Pleiotrophin and metabolic disorders: insights into its role in metabolism.

Pleiotrophin (PTN) is a cytokine which has been for long studied at the level of the central nervous system, however few studies focus on its role in the peripheral organs. The main aim of this review is to summarize the state of the art of what is known up to date about pleiotrophin and its implications in the main metabolic organs. In summary, pleiotrophin promotes the proliferation of preadipocytes, pancreatic ß cells, as well as cells during the mammary gland development. Moreover, this cytokine is important for the structural integrity of the liver and the neuromuscular junction in the skeletal muscle. From a metabolic point of view, pleiotrophin plays a key role in the maintenance of glucose and lipid as well as whole-body insulin homeostasis and favors oxidative metabolism in the skeletal muscle. All in all, this review proposes pleiotrophin as a druggable target to prevent from the development of insulin-resistance-related pathologies.

Receptor protein tyrosine phosphatase ß/ζ regulates loss of neurogenesis in the mouse hippocampus following adolescent acute ethanol exposure.

Adolescence is a critical period for brain maturation in which this organ is more vulnerable to the damaging effects of ethanol. Administration of ethanol in mice induces a rapid cerebral upregulation of pleiotrophin (PTN), a cytokine that regulates the neuroinflammatory processes induced by different insults and the behavioral effects of ethanol. PTN binds Receptor Protein Tyrosine Phosphatase (RPTP) ß/ζ and inhibits its phosphatase activity, suggesting that RPTPß/ζ may be involved in the regulation of ethanol effects. To test this hypothesis, we have treated adolescent mice with the RPTPß/ζ inhibitor MY10 (60 mg/kg) before an acute ethanol (6 g/kg) administration. Treatment with MY10 completely prevented the ethanol-induced neurogenic loss in the hippocampus of both male and female mice. In flow cytometry studies, ethanol tended to increase the number of NeuN+/activated Caspase-3+ cells particularly in female mice, but no significant effects were found. Ethanol increased Iba1+ cell area and the total marked area in the hippocampus of female mice, suggesting sex differences in ethanol-induced microgliosis. In addition, ethanol reduced the circulating levels of IL-6 and IL-10 in both sexes, although this reduction was only found significant in males and not affected by MY10 treatment. Interestingly, MY10 alone increased the total marked area and the number of Iba1+ cells only in the female hippocampus, but tended to reduce the circulating levels of TNF-α only in male mice. In summary, the data identify a novel modulatory role of RPTPß/ζ on ethanol-induced loss of hippocampal neurogenesis, which seems unrelated to glial and inflammatory responses. The data also suggest sex differences in RPTPß/ζ function that may be relevant to immune responses and ethanol-induced microglial responses.

Pleiotrophin Expression and Actions in Pancreatic ß-Cells.

Pleiotrophin (PTN) is a heparin-binding cytokine that is widely expressed during early development and increases in maternal circulation during pregnancy.Aged PTN-deficient mice exhibit insulin resistance, suggesting a role in metabolic control. The objectives of this study were to determine if PTN is expressed in mouse pancreatic ß-cells in young vs. adult animals, and its effects on DNA synthesis, ß-cell gene expression and glucose-stimulated insulin secretion (GSIS). The Ptn gene was expressed in isolated fractions of young mouse ß-cells, especially within immature ß-cells with low glucose transporter 2 expression. Expression was retained in the adult pancreas but did not significantly change during pregnancy. PTN and its receptor, phosphotyrosine phosphatase-ß/ζ, were also expressed in the proliferative INS1E ß-cell line. Fluorescence immunohistochemistry showed that PTN peptide was present in islets of Langerhans in adult mice, associated predominantly with ß-cells. The percentage of ß-cells staining for PTN did not alter during mouse pregnancy, but intense staining was seen during ß-cell regeneration in young mice following depletion of ß-cells with streptozotocin. Incubation of INS1E cells with PTN resulted in an increased DNA synthesis as measured by Ki67 localization and increased expression of Pdx1 and insulin. However, both DNA synthesis and GSIS were not altered by PTN in isolated adult mouse islets. The findings show that Ptn is expressed in mouse ß-cells in young and adult life and could potentially contribute to adaptive increases in ß-cell mass during early life or pregnancy.

Deletion of pleiotrophin impairs glucose tolerance and liver metabolism in pregnant mice: Moonlighting role of glycerol kinase.

Pleiotrophin is a pleiotropic cytokine that has been demonstrated to have a critical role in regulating energy metabolism, lipid turnover and plasticity of adipose tissue. Here, we hypothesize that this cytokine can be involved in regulatory processes of glucose and lipid homeostasis in the liver during pregnancy. Using 18-days pregnant Ptn-deficient mice, we evaluated the biochemical profile (circulating variables), tissue mRNA expression (qPCR) and protein levels of key enzymes and transcription factors involved in main metabolic pathways. Ptn deletion was associated with a reduction in body weight gain, hyperglycemia and glucose intolerance. Moreover, we observed an impairment in glucose synthesis and degradation during late pregnancy in Ptn-/- mice. Hepatic lipid content was significantly lower (73.6%) in Ptn-/- mice and was associated with a clear reduction in fatty acid, triacylglycerides and cholesterol synthesis. Ptn deletion was accompanying with a diabetogenic state in the mother and a decreased expression of key proteins involved in glucose and lipid uptake and metabolism. Moreover, Ptn-/- pregnant mice have a decreased expression of transcription factors, such as PPAR-α, regulating lipid uptake and glucose and lipid utilization. Furthermore, the augmented expression and nuclear translocation of glycerol kinase, and the decrease in NUR77 protein levels in the knock-out animals can further explain the alterations observed in hepatic glucose metabolism. Our results point out for the first time that pleiotrophin is an important player in maintaining hepatic metabolic homeostasis during late gestation, and further highlighted the moonlighting role of glycerol kinase in the regulation of maternal glucose homeostasis during pregnancy.

Pleiotrophin deletion alters glucose homeostasis, energy metabolism and brown fat thermogenic function in mice.

AIMS/HYPOTHESIS: Pleiotrophin, a developmentally regulated and highly conserved cytokine, exerts different functions including regulation of cell growth and survival. Here, we hypothesise that this cytokine can play a regulatory role in glucose and lipid homeostasis. METHODS: To test this hypothesis, we performed a longitudinal study characterising the metabolic profile (circulating variables and tissue mRNA expression) of gene-targeted Ptn-deficient female mice and their corresponding wild-type counterparts at different ages from young adulthood (3 months) to older age (15 months). Metabolic cages were used to investigate the respiratory exchange ratio and energy expenditure, at both 24°C and 30°C. Undifferentiated immortalised mouse brown adipocytes (mBAs) were treated with 0.1 µg/ml pleiotrophin until day 6 of differentiation, and markers of mBA differentiation were analysed by quantitative real-time PCR (qPCR). RESULTS: Ptn deletion was associated with a reduction in total body fat (20.2% in Ptn+/+ vs 13.9% in Ptn-/- mice) and an enhanced lipolytic response to isoprenaline in isolated adipocytes from 15-month-old mice (189% in Ptn+/+ vs 273% in Ptn-/- mice). We found that Ptn-/- mice exhibited a significantly lower QUICKI value and an altered lipid profile; plasma triacylglycerols and NEFA did not increase with age, as happens in Ptn+/+ mice. Furthermore, the contribution of cold-induced thermogenesis to energy expenditure was greater in Ptn-/- than Ptn+/+ mice (42.6% and 33.6%, respectively). Body temperature and the activity and expression of deiodinase, T3 and mitochondrial uncoupling protein-1 in the brown adipose tissue of Ptn-/- mice were higher than in wild-type controls. Finally, supplementing brown pre-adipocytes with pleiotrophin decreased the expression of the brown adipocyte markers Cidea (20% reduction), Prdm16 (21% reduction), and Pgc1-α (also known as Ppargc1a, 11% reduction). CONCLUSIONS/INTERPRETATION: Our results reveal for the first time that pleiotrophin is a key player in preserving insulin sensitivity, driving the dynamics of adipose tissue lipid turnover and plasticity, and regulating energy metabolism and thermogenesis. These findings open therapeutic avenues for the treatment of metabolic disorders by targeting pleiotrophin in the crosstalk between white and brown adipose tissue.

Antioxidants and Oxidative Stress: Focus in Obese Pregnancies.

The prevalence of obesity in women of childbearing age around the globe has dramatically increased in the last decades. Obesity is characterized by a low-state chronic inflammation, metabolism impairment and oxidative stress, among other pathological changes. Getting pregnant in this situation involves that gestation will occur in an unhealthy environment, that can potentially jeopardize both maternal and fetal health. In this review, we analyze the role of maternal obesity-induced oxidative stress as a risk factor to develop adverse outcomes during gestation, including reduced fertility, spontaneous abortion, teratogenesis, preeclampsia, and intrauterine growth restriction. Evidences of macromolecule oxidation increase in reactive oxygen species generation and antioxidant defense alterations are commonly described in maternal and fetal tissues. Thus, antioxidant supplementation become an interesting prophylactic and therapeutic tool, that yields positive results in cellular, and animal models. However, the results from most meta-analysis studying the effect of these therapies in complicated gestations in humans are not really encouraging. It is still to be analyzed whether these therapies could work if applied to cohorts of patients at a high risk, such as those with low concentration of antioxidants or obese pregnant women.