Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat

Abstract

Theys N, Bouckenooghe T, Ahn M-T, Remacle C, Reusens B. Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat. Am J Physiol Regul Integr Comp Physiol 297: R1516 -R1525, 2009. First published September 16, 2009; doi:10.1152/ajpregu.00280.2009.-Mitochondrial dysfunction may be a long-term consequence of a poor nutritional environment during early life. Our aim was to investigate whether a maternal low-protein (LP) diet may program mitochondrial dysfunction in islets of adult progeny before glucose intolerance ensues. To address this, pregnant Wistar rats were fed isocaloric diets containing either 20% protein (control) or 8% protein (LP diet) throughout gestation. From birth, offspring received the control diet. The mitochondrial function was analyzed in islets of 3-mo-old offspring. Related to their basal insulin release, cultured islets from both male and female LP offspring presented a lower response to glucose challenge and a blunted ATP production compared with control offspring. The expression of malate dehydrogenase as well as the subunit 6 of the ATP synthase encoded by mitochondrial genome (mtDNA) was lower in these islets, reducing the capacity of ATP production through the Krebs cycle and oxidative phosphorylation. However, mtDNA content was unchanged in LP islets compared with control. Several consequences of protein restriction during fetal life were more marked in male offspring. Only LP males showed an increased reactive oxygen species production associated with a higher expression of mitochondrial subunits of the electron transport chain NADH-ubiquinone oxireductase subunit 4L, an overexpression of peroxisome proliferator-activated receptor-␥ and uncoupling protein-2, and a strongly reduced beta-cell mass. In conclusion, mitochondrial function is clearly altered in islets from LP adult offspring in a sex-specific manner. That may provide a cellular explanation for the earlier development of glucose intolerance in male than in female offspring of dams fed an LP diet. developmental programming; malnutrition; metabolic syndrome; insulin secretion EPIDEMIOLOGICAL AND EXPERIMENTAL evidence shows a convincing relationship between a poor intrauterine nutritional environment and the subsequent development of metabolic disorders like insulin resistance, obesity, and cardiovascular disease in adulthood (11,12). The original concept of fetal programming of Type 2 diabetes mellitus (T2DM) was proposed by Hales et al. (12) who found in a cohort of adult men who had been smaller at birth that they were six times more prone to develop T2DM compared with individuals heavier at birth. These first epidemiological clues of programming have been largely replicated in many studies throughout the world (17, 27, 61). Currently, this concept is widely accepted, but the mechanistic basis is unclear.Recently, attention has focused on the involvement of mitochondria as putative targets linking physiological and molecular consequences of environmental disorders du...

Resveratrol reduces lipid peroxidation and increases sirtuin 1 expression in adult animals programed by neonatal protein restriction

“…The higher TAC found in LPHCprogramed animals is in agreement with previous studies showing that protein restriction during lactation induced an up-regulation of antioxidant defense capacity at adulthood, represented by increased expression of kidney antioxidant enzymes: glutathione peroxidase and glutathione reductase in 3-month-old rats and glutathione peroxidase, glutathione reductase, and manganese SOD in 1-year-old rodents (Tarry-Adkins et al 2007, Chen et al 2009a. On the other hand, other studies had associated protein restriction during neonatal life with increased oxidative stress and related detrimental effects (Fetoui et al 2009, Theys et al 2009. It has been shown that low-protein diets during gestation or gestation and lactation could predispose to pancreatic islet dysfunction later in life by an imbalance between higher concentration of superoxide radical-inactivating enzymes (SOD) and very low concentration of hydrogen peroxideinactivating enzymes (CAT and GPX) in islets of the progeny in 3-month-old rats (Theys et al 2009).…”

“…On the other hand, other studies had associated protein restriction during neonatal life with increased oxidative stress and related detrimental effects (Fetoui et al 2009, Theys et al 2009. It has been shown that low-protein diets during gestation or gestation and lactation could predispose to pancreatic islet dysfunction later in life by an imbalance between higher concentration of superoxide radical-inactivating enzymes (SOD) and very low concentration of hydrogen peroxideinactivating enzymes (CAT and GPX) in islets of the progeny in 3-month-old rats (Theys et al 2009). In addition, proteinrestricted diet given to mothers during late pregnancy and early postnatal periods induced oxidative stress in their pups on postnatal d14 (Fetoui et al 2009).…”

Maternal calorie restriction modulates placental mitochondrial biogenesis and bioenergetic efficiency: putative involvement in fetoplacental growth defects in rats

“…Finally, mitochondrial compensatory mechanisms would likely be mobilized in several organs of FR30 fetuses, and we can postulate that fetal organ mitochondrial abnormalities might persist in adult FR30 rats. In accord with this hypothesis, long-term mitochondrial dysfunctions have been demonstrated in the pancreatic ␤-cells of rats prenatally exposed to a low-protein diet (28,32). To conclude, growing evidence suggests that mitochondrial dysfunctions may be implicated in several metabolic diseases, such as type 2 diabetes (21), obesity (18), and vascular diseases (27), and our present findings suggest that placental mitochondrial defects may also be implicated in part in the etiology of fetal growth restriction.…”

Effects of moderate global maternal nutrient reduction on fetal baboon renal mitochondrial gene expression at 0.9 gestation

“…Using a maternal low-protein diet rat model, the expression of malate dehydrogenase, as well as the mitochondrial DNA-encoded subunit 6 of ATP synthase, was lower in the pancreatic islets, reducing the capacity of ATP production through mitochondrial oxidative metabolism. Interestingly, in agreement with our results, several consequences of protein restriction during fetal life were more marked in male offspring (60).…”