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1.
Hepatology ; 65(4): 1352-1368, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27981611

RESUMEN

Metabolic diseases such as obesity and type 2 diabetes are recognized as independent risk factors for hepatocellular carcinoma (HCC). Hyperinsulinemia, a hallmark of these pathologies, is suspected to be involved in HCC development. The molecular adapter growth factor receptor binding protein 14 (Grb14) is an inhibitor of insulin receptor catalytic activity, highly expressed in the liver. To study its involvement in hepatocyte proliferation, we specifically inhibited its liver expression using a short hairpin RNA strategy in mice. Enhanced insulin signaling upon Grb14 inhibition was accompanied by a transient induction of S-phase entrance by quiescent hepatocytes, indicating that Grb14 is a potent repressor of cell division. The proliferation of Grb14-deficient hepatocytes was cell-autonomous as it was also observed in primary cell cultures. Combined Grb14 down-regulation and insulin signaling blockade using pharmacological approaches as well as genetic mouse models demonstrated that Grb14 inhibition-mediated hepatocyte division involved insulin receptor activation and was mediated by the mechanistic target of rapamycin complex 1-S6K pathway and the transcription factor E2F1. In order to determine a potential dysregulation in GRB14 gene expression in human pathophysiology, a collection of 85 human HCCs was investigated. This revealed a highly significant and frequent decrease in GRB14 expression in hepatic tumors when compared to adjacent nontumoral parenchyma, with 60% of the tumors exhibiting a reduced Grb14 mRNA level. CONCLUSION: Our study establishes Grb14 as a physiological repressor of insulin mitogenic action in the liver and further supports that dysregulation of insulin signaling is associated with HCC. (Hepatology 2017;65:1352-1368).


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Carcinoma Hepatocelular/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Neoplasias Hepáticas/fisiopatología , Receptor de Insulina/metabolismo , Animales , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Células Cultivadas , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Distribución Aleatoria , Sensibilidad y Especificidad
3.
JHEP Rep ; 6(2): 100878, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38298740

RESUMEN

Background & Aims: O-GlcNAcylation is a reversible post-translational modification controlled by the activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). In the liver, O-GlcNAcylation has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease. Methods: To address whether OGT acts as a critical hepatic nutritional node, mice with a constitutive hepatocyte-specific deletion of OGT (OGTLKO) were generated and challenged with different carbohydrate- and lipid-containing diets. Results: Analyses of 4-week-old OGTLKO mice revealed significant oxidative and endoplasmic reticulum stress, and DNA damage, together with inflammation and fibrosis, in the liver. Susceptibility to oxidative and endoplasmic reticulum stress-induced apoptosis was also elevated in OGTLKO hepatocytes. Although OGT expression was partially recovered in the liver of 8-week-old OGTLKO mice, hepatic injury and fibrosis were not rescued but rather worsened with time. Interestingly, weaning of OGTLKO mice on a ketogenic diet (low carbohydrate, high fat) fully prevented the hepatic alterations induced by OGT deletion, indicating that reduced carbohydrate intake protects an OGT-deficient liver. Conclusions: These findings pinpoint OGT as a key mediator of hepatocyte homeostasis and survival upon carbohydrate intake and validate OGTLKO mice as a valuable model for assessing therapeutical approaches of advanced liver fibrosis. Impact and Implications: Our study shows that hepatocyte-specific deletion of O-GlcNAc transferase (OGT) leads to severe liver injury, reinforcing the importance of O-GlcNAcylation and OGT for hepatocyte homeostasis and survival. Our study also validates the Ogt liver-deficient mouse as a valuable model for the study of advanced liver fibrosis. Importantly, as the severe hepatic fibrosis of Ogt liver-deficient mice could be fully prevented upon feeding on a ketogenic diet (i.e. very-low-carbohydrate, high-fat diet) this work underlines the potential interest of nutritional intervention as antifibrogenic strategies.

4.
Mol Metab ; 57: 101438, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35007789

RESUMEN

OBJECTIVE: A common feature of metabolic diseases is their association with chronic low-grade inflammation. While enhanced gut permeability and systemic bacterial endotoxin translocation have been suggested as key players of this metaflammation, the mechanistic bases underlying these features upon the diabesity cascade remain partly understood. METHODS: Here, we show in mice that, independently of obesity, the induction of acute and global insulin resistance and associated hyperglycemia, upon treatment with an insulin receptor (IR) antagonist (S961), elicits gut hyperpermeability without triggering systemic inflammatory response. RESULTS: Of note, S961-treated diabetic mice display major defects of gut barrier epithelial functions, such as increased epithelial paracellular permeability and impaired cell-cell junction integrity. We also observed in these mice the early onset of a severe gut dysbiosis, as characterized by the bloom of pro-inflammatory Proteobacteria, and the later collapse of Paneth cells antimicrobial defense. Interestingly, S961 treatment discontinuation is sufficient to promptly restore both the gut microbial balance and the intestinal barrier integrity. Moreover, fecal transplant approaches further confirm that S961-mediated dybiosis contributes at least partly to the disruption of the gut selective epithelial permeability upon diabetic states. CONCLUSIONS: Together, our results highlight that insulin signaling is an indispensable gatekeeper of intestinal barrier integrity, acting as a safeguard against microbial imbalance and acute infections by enteropathogens.


Asunto(s)
Diabetes Mellitus Experimental , Microbioma Gastrointestinal , Resistencia a la Insulina , Animales , Disbiosis/metabolismo , Disbiosis/microbiología , Microbioma Gastrointestinal/fisiología , Inflamación/metabolismo , Ratones
5.
Sci Rep ; 10(1): 5186, 2020 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-32198362

RESUMEN

The Wnt/ß-catenin pathway plays a pivotal role in liver structural and metabolic homeostasis. Wnt activity is tightly regulated by the acyltransferase Porcupine through the addition of palmitoleate. Interestingly palmitoleate can be endogenously produced by the stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme transcriptionally regulated by insulin. This study aimed to determine whether nutritional conditions, and insulin, regulate Wnt pathway activity in liver. An adenoviral TRE-Luciferase reporter was used as a readout of Wnt/ß-catenin pathway activity, in vivo in mouse liver and in vitro in primary hepatocytes. Refeeding enhanced TRE-Luciferase activity and expression of Wnt target genes in mice liver, revealing a nutritional regulation of the Wnt/ß-catenin pathway. This effect was inhibited in liver specific insulin receptor KO (iLIRKO) mice and upon wortmannin or rapamycin treatment. Overexpression or inhibition of SCD1 expression regulated Wnt/ß-catenin activity in primary hepatocytes. Similarly, palmitoleate added exogenously or produced by SCD1-mediated desaturation of palmitate, induced Wnt signaling activity. Interestingly, this effect was abolished in the absence of Porcupine, suggesting that both SCD1 and Porcupine are key mediators of insulin-induced Wnt/ß-catenin activity in hepatocytes. Altogether, our findings suggest that insulin and lipogenesis act as potential novel physiological inducers of hepatic Wnt/ß-catenin pathway.


Asunto(s)
Insulina/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/efectos de los fármacos , Aciltransferasas/metabolismo , Animales , Ácidos Grasos Monoinsaturados/farmacología , Hepatocitos/metabolismo , Lipogénesis/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Vía de Señalización Wnt/fisiología , beta Catenina/metabolismo
6.
Proteomics ; 9(15): 3889-900, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19639598

RESUMEN

The Wnt/beta-catenin signaling pathway has been increasingly implicated in liver development and physiology. Aberrant activation of this pathway is one of the major genetic events observed during the process of human HCC development. To gain insight into the mechanism underlying beta-catenin action in the liver, we conducted a quantitative differential proteomic analysis using 2-D DIGE combined with MS, in mice with liver-specific deletion of Apc resulting in acute activation of beta-catenin signaling (Apc(KOliv) mice). We identified 94 protein spots showing differential expression between mutant Apc(KOliv) and control mice, corresponding to 56 individual proteins. Most of the proteins identified were associated with metabolic pathways, such as ammonia and glucose metabolism. Our analysis showed an increase in lactate dehydrogenase activity together with a downregulation of two mitochondrial ATPase subunits (ATP5a1 and ATP5b). These observations indicate that beta-catenin signaling may induce a shift in the glucose metabolism from oxidative phosphorylation to glycolysis, known as the "Warburg effect". Imaging with (18)F-fluoro-2-deoxy-D-glucose-positron emission tomography suggests that the specific metabolic reprogramming induced by beta-catenin in the liver does not imply the first step of glycolysis. This observation may explain why some HCCs are difficult to assess by fluoro-2-deoxy-D-glucose-positron emission tomography imaging.


Asunto(s)
Genes APC , Glucosa/metabolismo , Hígado/metabolismo , Proteoma/análisis , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animales , Electroforesis en Gel Bidimensional , Eliminación de Gen , Regulación de la Expresión Génica , Masculino , Espectrometría de Masas , Ratones , Proteoma/genética , Proteoma/metabolismo , Transducción de Señal
7.
Biochim Biophys Acta ; 1781(5): 239-44, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18374665

RESUMEN

The peroxisome proliferator-activated receptor alpha (PPARalpha) belongs to the nuclear receptor family and plays a central role in the regulation of lipid metabolism, glucose homeostasis and inflammatory processes. In addition to its ligand-induced activation, PPARalpha is regulated by phosphorylation via ERK-MAPK, PKA and PKC. In this study we examined the effect of p38-MAPK on PPARalpha transcriptional activity. In COS-7 cells, anisomycin, a p38 activator, induced a dose-dependent phosphorylation of PPARalpha and a 50% inhibition of its transcriptional activity. In H4IIE hepatoma cells, anisomycin-induced p38 phosphorylation decreased both endogenous and PPARalpha ligand-enhanced L-CPTI and ACO gene expression. Interestingly, PPARalpha/p38 interaction required the molecular adapter ZIP/p62. Reducing ZIP/p62 expression by siRNA, partially reversed the inhibitory effect of anisomycin on L-CPTI gene expression. In conclusion, we showed that p38 activation induced PPARalpha phosphorylation and inhibition of its transcriptional activity through a trimeric interaction between p38-MAPK, ZIP/p62 and PPARalpha.


Asunto(s)
Proteínas de Choque Térmico/metabolismo , PPAR alfa/metabolismo , Transcripción Genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Anisomicina/metabolismo , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Activación Enzimática , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas de Choque Térmico/genética , Sistema de Señalización de MAP Quinasas/fisiología , Inhibidores de la Síntesis del Ácido Nucleico/metabolismo , PPAR alfa/genética , Proteína Quinasa C/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ratas , Proteína Sequestosoma-1 , Proteínas Quinasas p38 Activadas por Mitógenos/genética
8.
Endocrinology ; 149(6): 3109-17, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18339716

RESUMEN

Tight control of insulin action in liver is a crucial determinant for the regulation of energy homeostasis. Growth factor receptor-bound protein 14 (Grb14) is a molecular adapter, highly expressed in liver, which binds to the activated insulin receptor and inhibits its tyrosine kinase activity. The physiological role of Grb14 in liver metabolism was unexplored. In this study we used RNA interference to investigate the consequences of Grb14 decrease on insulin-regulated intracellular signaling, and on glucose and lipid metabolism in mouse primary cultured hepatocytes. In Grb14-depleted hepatocytes, insulin-induced phosphorylation of Akt, and of its substrates glycogen synthase kinase 3 and fork-head box protein 1, was increased. These effects on insulin signaling are in agreement with the selective inhibitory effect of Grb14 on the receptor kinase. However, the metabolic and genic effects of insulin were differentially regulated after Grb14 down-regulation. Indeed, the insulin-mediated inhibition of hepatic glucose production and gluconeogenic gene expression was slightly increased. Surprisingly, despite the improved Akt pathway, the induction by insulin of sterol regulatory element binding protein-1c maturation was totally blunted. As a result, in the absence of Grb14, glycogen synthesis as well as glycolytic and lipogenic gene expression were not responsive to the stimulatory effect of insulin. This study provides evidence that Grb14 exerts a dual role on the regulation by insulin of hepatic metabolism. It inhibits insulin receptor catalytic activity, and acts also at a more distal step, i.e. sterol regulatory element binding protein-1c maturation, which effect is predominant under short-term inhibition of Grb14 expression.


Asunto(s)
Hepatocitos/fisiología , Insulina/farmacología , Proteínas/fisiología , Proteínas Adaptadoras Transductoras de Señales , Animales , Eliminación de Gen , Glucosa/metabolismo , Hepatocitos/efectos de los fármacos , Cinética , Lípidos/fisiología , Glucógeno Hepático/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas/genética , ARN Interferente Pequeño/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo
9.
Cell Rep ; 21(2): 403-416, 2017 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-29020627

RESUMEN

While the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor α (PPARα), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21. Glucose-challenged Chrebp-/- mice exhibit a marked reduction in FGF21 production, a decrease that was rescued by re-expression of an active ChREBP isoform in the liver of Chrebp-/- mice. Unexpectedly, carbohydrate challenge of hepatic Pparα knockout mice also demonstrated a PPARα-dependent glucose response for Fgf21 that was associated with an increased sucrose preference. This blunted response was due to decreased Fgf21 promoter accessibility and diminished ChREBP binding onto Fgf21 carbohydrate-responsive element (ChoRE) in hepatocytes lacking PPARα. Our study reports that PPARα is required for the ChREBP-induced glucose response of FGF21.


Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Glucosa/metabolismo , Proteínas Nucleares/metabolismo , PPAR alfa/metabolismo , Factores de Transcripción/metabolismo , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Células Cultivadas , Femenino , Factores de Crecimiento de Fibroblastos/genética , Hepatocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Nucleares/genética , PPAR alfa/genética , Elementos de Respuesta , Factores de Transcripción/genética
10.
Mol Cell Biol ; 36(16): 2168-81, 2016 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-27215388

RESUMEN

A long-standing paradox in the pathophysiology of metabolic diseases is the selective insulin resistance of the liver. It is characterized by a blunted action of insulin to reduce glucose production, contributing to hyperglycemia, while de novo lipogenesis remains insulin sensitive, participating in turn to hepatic steatosis onset. The underlying molecular bases of this conundrum are not yet fully understood. Here, we established a model of selective insulin resistance in mice by silencing an inhibitor of insulin receptor catalytic activity, the growth factor receptor binding protein 14 (Grb14) in liver. Indeed, Grb14 knockdown enhanced hepatic insulin signaling but also dramatically inhibited de novo fatty acid synthesis. In the liver of obese and insulin-resistant mice, downregulation of Grb14 markedly decreased blood glucose and improved liver steatosis. Mechanistic analyses showed that upon Grb14 knockdown, the release of p62/sqstm1, a partner of Grb14, activated the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), which in turn repressed the lipogenic nuclear liver X receptor (LXR). Our study reveals that Grb14 acts as a new signaling node that regulates lipogenesis and modulates insulin sensitivity in the liver by acting at a crossroad between the insulin receptor and the p62-Nrf2-LXR signaling pathways.


Asunto(s)
Resistencia a la Insulina , Lipogénesis , Hígado/metabolismo , Proteínas/genética , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales , Animales , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Hígado/citología , Receptores X del Hígado/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas/metabolismo , Receptor de Insulina/metabolismo
11.
Eur J Pharmacol ; 608(1-3): 104-11, 2009 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-19250932

RESUMEN

We examined whether S26948, a new specific peroxisome proliferator activated receptor gamma modulator prevented insulin-resistance induced by a 48 h intralipid-infusion in normal rat (IL rats). The effect of S26948 (30 mg/kg) was compared to rosiglitazone (10 mg/kg). Rats were catheterized in the right jugular vein 4 days before the beginning of the 48 h lipid or saline infusions. Animals were intraperitoneally injected once daily with vehicle, S26948 or rosiglitazone. At the end of the infusion the rats underwent either a glucose tolerance test or a euglycemic-hyperinsulinemic clamp. Finally isolation and incubation of hepatocytes in another series of rats were performed. Intralipid infusion leads to a 4-fold increase in plasma free fatty acid concentration compared to controls (C). Both S26948 and rosiglitazone decreased plasma free fatty acid concentration in IL rats compared to vehicle treated IL rats. Glucose-induced insulin secretion was significantly increased in IL compared to C and was associated with insulin resistance. Both S26948 and rosiglitazone treatments normalized glucose-induced insulin secretion and improved insulin action in IL rats. However, S26948 specifically improved hepatic insulin sensitivity whereas rosiglitazone improved both hepatic insulin sensitivity and insulin-stimulated glucose utilization. Finally, studies on isolated hepatocytes showed differential effect of both compounds on gene expression of key enzymes of glucose metabolism. Our data show that non thiazolidinedione S26948 may represent an alternative way for the management of dysregulated hepatic insulin sensitivity.


Asunto(s)
Ácidos Grasos no Esterificados/metabolismo , Hepatocitos/efectos de los fármacos , Resistencia a la Insulina , Hígado/metabolismo , PPAR gamma/farmacología , Adiponectina/sangre , Adiponectina/metabolismo , Animales , Benzotiazoles , Glucemia/metabolismo , Células Cultivadas , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Ácidos Grasos no Esterificados/sangre , Expresión Génica/efectos de los fármacos , Gluconeogénesis/efectos de los fármacos , Glucosa/antagonistas & inhibidores , Técnica de Clampeo de la Glucosa , Heparina/farmacología , Hepatocitos/metabolismo , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Infusiones Intravenosas , Insulina/metabolismo , Insulina/farmacología , Hígado/efectos de los fármacos , Masculino , Oxidación-Reducción , PPAR gamma/agonistas , Distribución Aleatoria , Ratas , Ratas Wistar , Rosiglitazona , Vena Safena , Tiazolidinedionas/farmacología , Factores de Tiempo
12.
J Nutr ; 135(10): 2313-9, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16177188

RESUMEN

Liver carnitine palmitoyl transferase (L-CPT) I is a key regulatory enzyme of long-chain fatty acid (LCFA) oxidation that ensures the first step of LCFA import into the mitochondrial matrix. In rat hepatocytes, we showed previously that L-CPT I gene expression was induced by LCFAs as well as by fibrates. The aim of this study was to determine whether LCFA-induced L-CPT I gene expression was mediated by PPARalpha. For this purpose, we constructed a PPARalpha-dominant negative receptor to inhibit endogenous PPARalpha signaling. Highly conserved hydrophobic and charged residues (Leu459 and Glu462) in helix 12 of the ligand-binding domain were mutated to alanine. These mutations led to a total loss of transcriptional activity due to impaired coactivator recruitment. Furthermore, competition studies confirmed that the mutated PPARalpha receptor abolished the wild-type PPARalpha receptor action and thus acted as a powerful dominant negative receptor. When overexpressed in rat hepatoma cells (H4IIE) using a recombinant adenovirus, the mutated PPARalpha receptor antagonized the clofibrate-induced L-CPT I gene expression, whereas it did not affect LCFA-induced L-CPT I. These results provide the first direct demonstration that LCFAs regulate L-CPT I transcription through a PPARalpha-independent pathway, at least in hepatoma cells.


Asunto(s)
Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Ácido Linoleico/farmacología , PPAR alfa/metabolismo , Adenoviridae/genética , Animales , Células COS , Carcinoma Hepatocelular , Línea Celular Tumoral , Chlorocebus aethiops , Clofibrato/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hipolipemiantes/farmacología , Neoplasias Hepáticas , PPAR alfa/genética , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Activación Transcripcional/efectos de los fármacos
13.
Gynecol Obstet Invest ; 55(3): 151-5, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12865594

RESUMEN

To investigate placental leptin production in placental insufficiency, placental leptin production was measured in women with severe preeclampsia (group 1) and in normotensive pregnancies associated with intrauterine growth restriction (group 2), compared to controls (group 3). Placental leptin content was increased 3-fold in group 1 compared to group 2 (192.5.1 +/- 39.5 vs. 67.8 +/- 10.6 ng/g) and 8-fold in group 1 compared to group 3 (192.5.1 +/- 39.5 vs. 25.4 +/- 6.9 ng/g). Placental leptin content was positively correlated with maternal leptin/BMI ratio (r = 0.62) and the resistance index of the umbilical artery (r = 0.60). These data demonstrate that placental insufficiency is associated with a dramatic increase in placental leptin production. This results in a rise in maternal leptinemia that may be taken as an early index of placental dysfunction.


Asunto(s)
Leptina/análisis , Placenta/química , Insuficiencia Placentaria/diagnóstico , Adulto , Peso al Nacer , Índice de Masa Corporal , Estudios Transversales , Femenino , Sangre Fetal/química , Retardo del Crecimiento Fetal/metabolismo , Humanos , Leptina/sangre , Leptina/genética , Tamaño de los Órganos , Placenta/anatomía & histología , Placenta/metabolismo , Insuficiencia Placentaria/metabolismo , Preeclampsia/metabolismo , Embarazo , ARN Mensajero/análisis , Arterias Umbilicales , Resistencia Vascular
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