledge both on presence and regulation of IGFs and IGFBPs in milk particularly from dairy animal species. As a rule higher levels of IGF-I, IGF-II, and IGFBPs are measured around parturition if compared to later time-points of lactation. In all farm animal species included in this review, it is found that the relative abundancies of IGFBPs in milk and serum are similar, with IGFBP-3 and -2 characterized by higher concentrations if compared to IGFBP-4 or -5. The concentrations of IGFs and IGFBPs in milk or dairy products can be altered by hormones, dairy processing, or fermentation. Because milk can be used for non-invasive biomarker research, quality management, and health monitoring, we discuss novel directions of IGF-analysis and potential on-site biomarker research in milk.
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http://dx.doi.org/10.1016/j.ghir.2017.05.004DOI Listing
August 2017