Examinando por Autor "Horrillo, Daniel"

Mostrando 1 - 5 de 5

Fibrosis hepática durante el envejecimiento: respuesta durante una restricción nutricional crónica.
(XXXII CONGRESO DE LA SOCIEDAD ESPAÑOLA DE BIOQUÍMICA Y BIOLOGÍA MOLECULAR., 2009-09-23) Horrillo, Daniel; Carrascosa, Jose María; García-San Frutos, Miriam; Barrús, María Teresa; Ros, Manuel; Fernández-Agulló, Teresa
NTRODUCCIÓN: El envejecimiento en la rata Wistar se asocia a una resistencia central y periférica a insulina que es revertida parcialmente con una restricción calórica. Teniendo en cuenta que la resistencia a insulina se ha asociado también a un estado de inflamación subcrónico en el presente trabajo hemos querido estudiar el estado inflamatorio de hígado durante el envejecimiento y el posible efecto de una restricción nutricional. MATERIAL Y MÉTODOS: Animales: ratas Wistar control de 3 meses y de 8 y 24 meses con y sin restricción nutricional crónica. ELISA para analizar los niveles de citoquinas proinflamatorias plasmáticas. WESTERN BLOT para analizar los niveles de serina quinasas como JNK que se han asociado con estados de resistencia a la insulina. Estudios histológicos para ver la distribución de células de Kupfer, detección de fibrosis mediante histoquímica, inmunohistoquímica utilizando anticuerpos específicos de macrófagos y de células estrelladas. RESULTADOS: De las citoquinas analizadas los niveles de PAI aumentan durante el envejecimiento y son parcialmente restaurados tras una restricción crónica moderada. A nivel histológico el envejecimiento se asocia con un aumento de macrófagos, una redistribución de los mismos y una ligera fibrosis que en otras modelos se ha asociado con un aumento de PAI. JNK y p38 también aumentan durante el envejecimiento. CONCLUSIONES: Durante el envejecimiento en la rata Wistar se observa un aumento en plasma de citoquinas proinflamatorias que en el hígado se asocian a un aumento en la expresión de las vía proinflamatorias, un aumento y redistribución de los macrófagos en el hígado y la aparición de fibrosis. Estos cambios son parcialmente restaurados con una restricción nutricional crónica y moderada.
Insulin-like Growth Factor I Couples Metabolism with Circadian Activity through Hypothalamic Orexin Neurons
(mdpi, 2022-04-23) Pignatelli, jaime; Fernandez de sevilla, maria estrella; Sperbek, jacob; Horrillo, Daniel; Medina-gomez, Gema; Torres Aleman, ignacio
Abstract: Uncoupling of metabolism and circadian activity is associated with an increased risk of a wide spectrum of pathologies. Recently, insulin and the closely related insulin-like growth factor I (IGF-I) were shown to entrain feeding patterns with circadian rhythms. Both hormones act centrally to modulate peripheral glucose metabolism; however, whereas central targets of insulin actions are intensely scrutinized, those mediating the actions of IGF-I remain less defined. We recently showed that IGF-I targets orexin neurons in the lateral hypothalamus, and now we evaluated whether IGF-I modulates orexin neurons to align circadian rhythms with metabolism. Mice with disrupted IGF-IR activity in orexin neurons (Firoc mice) showed sexually dimorphic alterations in daily glucose rhythms and feeding activity patterns which preceded the appearance of metabolic disturbances. Thus, Firoc males developed hyperglycemia and glucose intolerance, while females developed obesity. Since IGF-I directly modulates orexin levels and hepatic expression of KLF genes involved in circadian and metabolic entrainment in an orexin-dependent manner, it seems that IGF-I entrains metabolism and circadian rhythms by modulating the activity of orexin neurons.
Involvement of protein tyrosine phosphatases and inflammation in hypothalamus insulin resistance associated with ageing: effect of caloric restriction
(Elsevier, 2012) García-San Frutos, Miriam; Fernández-Agulló, Teresa; Carrascosa, Jose María; Horrillo, Daniel; Barrús, María Teresa; Oliveros, Eva; Sierra, Johanna; Ros, Manuel
Aged Wistar rats present central insulin resistance associated with ageing. Several steps of the insulin signaling pathway have been described to be impaired in aged rats at hypothalamic level. In the present article we have explored possible alterations in protein tyrosine phosphatases (PTPs) involved in insulin receptor dephosphorylation, as well as pro-inflammatory pathways and serine kinases such as inhibitory kappa ß kinase-nuclear factor kappa-B (IKKß-NF¿B), p38 mitogen-activated protein kinase (p38) and protein kinase C ¿ (PKC¿) that may also be involved in insulin signaling decrease during ageing. We detected that ageing brings about a specific increase in insulin receptor PTP activity and PTP1B serine phosphorylation. Increased association of PTP1B and leukocyte common antigen-related tyrosine protein phosphatase (LAR) with insulin receptor was also observed in hypothalamus from aged rats. Besides these mechanisms, increased activation of the IKKß-NF¿B pathway, p38 and PKC¿ serine/threonine kinases were also detected. These data contribute to explain the hypothalamic insulin resistance associated with ageing. Caloric restriction ameliorates most of the effects of ageing on the above mentioned increases in PTPs and serine/threonine kinases activities and points to age-associated adiposity and inflammation as key factors in the development of age-associated insulin resistance.
Myeloid p38 activation maintains macrophage–liver crosstalk and BAT thermogenesis through IL‐12–FGF21 axis
(Wolters Kluwer Health, Inc, 2023) Crespo, Maria; nikolic, ivana; mora, alfonso; rodriguez, elena; leiva-vega, luis; pintor-chocano, aranzazu; Horrillo, Daniel; hernandez-cosido, lourdes; torres, Jorge; Novoa, Eva; Nogueiras, ruben; medina-gomez, Gema; marcos, miguel; leiva, magdalena; sabio, guadalupe
Obesity features excessive fat accumulation in several body tissues and induces a state of chronic low-grade inflammation that contributes to the development of diabetes, steatosis and insulin resistance. Recent research has shown that this chronic inflammation is crucially dependent on p38 pathway activity in macrophages, suggesting p38 inhibitio n as a possible treatment for obesity comorbidities Nevertheless, we report here that lack of p38 activation in myeloid cells worsens high fat diet-induced obesity, diabetes, and steatosis. Deficient p38 activation increases macrophage IL-12 production, leading to inhibition of hepatic FGF21 and reduction of thermogenesis in the brown fat. The implication of FGF21 in the phenotype was confirmed by its specific deletion in hepatocytes. We also found that IL-12 correlates with liver damage in human biopsies, indicating the translational potential of our results. Our findings suggest that myeloid p38 has a dual role in inflammation and that drugs targeting IL-12 might improve the homeostatic regulation of energy balance in response to metabolic stress.
Pleiotrophin deletion alters glucose homeostasis, energy metabolism and brown fat thermogenic function in mice
(Springer-Verlag, 2019-08-22) Sevillano, julio; Sánchez-Alonso, Maria Gracia; Zapateria, begoña; calderon, maria; alcala, maria; limones, maria; pita, jimena; gramage, esther; vivente-rodriguez, marta; Horrillo, Daniel; Medina-gomez, Gema; Obregon, maria jesus; viana, marta; valladoliz-acebes, Ismael; herradon, gonzalo; Ramos-alvarez, pilar
Abstract 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 24ºC and 30ºC. 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 +t+ vs 13.9% in Ptn -I- mice) and an enhanced lipolytic response to isoprenaline in isolated adipocytes from 15-month-old mice (189% in Ptn+t+ vs 273% in Ptn _1_ mice). We found that Ptn -t- mice exhibited a significantly lower QUICK.l value and an altered lipid profile; plasma triacylglycerols and NEFA did not increase with age, as happens in Ptn+t+ mice. Furthermore, the contribution of cold-induced thermogenesis to energy expenditure was greater in Ptn -I- 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 ofthe brown adipocyte markers Cidea (20% reduction), Prdml 6 (21 % reduction), and Pgcl-a (also known as Ppargcl a, 11 % reduction). Conclusions/interpretation Our results revea] for the first time that pleiotrophin is a key player in preserving insulin sensitivity, driving the dynarnics of adipose tissue lipid turnover and plasticity, and regulating energy metabolism and thermogenesis. These findings open therapeutic avenues for the treatrnent of metabolic disorders by targeting pleiotrophin in the crosstalk between white and brown adipose tissue.