RESUMEN
The increasing prevalence of diabetes is of particular concern in women of childbearing age because of the short and long-term consequences of maternal diabetes for the health of the offspring, such as a greater risk of developing metabolic impairments and cognitive deficits. In addition, maternal diet during pregnancy and lactation might contribute to preventing or ameliorating adverse offspring outcomes. Recently, we described that access to snacks exacerbates glucose intolerance in mildly hyperglycemic pregnant dams. Therefore, we hypothesized that these offspring would show greater impairment in metabolic and behavioral outcomes across the lifespan. Neonatal STZ treatment was employed to induce maternal mild hyperglycemia in females. After mating, normo- and hyperglycemic dams were given access either to standard chow or standard show plus snacks. Male and female offspring were evaluated on postnatal days (PND) 30, 90, and 360. Offspring behavior was assessed in the marble burying task, the open-field test, the elevated-plus maze, and sucrose preference. Glucose tolerance and morphometric analyses were also carried out. Maternal hyperglycemia increased body weight and fat deposition only on PND 30, while retroperitoneal fat deposition was reduced in the offspring of snack-fed dams. However, maternal snack intake reduced offspring body weight and length on PND 90. Fasting glucose was increased in females born to hyperglycemic, snack-fed dams on PND 90. Glucose clearance was altered by both maternal conditions in male offspring on PND 30, however, this sex difference was reversed on PND 90, with maternal hyperglycemia impairing glucose clearance only in females. In addition, maternal hyperglycemia reduced anxiety-like behavior in female offspring on PND 30, especially in the offspring of snack-fed dams, while maternal snack intake reduced sucrose preference in both males and females in adulthood. These results suggest that the effects of maternal hyperglycemia during pregnancy and lactation on offspring outcomes were not exacerbated by snack intake. Although additive effects of the two maternal conditions were hypothesized, the absence of such effects could be related to the mild maternal hyperglycemia induced by STZ treatment even when combined with snack intake. While maternal hyperglycemia alone impaired some offspring outcomes, its association with snack intake did not aggravate those impairments but rather resulted in outcomes more similar to those of offspring born to normoglycemic dams. Finally, females were found to be more susceptible to both the effects of maternal hyperglycemia and snack intake on metabolism and behavior.
Asunto(s)
Diabetes Mellitus , Intolerancia a la Glucosa , Efectos Tardíos de la Exposición Prenatal , Embarazo , Recién Nacido , Femenino , Masculino , Humanos , Bocadillos , Longevidad , Efectos Tardíos de la Exposición Prenatal/metabolismo , Peso Corporal , Glucosa , Sacarosa , Dieta Alta en Grasa/efectos adversos , Fenómenos Fisiologicos Nutricionales MaternosRESUMEN
Introduction: Gestational diabetes (GDM) is associated with negative outcomes in mothers and their offspring, including greater risks of macrosomia at birth and the development of metabolic disorders. While these outcomes are well-established, the mechanisms by which this increased metabolic vulnerability is conferred on the offspring are comparatively lacking. One proposed mechanism is that maternal glycemic dysregulation alters the development of the hypothalamic regions related to metabolism and energy balance. Methods: To investigate this possibility, in this study, we first examined the effects of STZ-induced maternal glucose intolerance on the offspring on pregnancy day (PD) 19, and, in a second experiment, in early adulthood (postnatal day (PND) 60). Whether effects would be influenced by sex, or exposure of offspring to a high-fat diet was also investigated. The impact of maternal STZ treatment on POMC neuron number in the ARC of offspring at both time points was also examined. Results: As expected, STZ administration on PD 7 decreased maternal glucose tolerance, and increased risk for macrosomia, and loss of pups at birth. Offspring of STZ-treated mothers were also more vulnerable to developing metabolic impairments in adulthood. These were accompanied by sex-specific effects of maternal STZ treatment in the offspring, including fewer POMC neurons in the ARC of female but not male infants in late pregnancy and a higher number of POMC neurons in the ARC of both male and female adult offspring of STZ-treated dams, which was exacerbated in females exposed to a high-fat diet after weaning. Discussion: This work suggests that maternal hyperglycemia induced by STZ treatment, in combination with early-life exposure to an obesogenic diet, leads to adult metabolic alterations that correlate with the increased hypothalamic expression of POMC, showing that maternal glycemic dysregulation can impact the development of hypothalamic circuits regulating energy state with a stronger impact on female offspring.
Asunto(s)
Diabetes Gestacional , Intolerancia a la Glucosa , Efectos Tardíos de la Exposición Prenatal , Masculino , Recién Nacido , Embarazo , Humanos , Femenino , Adulto , Macrosomía Fetal , Intolerancia a la Glucosa/etiología , Proopiomelanocortina/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Dieta Alta en Grasa/efectos adversosRESUMEN
Metabolic disorders, like diabetes, as well as maternal diet, alter nutrient availability in utero, inducing adaptations in the offspring. Whether the effects of maternal hyperglycemia are modulated by diet, however, has yet to be explored. In the current study, we examined this issue by giving females rats, treated neonatally with STZ to induce mild hyperglycemia, and control littermates either ad libitum access to standard chow (Control n = 17; STZ n = 16) or standard chow and snacks (Control-snack n = 18; STZ-snack n = 19) (potato chips and a red fruit-flavored sucrose syrup solution 1.5%) throughout pregnancy and lactation. We hypothesized that the maternal glucose intolerance typically seen in female rats treated neonatally with STZ would be exacerbated by snack intake, and that the combination of snack intake and STZ treatment would lead to alterations in maternal behavior and offspring development. Maternal body weight and food intake were measured daily through pregnancy and lactation and litter weight throughout lactation. At birth, litter size, offspring weight, body length, and anogenital distance were obtained and offspring were classified according to their weight. Measures of nursing and retrieval behavior, as well as exploration in the open field and the elevated plus-maze were also recorded. As predicted, snack intake tended to aggravate the glucose intolerance of STZ-treated rats during pregnancy. Both Control and STZ-treated females that had access to snacks ate more calories and fat, but less carbohydrate and protein than females having access to chow alone. Overall, STZ-treated dams gave birth to fewer pups. Chow-fed STZ females gave birth to a greater proportion of large for pregnancy age pups, whereas dams in the Control-snack group gave birth to a greater proportion of small pups. The birth weight classification of pups born to STZ-snack rats, however, resembled that of the Control chow-fed females. Although all litters gained weight during lactation, litters from snack-fed dams gained less weight regardless of maternal hyperglycemia and did not show catch-up growth by weaning. Overall, STZ rats spent more time nest building, whereas the average inter milk ejection interval was higher in snack-fed females. STZ-snack dams retrieved the complete litter faster than dams in the other groups. Together, these data suggest that when mild hyperglycemic females are given access to snacks throughout pregnancy and lactation their intake is similar to that of Control females given snack access. The combination of hyperglycemia and snack access tended to decrease glucose tolerance in pregnancy, and normalized birth weight classification, but produced few other effects that were not seen as a function of snack intake or hyperglycemia alone. Since birth weight is a strong predictor of health issues, future studies will further investigate offspring behavioral and metabolic outcomes later in life.