RESUMO
BACKGROUND/OBJECTIVES: It is well known that increased abdominal fat is associated with cardiovascular (CV) risk. Perirenal fat has been recently associated with CV risk in adults. However, studies with children are lacking. We investigated the relationship of perirenal fat and other abdominal fat depots (including preperitoneal, intra-abdominal and subcutaneous fat) with carotid intima-media thickness (cIMT-a surrogate marker of CV risk) in prepubertal children, so as to identify novel markers that can be easily assessed and used in the early prevention of cardiovascular disease. SUBJECTS/METHODS: Subjects were 702 asymptomatic prepubertal Caucasian children (418 lean, 142 overweight and 142 obese) who were recruited in a primary care setting. Ultrasound measurements (perirenal, preperitoneal, intra-abdominal and subcutaneous fat and cIMT), clinical (body mass index (BMI) and systolic blood pressure) and metabolic parameters (insulin resistance (HOMA-IR), high molecular weight (HMW) adiponectin and serum lipids) were assessed. RESULTS: Perirenal fat was associated with diverse metabolic and CV risk factors in all the studied subjects. However, in overweight and obese children, perirenal fat was mostly associated with cIMT (P<0.001) and was the only fat depot that showed independent associations with cIMT in multivariate analyses (overweight chidren: ß=0.250, P=0.003, r2=12.8%; obese children: ß=0.254, P=0.002, r2=15.5%) after adjusting for BMI, gender, age and metabolic parameters. Perirenal fat was also the only fat depot that showed independent associations with HMW-adiponectin in obese children (ß=-0.263, P=0.006, r2=22.8%). CONCLUSIONS: Perirenal fat is the main abdominal fat depot associated with cIMT, especially in overweight and obese children, and may thus represent a helpful parameter for assessing CV risk in the pediatric population.
Assuntos
Gordura Abdominal/diagnóstico por imagem , Espessura Intima-Media Carotídea/estatística & dados numéricos , Adiponectina/sangue , Pressão Sanguínea/fisiologia , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Obesidade/epidemiologia , Sobrepeso/epidemiologia , Fatores de RiscoRESUMO
AIMS/HYPOTHESIS: Plasma glucagon concentrations rise sharply during the early postnatal period. This condition is associated with increased alpha cell mass. However, the trophic factors that regulate alpha cell turnover during the perinatal period have not been studied. Macrophage infiltrations are present in the neonatal pancreas, and this cell type releases cytokines such as IL-6. Alpha cells have been identified as a primary target of IL-6 actions. We therefore investigated the physiological relevance of IL-6 to neonatal pancreatic alpha cell maturation. METHODS: Histochemical analyses were performed to quantify alpha cell mass, replication and apoptosis. Pancreatic Il6 expression was determined by quantitative RT-PCR. The biological effect of IL-6 was tested in two in vivo rat models of IL-6 blockade and chronic undernutrition. RESULTS: Alpha cell mass increased sharply shortly after birth but decreased significantly after weaning. Pancreatic alpha cell proliferation was as high as 2.5% at the beginning of suckling but diminished with time to 1.2% in adulthood. Similarly, alpha cell neoformation was remarkably high on postnatal day (PN) 4, whereas alpha cell apoptosis was low throughout the neonatal period. Moreover, Il6 mRNA exhibited developmental upregulation in the pancreas of suckling rats, with the highest expression on PN2. Neutralisation of IL-6 reduced alpha cell mass expansion and glucagon production. IL-6 staining was detected within the islets, mainly in the alpha cells. Finally, undernourished neonates showed altered alpha cell number and function and delayed appearance of IL-6 in the pancreas. CONCLUSIONS/INTERPRETATION: These data point to a potential role for local IL-6 in the regulation of alpha cell growth and function during suckling.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Células Secretoras de Glucagon/metabolismo , Glucagon/metabolismo , Interleucina-6/metabolismo , Pâncreas/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos , Animais Lactentes , Apoptose , Proliferação de Células , Células Cultivadas , Feminino , Glucagon/genética , Células Secretoras de Glucagon/citologia , Células Secretoras de Glucagon/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Masculino , Desnutrição/imunologia , Desnutrição/metabolismo , Desnutrição/patologia , Fenômenos Fisiológicos da Nutrição Materna , Pâncreas/imunologia , Pâncreas/metabolismo , Gravidez , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de Glucagon/genética , Receptores de Glucagon/metabolismo , Transdução de Sinais , Técnicas de Cultura de TecidosRESUMO
Previous comparative studies of fumarate hydratase (FH) protein density revealed that the enzyme was overexpressed in the striatum of rodents that are less influenced by rewarding stimuli, from cocaine to food. Therefore, we recently proposed FH as a potential striatal biomarker of brain reward deficiency and addiction vulnerability. This work has been focused to investigate FH activity in the Nucleus Accumbens (NAc) of undernourished rats, taking into account that malnutrition has been related to increased responsiveness to food and drug reward. To this end, we have studied adult female Wistar rats severely food restricted from the 16th day of intrauterine life until adulthood. Animals were sacrificed to dissect the NAc and obtain mitochondrial and cytosolic fractions after homogenisation and centrifugation. FH activity was measured by conversion of malate to fumarate, and protein levels were compared by Western blot analysis when fractions showed differences in activity. Undernutrition did not change cytosolic FH activity but led to a marked increase of mitochondrial FH activity (72 %) and protein content (50 %) in the NAc. This change was in the opposite direction that one would predict if it was related to addiction vulnerability of some kind, but strongly suggests that mitochondrial FH needs to be at some optimal level for normal reward responsiveness.
Assuntos
Fumarato Hidratase/metabolismo , Desnutrição/enzimologia , Núcleo Accumbens/enzimologia , Animais , Feminino , Ratos , Ratos Wistar , Recompensa , Regulação para CimaRESUMO
Oxidative stress plays an important role in the development of beta-cell dysfunction and insulin resistance, two major pathophysiological abnormalities of type 2 diabetes. Expression levels of antioxidant enzymes in beta cells are very low, rendering them more susceptible to damage caused by reactive oxygen species (ROS). Although the antioxidant effects of glucagon-like peptide-1 (GLP-1) and its analogs have been previously reported, the exact mechanisms involved are still unclear. In this study, we demonstrated that GLP-1 was able to effectively inhibit oxidative stress and cell death of INS-1E beta cells induced by the pro-oxidant tert-butyl hydroperoxide (tert-BOOH). Incubation with GLP-1 enhanced cellular levels of glutathione and the activity of its related enzymes, glutathione-peroxidase (GPx) and -reductase (GR) in beta cells. However, inhibition of ERK, but not of the PI3K/AKT pathway abolished, at least in part, the antioxidant effect of GLP-1. Moreover, ERK activation seems to be protein kinase A (PKA)-dependent because inhibition of PKA with H-89 was sufficient to block the GLP-1-derived protective effect on beta cells. GLP-1 likewise increased the synthesis of GR and favored the translocation of the nuclear transcription factor erythroid 2p45-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Glucose-stimulated insulin secretion was also preserved in beta-cells challenged with tert-BOOH but pre-treated with GLP-1, probably through the down-regulation of the mitochondrial uncoupling-protein2 (UCP2). Thus, our results provide additional mechanisms of action of GLP-1 to prevent oxidative damage in beta cells through the modulation of signaling pathways involved in antioxidant enzyme regulation.
Assuntos
Diabetes Mellitus Tipo 2/genética , Peptídeo 1 Semelhante ao Glucagon/genética , Fator 2 Relacionado a NF-E2/genética , Proteína Desacopladora 2/genética , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , MAP Quinases Reguladas por Sinal Extracelular/genética , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Glucose/metabolismo , Glutationa/biossíntese , Glutationa Redutase/biossíntese , Glutationa Redutase/genética , Humanos , Insulina/metabolismo , Resistência à Insulina/genética , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Isoquinolinas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/genética , Ratos , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia , Proteína Desacopladora 2/metabolismo , terc-Butil Hidroperóxido/metabolismoRESUMO
Catch-up growth has been associated with the appearance of metabolic dysfunctions such as obesity and type 2 diabetes in adulthood. Because the entero-insular axis is critical to glucose homeostasis control, we explored the relevance of the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the development of these pathologies. Offspring of rat dams fed ad libitum (control [C]) or 65% food-restricted during pregnancy and suckling time (undernourished [U]) were weaned onto a high-fat (HF) diet (CHF and UHF, respectively) to drive catch-up growth. Both male and female UHF rats showed an obese phenotype characterized by hyperphagy, visceral fat accumulation, and adipocyte hypertrophy. High-fat diet induced deterioration of glucose tolerance in a sex-dependent manner. Female UHF rats experienced much more severe glucose intolerance than males, which was not compensated by insulin hypersecretion, suggesting insulin resistance, as shown by homeostatic model assessment of insulin resistance values. Moreover, female, but not male, UHF rats displayed enhanced GIP but not GLP-1 secretion during oral glucose tolerance test. Administration of the GIP receptor antagonist (Pro3)GIP to UHF female rats over 21 days markedly reduced visceral fat mass and adipocyte hypertrophy without variations in food intake or body weight. These changes were accompanied by improvement of glucose tolerance and insulin sensitivity. In conclusion, the exacerbated production and secretion of GIP after the catch-up growth seems to represent the stimulus for insulin hypersecretion and insulin resistance, ultimately resulting in derangement of glucose homeostasis. Overall, these data evidence the role of GIP as a critical link between catch-up growth and the development of metabolic disturbances.