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.

Pleiotrophin regulates microglia-mediated neuroinflammation.

BACKGROUND: Pleiotrophin (PTN) is a cytokine found highly upregulated in the brain in different disorders characterized by overt neuroinflammation such as neurodegenerative diseases, drug addiction, traumatic injury, and ischemia. In the present work, we have explored whether PTN modulates neuroinflammation and if Toll-like receptor 4 (TLR4), crucial in the initiation of an immune response, is involved. METHODS: In immunohistochemistry assays, we studied lipopolysaccharide (LPS, 7.5 mg/kg i.p.)-induced changes in glial fibrillary acidic protein (GFAP, astrocyte marker) and ionized calcium-binding adaptor molecule 1 (Iba1, microglia marker) expression in the prefrontal cortex (PFC) and striatum of mice with transgenic PTN overexpression in the brain (PTN-Tg) and in wild-type (WT) mice. Cytokine protein levels were assessed in the PFC by X-MAP technology. The influence of TLR4 signaling in LPS effects in both genotypes was assessed by pretreatment with the TLR4 antagonist (TAK-242, 3.0 mg/kg i.p.). Murine BV2 microglial cells were treated with PTN (0.5 µg/ml) and LPS (1.0 µg/ml) and assessed for the release of nitric oxide (NO). RESULTS: We found that LPS-induced microglial activation is significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. The levels of TNF-α, IL-6, and MCP-1 in response to LPS were significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. Pretreatment with TAK-242 efficiently blocked increases in cytokine contents in a similar manner in both genotypes. Concomitant incubation of BV2 cells with LPS and PTN significantly potentiated the production of NO compared to cells only treated with LPS. CONCLUSIONS: Our findings identify for the first time that PTN is a novel and potent regulator of neuroinflammation. Pleiotrophin potentiates LPS-stimulated microglia activation. Our results suggest that regulation of the PTN signaling pathways may constitute new therapeutic opportunities particularly in those neurological disorders characterized by increased PTN cerebral levels and neuroinflammation.

Circulating kisspeptin levels exhibit sexual dimorphism in adults, are increased in obese prepubertal girls and do not suffer modifications in girls with idiopathic central precocious puberty.

The system KISS1-KISS1R is one of the main regulators of the hypothalamic-pituitary-gonadal axis and constitutes a link between metabolism and reproduction through its interaction with leptin. The aim of this study was to clarify the possible utility of kisspeptin as a pubertal marker and/or the possible influence of nutritional status in kisspeptin levels. To this end, we have studied kisspeptin plasma levels throughout sexual development and in prepubertal obese girls and girls affected by idiopathic central precocious puberty (CPP). Plasma kisspeptin concentrations were analyzed by RIA. An increase in kisspeptin levels was observed in adult females compared to healthy prepubertal and pubertal girls (p<0.001) and to adult males (p<0.001). Additionally, kisspeptin was increased in prepubertal obese girls compared to healthy prepubertal girls (p<0.01) and girls with idiopathic CPP (p<0.05). As revealed by the regression analysis, in prepubertal healthy and obese girls and girls with idiopathic CCP, the parameters that influenced kisspeptin levels were BMI (R(2)=0.10, p<0.05) and leptin levels (R(2)=0.14, p<0.01). In conclusion, kisspeptin levels do not seem to be a good pubertal marker. The results obtained in prepubertal and idiopathic CCP girls point to a relationship between leptin, BMI and kisspeptin at least in this group, and suggest a possible role for adipose tissue in the modulation kisspeptin synthesis.

Plasma kisspeptin levels are elevated in cord blood and present sexual dimorphism in the adult population: relation with leptin, gonadotropins and anthropometrical data.

Kisspeptin, the product of the hypothalamic KISS1 gene, is a main regulator of the hypothalamic-pituitary-gonadal axis and could be a link between metabolism and reproduction through its interaction with leptin. Kisspeptin could be involved in gonadotropin regulation and responsive to leptin levels from the first stages of life, exhibiting, as does leptin, sexual dimorphism. To test our hypothesis, we have analyzed plasma kisspeptin levels and their possible relationship with gonadotropins and leptin in a cohort composed of newborns (n = 86) and adults (n = 55). Plasma kisspeptin, gonadotropin and leptin levels were measured by RIA and multiplexed bead immunoassays, respectively. We have built a multivariate linear regression model (analyzing kisspeptin and LH separately as dependent variables) by stepwise analysis, incorporating the variables that had shown significant correlation in the univariate analysis. Cord blood samples exhibited high kisspeptin levels 127.01(113-141.02 pmol/l), but these were not sexually dimorphic. The adult population exhibited sexual dimorphism (3.72(2.95-4.49) vs. 1.77(1.23-2.31)pmol/l women vs. men, p<0.05). Leptin levels showed sexual dimorphism in cord blood samples and also in the adult population. Furthermore, there was a significant interaction between LH and kisspeptin levels and kisspeptin was negatively correlated with age. The high kisspeptin levels observed in cord blood, with no sexual dimorphism, suggest a placental source. The sexual dimorphism exhibited in adulthood supports the notion that there are different sources and/or differential kisspeptin regulation between men and women.

High-sensitivity C-reactive protein is a good marker of cardiovascular risk in obese children and adolescents.

OBJECTIVE: We intend to assess the utility of the high-sensitivity C-reactive protein (hs-CRP) as a marker of cardiovascular risk in obese children and adolescents. METHODS: The study included children and adolescents between 6 and 18 years of age with a body mass index (BMI) higher than 2 SDS. All the patients had their blood pressure taken and hs-CRP, hepatic function, lipid profile and uric acid were determined after 12 h of fasting. Likewise, an oral glucose tolerance test was performed, determining basal glucose and insulin levels, and after stimulus. We considered the presence of metabolic syndrome when the obese children and teenagers showed at least two of the following conditions: decreased high density lipoprotein (HDL)-cholesterol, hypertriglyceridemia, hypertension or alteration in glucose metabolism. RESULTS: Out of the 115 obese children studied, 24% showed signs of metabolic syndrome. Those with metabolic syndrome presented higher levels of hs-CRP (mean: 3.8 mg/l; 95% CI: 2.8-4.8) in comparison with the obese patients who did not show signs of metabolic syndrome (mean: 2 mg/l; 95% CI: 1.5-2.5). After a multivariate analysis, the variables that appear to influence the changes in hs-CRP were BMI, triglycerides and HDL-cholesterol levels. CONCLUSION: The hs-CRP is a useful tool for early diagnosis of cardiovascular risk in obese children and teenagers.