Inflammation is a common factor of pathologies such as obesity, type 2 diabetes or neurodegenerative diseases. Chronic inflammation is considered part of the pathogenic mechanisms of different disorders associated with aging. Interestingly, peripheral inflammation and the associated metabolic alterations not only facilitate insulin resistance and diabetes but also neurodegenerative disorders. Therefore, the identification of novel pathways, common to the development of these diseases, which modulate the immune response and signaling is key. It will provide highly relevant information to advance our knowledge of the multifactorial process of aging, and to establish new biomarkers and/or therapeutic targets to counteract the underlying chronic inflammatory processes. One novel pathway that regulates peripheral and central immune responses is triggered by the cytokines pleiotrophin (PTN) and midkine (MK), which bind its receptor, Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, and inactivate its phosphatase activity. In this review, we compile a growing body of knowledge suggesting that PTN and MK modulate the immune response and/or inflammation in different pathologies characterized by peripheral inflammation associated with insulin resistance, such as aging, and in central disorders characterized by overt neuroinflammation, such as neurodegenerative diseases and endotoxemia. Evidence strongly suggests that regulation of the PTN and MK signaling pathways may provide new therapeutic opportunities particularly in those neurological disorders characterized by increased PTN and/or MK cerebral levels and neuroinflammation. Importantly, we discuss existing therapeutics, and others being developed, that modulate these signaling pathways, and their potential use in pathologies characterized by overt neuroinflammation.

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, T 3 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.

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.

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 β-cells in young vs. adult animals, and its effects on DNA synthesis, β-cell gene expression and glucose-stimulated insulin secretion (GSIS). The Ptn gene was expressed in isolated fractions of young mouse β-cells, especially within immature β-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-β/ζ, were also expressed in the proliferative INS1E β-cell line. Fluorescence immunohistochemistry showed that PTN peptide was present in islets of Langerhans in adult mice, associated predominantly with β-cells. The percentage of β-cells staining for PTN did not alter during mouse pregnancy, but intense staining was seen during β-cell regeneration in young mice following depletion of β-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 β-cells in young and adult life and could potentially contribute to adaptive increases in β-cell mass during early life or pregnancy.

Changes in lifestyle in developed countries have triggered the prevalence of obesity and type 2 diabetes mellitus (T2DM) in the latest years. Consequently, these metabolic diseases associated to insulin resistance, and the morbidity associated with them, accounts for enormous costs for the health systems. The best way to face this problem is to identify potential therapeutic targets and/or early biomarkers to help in the treatment and in the early detection. In the insulin receptor signaling cascade, the activities of protein tyrosine kinases and phosphatases are coordinated, thus, protein tyrosine kinases amplify the insulin signaling response, whereas phosphatases are required for the regulation of the rate and duration of that response. The focus of this review is to summarize the impact of transmembrane receptor protein tyrosine phosphatase (RPTPs) in the insulin signaling cascade and secretion, and their implication in metabolic diseases such as obesity and T2DM.

Pleiotrophin (PTN) is a cytokine that is upregulated in different neuroinflammatory disorders. Using mice with transgenic PTN overexpression in the brain (Ptn-Tg), we have found a positive correlation between iNos and Tnfα mRNA and Ptn mRNA levels in the prefrontal cortex (PFC) of LPS-treated mice. PTN is an inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, which is mainly expressed in the central nervous system. We aimed to test if RPTPβ/ζ is involved in the modulation of neuroinflammatory responses using specific inhibitors of RPTPβ/ζ (MY10 and MY33-3). Treatment with MY10 potentiated LPS-induced microglial responses in the mouse PFC. Surprisingly, MY10 caused a decrease in LPS-induced NF-κB p65 expression, suggesting that RPTPβ/ζ may be involved in a novel mechanism of potentiation of microglial activation independent of the NF-κB p65 pathway. MY33-3 and MY10 limited LPS-induced nitrites production and iNos increases in BV2 microglial cells. SH-SY5Y neuronal cells were treated with the conditioned media from MY10/LPS-treated BV2 cells. Conditioned media from non-stimulated and from LPS-stimulated BV2 cells increased the viability of SH-SY5Y cultures. RPTPβ/ζ inhibition in microglial cells disrupted this neurotrophic effect of microglia, suggesting that RPTPβ/ζ plays a role in the neurotrophic phenotype of microglia and in microglia-neuron communication.

Introduction. The study of placental lipid metabolism in uncomplicated pregnancies has not been 2 developed in the literature to date. Its importance lies in expanding the knowledge of placental function to 3 enable comparison with pathological pregnancies in future research. The aim of the present study was to 4 compare the lipid metabolic activity and storage of the maternal and fetal sides of the placenta in healthy 5 pregnancies. Moreover, we compare singleton vs. twin pregnancies to determine if placental metabolic 6 needs differ. 7Material and Methods. We analyzed placental explants from uncomplicated pregnancies, 20 from 8 singleton and 8 from bichorial-biamniotic twin pregnancies (n=28). Six cotyledon fragments were 9 collected from each placenta at different distances from the umbilical cord, three close to the chorionic 10 plate (hereinafter we will refer to them as "fetal side") and another three close to the anchoring villi into 11 the decidua basalis (referred to as "maternal side"). The samples were analyzed for quantitative assay 12 placental fatty acid oxidation (FAO) and esterification (FAE) activities and triglyceride levels. The 13 location of lipid storage in the chorionic villi was assessed by Oil red-O staining. 14Results. Placental fatty acid oxidation did not show differences when comparing the maternal and fetal 15 sides of the placenta or between single and twin pregnancies. When comparing placental sides, FAE was 16 increased two-fold in the maternal side compared to the fetal side of the placenta (P = 0.013). The 17 tendency for lipogenesis in the placenta was exemplified by the FAE/FAO ratio, which was a 37.1% 18 higher on the maternal side (P = 0.019). Despite this, triglyceride levels were five times higher in the fetal 19 side than in the maternal one (P = 0.024). When analyzing singleton vs. twins, FAE was superior in the 20 fetal side in multiple pregnancies (×2.6, P = 0.007) and the FAE/FAO ratio was significantly higher in 21 twins than in singleton pregnancies, on both sides of the placenta. Despite this finding, triglyceride levels 22 were similar in twin and singleton pregnancies. Comparing the placentas of twins in the same pregnancy, 23 there were no differences in lipid metabolism (FAO or FAE) or placental triglyceride levels between the 24 two co-twins. Using Oil red-O staining, lipid storage in chorionic villi was found to be located on the 25 syncytiotrophoblast cells and not in the connecting axis. 26Conclusion. The maternal side of the placenta is more active in the esterification of fatty acids, while the 27 storage of neutral lipids concentrates on the fetal side. Moreover, multiple gestations have increased 28 esterification without changes in the concentration of placental triglycerides, probably due to a higher 29 transfer to the fetal circulation in response to the greater energy demand from twin fetuses. 30

Antiangiogenic factors are currently used for the prediction of preeclampsia. The present study aimed to evaluate the relationship between antiangiogenic factors and lipid and carbohydrate metabolism in maternal plasma and placenta. We analyzed 56 pregnant women, 30 healthy and 26 with preeclampsia (including early and late onset). We compared antiangiogenic factors soluble Fms-like Tyrosine Kinase-1 (sfLt-1), placental growth factor (PlGF), and soluble endoglin (sEng)), lipid and carbohydrate metabolism in maternal plasma, and lipid metabolism in the placenta from assays of fatty acid oxidation, fatty acid esterification, and triglyceride levels in all groups. Antiangiogenic factors sFlt-1, sFlt-1/PlGF ratio, and sEng showed a positive correlation with triglyceride, free fatty acid, and C-peptide maternal serum levels. However, there was no relationship between angiogenic factors and placental lipid metabolism parameters. Free fatty acids were predictive of elevated sFlt-1 and sEng, while C-peptide was predictive of an elevated sFlt1/PlGF ratio. The findings in this study generate a model to predict elevated antiangiogenic factor values and the relationship between them with different products of lipid and carbohydrate metabolism in maternal serum and placenta in preeclampsia.