Origen neonatal de la síndrome metabòlica en l'adult

[cat] Es coneix que la nutrició en les primeres etapes de la vida és un factor clau que contribueix a la prevalença de l'obesitat, així com la resta de característiques de la Síndrome Metabòlica en l'edat adulta (Langley-Evans SC, 2006; Neu J, 2007; Patel MS, 2011; Jimenez-Chillaron JC, 2012; Wang X, 2013; Waterland RA, 2013). Nombrosos estudis fets en models experimentals i corroborats en humans demostren una interelació entre la nutrició postnatal, el patró de creixement durant la infància i les alteracions metabòliques que s'observen en l'edat adulta (Neu J, 2007). Aquest fenomen es clau en determinar la salut de l'individu al llarg de la vida. De fet, aquestes observacions es recullen en la hipòtesi, ja descrita, de l'Origen Primerenc de la Salut i la Malaltia en l'Adult (Developmental Origins of Health and Disease, DOHaD), que proposa el programming o efecte permanent de les condicions primerenques com a influència en el creixement i metabolisme en l'edat adulta (Lucas A, 1991; Gluckman P, 2004; Wang X, 2013). Hem desenvolupat al laboratori un model murí de sobrenutrició neonatal amb creixement postnatal accelerat que desenvolupa moltes de les característiques de la Síndrome metabòlica en l'adult, on els animals desenvolupen hipertriglicèridèmia, hiperinsulinèmia, intolerància a la glucosa i resistència a la insulina (Pentinat T, 2010). L'alteració de la tolerància a la glucosa sembla que es deu a una resistència perifèrica a la insulina, donat que la funció de la cèl·lula beta és normal. Per contra, via de senyalització de la insulina es troba alterada des de les primeres setmanes de vida. Sorprenentment, els canvis induïts durant les primeres setmanes de vida no solament afecten la salut de l'individu adult, sinó també la seva descendència. La progressió transgeneracional del fenotip metabòlic a través del llinatge patern suggereix l'epigenètica com a mecanismes responsables.[eng] Epidemiological and clinical data show that rapid weight gain in early life is strongly associated with several components of the metabolic syndrome and influence risk in subsequent generations. In order to determine which events occurring at early life determined the adverse metabolic consequences in adulthood we have developed a mouse model of postnatal accelerated growth rate by neonatal overnutrition, ON. We forced neonatal overfeeding by culling the offspring to 4 male pups per mouse during lactation. As expected, ON mice exhibited accelerated growth and by age 4 months, developed many features of the metabolic syndrome, including obesity , impaired glucose tolerance and insulin resistance. Impaired glucose tolerance in ON mice appeared to be accounted for primarily by peripheral insulin resistance, because beta-cell function remained normal. In contrast, insulin signaling was impaired since early life. Likewise, ON mice show altered lipid metabolism in early life with impaired lipogenic gene expression and impaired lipogenesis de novo that together leads to TAG accumulation. Interestingly, the observed features occurring in early life not only affects the lifespan of affected individuals, but also subsequent generations. Transgenerational progression of metabolic phenotypes through the paternal lineage suggests the role for epigenetic mechanisms in mediating these effects

Fatty acid transport protein 1 (FATP1) delivered into skeletal muscle localizes in mitochondria and regulates lipid and ketone body disposal

FATP1 mediates skeletal muscle cell fatty acid import, yet its intracellular localization and metabolic control role are not completely defined. Here, we examine FATP1 localization and metabolic effects of its overexpression in mouse skeletal muscle. The FATP1 protein was detected in mitochondrial and plasma membrane fractions, obtained by differential centrifugation, of mouse gastrocnemius muscle. FATP1 was most abundant in purified mitochondria, and in the outer membrane and soluble intermembrane, but not in the inner membrane plus matrix, enriched subfractions of purified mitochondria. Immunogold electron microscopy localized FATP1-GFP in mitochondria of transfected C2C12 myotubes. FATP1 was overexpressed in gastrocnemius mouse muscle, by adenovirus-mediated delivery of the gene into hindlimb muscles of newborn mice, fed after weaning a chow or high-fat diet. Compared to GFP delivery, FATP1 did not alter body weight, serum fed glucose, insulin and triglyceride levels, and whole-body glucose tolerance, in either diet. However, fatty acid levels were lower and beta-hydroxybutyrate levels were higher in FATP1-than GFP-mice, irrespective of diet. Moreover, intramuscular triglyceride content was lower in FATP1-versus GFP-mice regardless of diet, and beta-hydroxybutyrate content was unchanged in high-fat-fed mice. Electroporation-mediated FATP1 overexpression enhanced palmitate oxidation to CO2, but not to acid-soluble intermediate metabolites, while CO2 production from beta-hydroxybutyrate was inhibited and that from glucose unchanged, in isolated mouse gastrocnemius strips. In summary, FATP1 was localized in mitochondria, in the outer membrane and intermembrane parts, of mouse skeletal muscle, what may be crucial for its metabolic effects. Overexpressed FATP1 enhanced disposal of both systemic fatty acids and intramuscular triglycerides. Consistently, it did not contribute to the high-fat diet-induced metabolic dysregulation. However, FATP1 lead to hyperketonemia, likely secondary to the sparing of ketone body oxidation by the enhanced oxidation of fatty acids

Fatty acid transport protein 1 (FATP1) delivered into skeletal muscle localizes in mitochondria and regulates lipid and ketone body disposal

FATP1 mediates skeletal muscle cell fatty acid import, yet its intracellular localization and metabolic control role are not completely defined. Here, we examine FATP1 localization and metabolic effects of its overexpression in mouse skeletal muscle. The FATP1 protein was detected in mitochondrial and plasma membrane fractions, obtained by differential centrifugation, of mouse gastrocnemius muscle. FATP1 was most abundant in purified mitochondria, and in the outer membrane and soluble intermembrane, but not in the inner membrane plus matrix, enriched subfractions of purified mitochondria. Immunogold electron microscopy localized FATP1-GFP in mitochondria of transfected C2C12 myotubes. FATP1 was overexpressed in gastrocnemius mouse muscle, by adenovirus-mediated delivery of the gene into hindlimb muscles of newborn mice, fed after weaning a chow or high-fat diet. Compared to GFP delivery, FATP1 did not alter body weight, serum fed glucose, insulin and triglyceride levels, and whole-body glucose tolerance, in either diet. However, fatty acid levels were lower and beta-hydroxybutyrate levels were higher in FATP1-than GFP-mice, irrespective of diet. Moreover, intramuscular triglyceride content was lower in FATP1-versus GFP-mice regardless of diet, and beta-hydroxybutyrate content was unchanged in high-fat-fed mice. Electroporation-mediated FATP1 overexpression enhanced palmitate oxidation to CO2, but not to acid-soluble intermediate metabolites, while CO2 production from beta-hydroxybutyrate was inhibited and that from glucose unchanged, in isolated mouse gastrocnemius strips. In summary, FATP1 was localized in mitochondria, in the outer membrane and intermembrane parts, of mouse skeletal muscle, what may be crucial for its metabolic effects. Overexpressed FATP1 enhanced disposal of both systemic fatty acids and intramuscular triglycerides. Consistently, it did not contribute to the high-fat diet-induced metabolic dysregulation. However, FATP1 lead to hyperketonemia, likely secondary to the sparing of ketone body oxidation by the enhanced oxidation of fatty acids

Fatty acid transport protein 1 (FATP1) delivered into skeletal muscle localizes in mitochondria and regulates lipid and ketone body disposal

FATP1 mediates skeletal muscle cell fatty acid import, yet its intracellular localization and metabolic control role are not completely defined. Here, we examine FATP1 localization and metabolic effects of its overexpression in mouse skeletal muscle. The FATP1 protein was detected in mitochondrial and plasma membrane fractions, obtained by differential centrifugation, of mouse gastrocnemius muscle. FATP1 was most abundant in purified mitochondria, and in the outer membrane and soluble intermembrane, but not in the inner membrane plus matrix, enriched subfractions of purified mitochondria. Immunogold electron microscopy localized FATP1-GFP in mitochondria of transfected C2C12 myotubes. FATP1 was overexpressed in gastrocnemius mouse muscle, by adenovirus-mediated delivery of the gene into hindlimb muscles of newborn mice, fed after weaning a chow or high-fat diet. Compared to GFP delivery, FATP1 did not alter body weight, serum fed glucose, insulin and triglyceride levels, and whole-body glucose tolerance, in either diet. However, fatty acid levels were lower and beta-hydroxybutyrate levels were higher in FATP1-than GFP-mice, irrespective of diet. Moreover, intramuscular triglyceride content was lower in FATP1-versus GFP-mice regardless of diet, and beta-hydroxybutyrate content was unchanged in high-fat-fed mice. Electroporation-mediated FATP1 overexpression enhanced palmitate oxidation to CO2, but not to acid-soluble intermediate metabolites, while CO2 production from beta-hydroxybutyrate was inhibited and that from glucose unchanged, in isolated mouse gastrocnemius strips. In summary, FATP1 was localized in mitochondria, in the outer membrane and intermembrane parts, of mouse skeletal muscle, what may be crucial for its metabolic effects. Overexpressed FATP1 enhanced disposal of both systemic fatty acids and intramuscular triglycerides. Consistently, it did not contribute to the high-fat diet-induced metabolic dysregulation. However, FATP1 lead to hyperketonemia, likely secondary to the sparing of ketone body oxidation by the enhanced oxidation of fatty acids

Preclinical evaluation of a COVID-19 vaccine candidate based on a recombinant RBD fusion heterodimer of SARS-CoV-2

Current COVID-19 vaccines have been associated with a decline in infection rates, prevention of severe disease and a decrease in mortality rates. However, SARS-CoV-2 variants are continuously evolving, and development of new accessible COVID-19 vaccines is essential to mitigate the pandemic. Here, we present data on preclinical studies in mice of a receptor-binding domain (RBD)-based recombinant protein vaccine (PHH-1V) consisting of an RBD fusion heterodimer comprising the B.1.351 and B.1.1.7 SARS-CoV-2 variants formulated in SQBA adjuvant, an oil-in-water emulsion. A prime-boost immunisation with PHH-1V in BALB/c and K18-hACE2 mice induced a CD4 + and CD8 + T cell response and RBD-binding antibodies with neutralising activity against several variants, and also showed a good tolerability profile. Significantly, RBD fusion heterodimer vaccination conferred 100% efficacy, preventing mortality in SARS-CoV-2 infected K18-hACE2 mice, but also reducing Beta, Delta and Omicron infection in lower respiratory airways. These findings demonstrate the feasibility of this recombinant vaccine strategy