RESUMEN
Glucocorticoid (GC) excess promotes adipose tissue accumulation, and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) plays an important role in the local amplification of GC. Therefore, in this study, we investigated the effects of carbenoxolone (CBX), an 11ß-HSD1 inhibitor, on morphological changes in visceral fat, and the expression of genes involved in adipogenesis and lipid metabolism in high-fat (HF) diet-fed mice. Mice were fed a HF diet from 5 weeks of age. At 10 weeks of age, the mice received an intraperitoneal injection of CBX or vehicle every day for 2 weeks. CBX decreased body weight and visceral fat mass, and improved insulin sensitivity in HF-fed mice. This was accompanied by reduced adipocyte size and a decrease in large-sized adipocytes in visceral fat. The expression of adipogenesis (PPARγ and C/EBPα), glucose transport (GLUT4) and lipid metabolism (LPL, ATGL, and HSL)-related genes were suppressed in CBX mice. CBX treatment induced beneficial morphological changes in visceral fat and decreased the expression of adipogenesis, glucose transport and lipid metabolism-related genes. These findings reveal a potential mechanism underling the effects of CBX on reduced fat accumulation and improved insulin sensitivity.
Asunto(s)
Adipogénesis/genética , Tejido Adiposo/anatomía & histología , Tejido Adiposo/metabolismo , Carbenoxolona/farmacología , Regulación hacia Abajo/efectos de los fármacos , Glucosa/metabolismo , Metabolismo de los Lípidos/genética , Adipocitos/citología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipogénesis/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Animales , Transporte Biológico/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Dieta Alta en Grasa , Regulación hacia Abajo/genética , Conducta Alimentaria/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Insulina/metabolismo , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Lipogénesis/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Tamaño de los Órganos/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Intrauterine growth restriction (IUGR) is associated with a substantially greater incidence of metabolic syndrome in adulthood. Animal studies have shown that IUGR offspring are hyperphagic during the early postnatal period and therefore exhibit obesity. The molecular mechanisms underlying food intake regulation in the gastrointestinal tract have not been clarified in IUGR. In the present study, we utilized a rat model of IUGR by restricting the food intake of the mother (50% of the normal intake, ad libitum; FR group) from day 7 of gestation until delivery. Pups from undernourished mothers were fostered by control mothers. We examined the food intake and assessed the gene expressions of ghrelin, peptide YY (PYY), and cholecystokinin (CCK) in the alimentary tract of male newborns (postnatal day1) and adult offspring (age, 7 months). Compared to the offspring whose mothers received the standard diet ad libitum (CON offspring), FR offspring were hyperphagic from the weaning time until the end of the experiment, and resulted in a heavier final weight. Both newborn and adult FR offspring had higher ghrelin gene expression in the stomach and higher ghrelin plasma levels than did the controls. Although the gastrointestinal gene expressions and plasma levels of the anorexic peptides, PYY and CCK, were elevated in the FR newborns, they decreased in the FR adults. Our findings suggest that the altered gene expressions of orexigenic and anorexigenic gut peptides in the gastrointestinal tract in the maternal undernutrition-induced IUGR offspring provide a potential mechanism to explain hyperphagia and obesity seen in these offspring.
Asunto(s)
Colecistoquinina/genética , Retardo del Crecimiento Fetal/genética , Tracto Gastrointestinal/metabolismo , Ghrelina/genética , Hiperfagia/genética , Péptido YY/genética , Regulación hacia Arriba , Adulto , Animales , Animales Recién Nacidos , Peso Corporal , Colecistoquinina/sangre , Modelos Animales de Enfermedad , Ingestión de Alimentos , Femenino , Retardo del Crecimiento Fetal/sangre , Retardo del Crecimiento Fetal/fisiopatología , Tracto Gastrointestinal/crecimiento & desarrollo , Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Ghrelina/sangre , Humanos , Hiperfagia/sangre , Hiperfagia/fisiopatología , Masculino , Péptido YY/sangre , Ratas , Ratas Sprague-DawleyRESUMEN
Peroxisomal proliferator-activated receptors (PPARs) play an important role in the regulation of lipid metabolism. The aim of this study was to investigate the effects of a maternal high-fat (HF) diet on serum lipid concentration and PPAR gene expression in liver and adipose tissue in the early life of the rat offspring. Female Sprague-Dawley rats were fed either an HF or control (CON) diet 6 weeks before mating and throughout gestation and lactation. Blood and tissue samplings of male offspring were carried out at birth or weaning. Birth weights were similar and serum triglyceride (TG) and nonesterified fatty acid (NEFA) levels showed no significant difference between HF and CON newborns, despite greatly increased hepatic PPARα mRNA expression in the HF newborns (p<0.05). Both HF newborns and weanlings revealed significantly decreased hepatic PPARγ expression compared with controls (p<0.0001). Hepatic PPARα expression in the HF weanlings was reduced markedly compared with CON weanlings (p<0.0001) and showed a negative correlation with serum TG levels (r=-0.743, p<0.05). However, epididymal expression of PPARγ in the HF weanlings was upregulated significantly compared with controls (p<0.05) and demonstrated a positive correlation with epididymal fat mass (r=0.733, p<0.05). These were accompanied by obesity as well as a rise in serum TG by 79% (p<0.05) and NEFA concentration by 36% (p<0.05) in these HF weanlings. Our findings suggest that maternal HF diet leads to alterations in PPAR gene expression in the weanling offspring, which is associated with the disturbed lipid homeostasis.