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Int J Obes (Lond) ; 44(9): 1946-1957, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32719434


BACKGROUND: Though it is well established that neonatal nutrition plays a major role in lifelong offspring health, the mechanisms underpinning this have not been well defined. Early postnatal accelerated growth resulting from maternal nutritional status is associated with increased appetite and body weight. Likewise, slow growth correlates with decreased appetite and body weight. Food consumption and food-seeking behaviour are directly modulated by central serotonergic (5-hydroxytryptamine, 5-HT) pathways. This study examined the effect of a rat maternal postnatal low protein (PLP) diet on 5-HT receptor mediated food intake in offspring. METHODS: Microarray analyses, in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR were used to identify genes up- or down-regulated in the arcuate nucleus of the hypothalamus (ARC) of 3-month-old male PLP rats. Third ventricle cannulation was used to identify altered sensitivity to serotonin receptor agonists and antagonists with respect to food intake. RESULTS: Male PLP offspring consumed less food and had lower growth rates up to 3 months of age compared with Control offspring from dams fed a normal diet. In total, 97 genes were upregulated including the 5-HT5A receptor (5-HT5AR) and 149 downregulated genes in PLP rats compared with Controls. The former obesity medication fenfluramine and the 5-HT receptor agonist 5-Carboxamidotryptamine (5-CT) significantly suppressed food intake in both groups, but the PLP offspring were more sensitive to d-fenfluramine and 5-CT compared with Controls. The effect of 5-CT was antagonized by the 5-HT5AR antagonist SB699551. 5-CT also reduced NPY-induced hyperphagia in both Control and PLP rats but was more effective in PLP offspring. CONCLUSIONS: Postnatal low protein programming of growth in rats enhances the central effects of serotonin on appetite by increasing hypothalamic 5-HT5AR expression and sensitivity. These findings provide insight into the possible mechanisms through which a maternal low protein diet during lactation programs reduced growth and appetite in offspring.

Apetito/fisiología , Peso Corporal/fisiología , Regulación del Desarrollo de la Expresión Génica/genética , Hipotálamo/metabolismo , Receptores de Serotonina , Animales , Dieta , Femenino , Masculino , Obesidad/metabolismo , Ratas , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Transcriptoma/genética
Dis Model Mech ; 9(4): 401-12, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26769798


Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus ofin uterogrowth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist.

Crecimiento y Desarrollo , Hipotálamo/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Animales , Animales Recién Nacidos , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/metabolismo , Peso Corporal/efectos de los fármacos , Proteínas en la Dieta/farmacología , Conducta Alimentaria/efectos de los fármacos , Femenino , Fenfluramina/administración & dosificación , Fenfluramina/farmacología , Feto/efectos de los fármacos , Feto/metabolismo , Crecimiento y Desarrollo/efectos de los fármacos , Hipotálamo/anatomía & histología , Hipotálamo/efectos de los fármacos , Hipotálamo/crecimiento & desarrollo , Captura por Microdisección con Láser , Masculino , Neuronas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Ratas Wistar , Reproducibilidad de los Resultados , Serotonina/metabolismo , Factores de Tiempo , Triptófano/metabolismo
Am J Clin Nutr ; 103(2): 579-88, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26718412


BACKGROUND: It is well established that low birth weight and accelerated postnatal growth increase the risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental programming are not well characterized, and potential intervention strategies are poorly defined. OBJECTIVES: We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed phenotype. DESIGN: A rat model of maternal protein restriction was used to generate low-birth-weight offspring that underwent accelerated postnatal growth (termed "recuperated"). These were compared with control rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress, and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase-polymerase chain reaction. RESULTS: Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ± SEM: 12 ± 2 µm) than in controls (5 ± 0.5 µm) (P < 0.001). This was associated with greater inflammation (interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor α: 64% ± 24% increase; P < 0.05), lipid peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 µg/mL per µg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01) hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01). CONCLUSIONS: Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by downregulation of oxidative stress, inflammation, and hyperinsulinemia.

Antiinflamatorios no Esteroideos/uso terapéutico , Suplementos Dietéticos , Retardo del Crecimiento Fetal/dietoterapia , Hepatitis/prevención & control , Cirrosis Hepática/prevención & control , Estrés Oxidativo , Ubiquinona/análogos & derivados , Animales , Citocinas/antagonistas & inhibidores , Citocinas/sangre , Citocinas/metabolismo , Dieta con Restricción de Proteínas/efectos adversos , Femenino , Desarrollo Fetal , Retardo del Crecimiento Fetal/etiología , Retardo del Crecimiento Fetal/inmunología , Retardo del Crecimiento Fetal/fisiopatología , Hepatitis/etiología , Hepatitis/metabolismo , Hepatitis/patología , Hiperinsulinismo/etiología , Hiperinsulinismo/prevención & control , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/etiología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Desnutrición/fisiopatología , Fenómenos Fisiologicos Nutricionales Maternos , Embarazo , Complicaciones del Embarazo/fisiopatología , Ratas Wistar , Organismos Libres de Patógenos Específicos , Ubiquinona/uso terapéutico , Destete
FASEB J ; 28(12): 5398-405, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25172893


Low birth weight and rapid postnatal growth increases risk of cardiovascular-disease (CVD); however, underlying mechanisms are poorly understood. Previously, we demonstrated that rats exposed to a low-protein diet in utero that underwent postnatal catch-up growth (recuperated) have a programmed deficit in cardiac coenzyme Q (CoQ) that was associated with accelerated cardiac aging. It is unknown whether this deficit occurs in all tissues, including those that are clinically accessible. We investigated whether aortic and white blood cell (WBC) CoQ is programmed by suboptimal early nutrition and whether postweaning dietary supplementation with CoQ could prevent programmed accelerated aging. Recuperated male rats had reduced aortic CoQ [22 d (35±8.4%; P<0.05); 12 m (53±8.8%; P<0.05)], accelerated aortic telomere shortening (P<0.01), increased DNA damage (79±13% increase in nei-endonucleaseVIII-like-1), increased oxidative stress (458±67% increase in NAPDH-oxidase-4; P<0.001), and decreased mitochondrial complex II-III activity (P<0.05). Postweaning dietary supplementation with CoQ prevented these detrimental programming effects. Recuperated WBCs also had reduced CoQ (74±5.8%; P<0.05). Notably, WBC CoQ levels correlated with aortic telomere-length (P<0.0001) suggesting its potential as a diagnostic marker of vascular aging. We conclude that early intervention with CoQ in at-risk individuals may be a cost-effective and safe way of reducing the global burden of CVDs.

Enfermedades Cardiovasculares/prevención & control , Suplementos Dietéticos , Ubiquinona/metabolismo , Animales , Enfermedades Cardiovasculares/enzimología , Femenino , Estrés Oxidativo , Embarazo , Ratas Wistar , Telomerasa/metabolismo , Ubiquinona/administración & dosificación
Mol Metab ; 2(4): 480-90, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24327963


Studies in human and animals have demonstrated that nutritionally induced low birth-weight followed by rapid postnatal growth increases the risk of metabolic syndrome and cardiovascular disease. Although the mechanisms underlying such nutritional programming are not clearly defined, increased oxidative-stress leading to accelerated cellular aging has been proposed to play an important role. Using an established rodent model of low birth-weight and catch-up growth, we show here that post-weaning dietary supplementation with coenzyme Q10, a key component of the electron transport chain and a potent antioxidant rescued many of the detrimental effects of nutritional programming on cardiac aging. This included a reduction in nitrosative and oxidative-stress, telomere shortening, DNA damage, cellular senescence and apoptosis. These findings demonstrate the potential for postnatal antioxidant intervention to reverse deleterious phenotypes of developmental programming and therefore provide insight into a potential translatable therapy to prevent cardiovascular disease in at risk humans.

Proteomics ; 12(22): 3386-92, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22997143


Studies of neuronal, endocrine, and metabolic disorders would be facilitated by characterization of the hypothalamus proteome. Protein extracts prepared from 16 whole rat hypothalami were measured by data-independent label-free nano LC-MS/MS. Peptide features were detected, aligned, and searched against a rat Swiss-Prot database using ProteinLynx Global Server v.2.5. The final combined dataset comprised 21 455 peptides, corresponding to 622 unique proteins, each identified by a minimum of two distinct peptides. The majority of the proteins (69%) were cytosolic, and 16% were membrane proteins. Important proteins involved in neurological and synaptic function were identified including several members of the Ras-related protein family and proteins involved in glutamate biosynthesis.

Cromatografía Liquida/métodos , Hipotálamo/química , Proteínas del Tejido Nervioso/análisis , Proteoma/análisis , Espectrometría de Masas en Tándem/métodos , Animales , Biomarcadores/análisis , Bases de Datos de Proteínas , Hipotálamo/metabolismo , Punto Isoeléctrico , Proteínas del Tejido Nervioso/química , Fragmentos de Péptidos/análisis , Proteoma/química , Proteómica , Ratas , Ratas Wistar