Implication of the PTN/RPTPß/ζ Signaling Pathway in Acute Ethanol Neuroinflammation in Both Sexes: A Comparative Study with LPS.

Binge drinking during adolescence increases the risk of alcohol use disorder, possibly by involving alterations of neuroimmune responses. Pleiotrophin (PTN) is a cytokine that inhibits Receptor Protein Tyrosine Phosphatase (RPTP) ß/ζ. PTN and MY10, an RPTPß/ζ pharmacological inhibitor, modulate ethanol behavioral and microglial responses in adult mice. Now, to study the contribution of endogenous PTN and the implication of its receptor RPTPß/ζ in the neuroinflammatory response in the prefrontal cortex (PFC) after acute ethanol exposure in adolescence, we used MY10 (60 mg/kg) treatment and mice with transgenic PTN overexpression in the brain. Cytokine levels by X-MAP technology and gene expression of neuroinflammatory markers were determined 18 h after ethanol administration (6 g/kg) and compared with determinations performed 18 h after LPS administration (5 g/kg). Our data indicate that Ccl2, Il6, and Tnfa play important roles as mediators of PTN modulatory actions on the effects of ethanol in the adolescent PFC. The data suggest PTN and RPTPß/ζ as targets to differentially modulate neuroinflammation in different contexts. In this regard, we identified for the first time important sex differences that affect the ability of the PTN/RPTPß/ζ signaling pathway to modulate ethanol and LPS actions in the adolescent mouse brain.

Pleiotrophin deficiency protects against high-fat diet-induced neuroinflammation: Implications for brain mitochondrial dysfunction and aberrant protein aggregation.

Metabolic Syndrome (MetS) is a risk factor for the development of neurodegenerative diseases. Neuroinflammation associated with MetS may contribute significantly to neurodegeneration. Pleiotrophin (PTN) is a neurotrophic factor that modulates neuroinflammation and is a key player in regulating energy metabolism and thermogenesis, suggesting that PTN could be important in the connection between MetS and neuroinflammation. We have now used a high-fat diet (HFD)-induced obesity model in Ptn-/- mice. HFD and Ptn deletion caused alterations in circulating hormones including GIP, leptin and resistin. HFD produced in Ptn+/+ mice a neuroinflammatory state as observed in cerebral quantifications of proinflammatory markers, including Il1ß, Tnfα and Ccl2. The upregulation of neuroinflammatory markers was prevented in Ptn-/- mice. Changes induced by HFD in genes related to mitochondrial biogenesis and dynamics were less pronounced in the brain of Ptn-/- mice and were accompanied by significant increases in the protein expression of mitochondrial oxidative phosphorylation (OXPHOS) complexes I and IV. HFD-induced changes in genes related to the elimination of protein aggregates were also less pronounced in the brain of Ptn-/- mice. This study provides substantial evidence that Ptn deletion protects against HFD-induced neuroinflammation, mitochondrial dysfunction, and aberrant protein aggregation, prominent features in neurodegenerative diseases.

Influence of Diet and Lifestyle on the Development of Gestational Diabetes Mellitus and on Perinatal Results.

GDM is a multifactorial disease, so there is controversy regarding the mechanisms involved in its pathogenesis. We speculate whether lifestyle and eating habits influenced the appearance and pathogenesis of GDM. To explore this issue, the aim of the present study was to analyze maternal diet and lifestyle characteristics in early pregnancy and their influence on the development of GDM. The study included 103 pregnant women who completed a questionnaire on nutritional knowledge, lifestyle and eating habits. Perinatal and biochemical outcomes as well as pregestational lifestyle and eating habits were compared between normoglycemic women and those who developed GDM. The results obtained showed that women who developed GDM had erroneous knowledge regarding nutrition. Consumption of white bread (p = 0.018), added sugars (p = 0.037), legumes (p = 0.025), fish (p = 0.014), butter (p = 0.010) and the performance of less physical activity (p = 0.024) correlated with glucose intolerance in pregnant women. In conclusion, we found a relationship between dietary and lifestyle habits at the beginning of pregnancy and the later diagnosis of GDM.

Pleiotrophin Deficiency Induces Browning of Periovarian Adipose Tissue and Protects against High-Fat Diet-Induced Hepatic Steatosis.

(1) Background: Pleiotrophin preserves insulin sensitivity, regulates adipose tissue lipid turnover and plasticity, energy metabolism and thermogenesis. The aim of this study was to determine the role of pleiotrophin in hepatic lipid metabolism and in the metabolic crosstalk between the liver and brown and white adipose tissue (AT) in a high-fat diet-induced (HFD) obesity mice model. (2) Methods: We analyzed circulating variables, lipid metabolism (hepatic lipid content and mRNA expression), brown AT thermogenesis (UCP-1 expression) and periovarian AT browning (brown adipocyte markers mRNA and immunodetection) in Ptn-/- mice either fed with standard-chow diet or with HFD and in their corresponding Ptn+/+ counterparts. (3) Results: HFD-Ptn-/- mice are protected against the development of HFD-induced insulin resistance, had lower liver lipid content and lower expression of the key enzymes involved in triacylglycerides and fatty acid synthesis in liver. HFD-Ptn-/- mice showed higher UCP-1 expression in brown AT. Moreover, Ptn deletion increased the expression of specific markers of brown/beige adipocytes and was associated with the immunodetection of UCP-1 enriched multilocular adipocytes in periovarian AT. (4) Conclusions: Ptn deletion protects against the development of HFD-induced insulin resistance and liver steatosis, by increasing UCP-1 expression in brown AT and promoting periovarian AT browning.

Role of Receptor Protein Tyrosine Phosphatases (RPTPs) in Insulin Signaling and Secretion.

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.

Metabolic alterations associated with maternal undernutrition during the first half of gestation lead to a diabetogenic state in the rat.

BACKGROUND: Although recent studies have investigated the effect of maternal nutrition on metabolic programming of the offspring, the question whether a nutritional insult during early gestation favours an altered metabolic state of the mother that persists during the remainder period of pregnancy, when foetal growth is maximal, remains to be answered. METHODS: To address this issue, we analysed the effect of 40% food restriction during the first 12 days of gestation on glucose tolerance, as well as on liver and adipose tissue metabolism, in Sprague-Dawley pregnant rats. RESULTS: We found that undernutrition at early gestation blocks pregnancy-associated accumulation of fat, leading to a net breakdown of lipids that may account for an increased delivery of fatty acids and glycerol to the liver. Together with altered expression of hepatic enzymes, this creates a catabolic state, characterized by decreased lipogenesis and increased ß-oxidation, which contributes to the ketonemia of underfed mothers. Furthermore, we observed that undernutrition during early pregnancy impairs insulin sensitivity at this stage and, importantly, exacerbates insulin resistance at late gestation, contributing to a diabetogenic state. CONCLUSION: Undernutrition during the first half of pregnancy not only alters liver and adipose tissue metabolism, but also exacerbates the maternal insulin resistance at late gestation, which may increase their risk of gestational diabetes. GENERAL SIGNIFICANCE: Together, these findings highlight the persistent impact of maternal nutrition during early gestation on the metabolism of the mother during late pregnancy.