Intrauterine programming of fetal islet gene expression in rats?effects of maternal protein restriction during gestation revealed by proteome analysis

Sparre, Thomas; Reusens, Brigitte; Cherif, H.; Larsen, Martin R.; Roepstorff, Peter; Fey, Stephen J.; Larsen, Peter Mose; Remacle, Claude; Nerup, Jørn

doi:10.1007/s00125-003-1208-3

Cited by 48 publications

(40 citation statements)

References 95 publications

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“…The increased expression of Osr1 could contribute to the higher vulnerability. Ten proteins involved in protein folding and chaperoning were found to be altered by the LP diet in proteomic analyses [20]. The microarray analysis also revealed that increased expression of Hmox2, Prdx3 and Mgmt involved cellular defence and DNA repair.…”

Section: Discussionmentioning

confidence: 96%

“…Previously, we have used proteomics to study fetal rat islet protein expression in animals fed a control or a LP diet, demonstrating that expression of proteins involved in a number of different biological pathways was modified by a maternal LP diet [20]. The present study aimed: (1) to determine the changes in gene expression that are induced by the maternal LP diet and may favour a 'prediabetic phenotype' and (2) to investigate to what extent and by which pathways maternal taurine supplementation restores the normal phenotype.…”

Section: Introductionmentioning

confidence: 99%

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The intrauterine metabolic environment modulates the gene expression pattern in fetal rat islets: prevention by maternal taurine supplementation

et al. 2008

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Aims/hypothesis Events during fetal life may in critical time windows programme tissue development leading to organ dysfunction with potentially harmful consequences in adulthood such as diabetes. In rats, the beta cell mass of progeny from dams fed with a low-protein (LP) diet during gestation is decreased at birth and metabolic perturbation lasts through adulthood even though a normal diet is given after birth or after weaning. Maternal and fetal plasma taurine levels are suboptimal. Maternal taurine supplementation prevents these induced abnormalities. In this study, we aimed to reveal changes in gene expression in fetal islets affected by the LP diet and how taurine may prevent these changes. Methods Pregnant Wistar rats were fed an LP diet (8% [wt/wt] protein) supplemented or not with taurine in the drinking water or a control diet (20% [wt/wt] protein). At 21.5 days of gestation, fetal pancreases were removed, digested and cultured for 7 days. Neoformed islets were collected and transcriptome analysis was performed. Results Maternal LP diet significantly changed the expression of more than 10% of the genes. Tricarboxylic acid cycle and ATP production were highly targeted, but so too were cell proliferation and defence. Maternal taurine supplementation normalised the expression of all altered genes. Conclusions/interpretation Development of the beta cells and particularly their respiration is modulated by the intrauterine environment, which may epigenetically modify expression of the genome and programme the beta cell towards a pre-diabetic phenotype. This mis-programming by maternal LP diet was prevented by early taurine intervention.Keywords Diabetes . Early programming . Fetal islets . Maternal low-protein diet . Rats . Taurine . Transcriptome Abbreviations EST expressed sequence tag LP low protein LPT low-protein diet supplemented with taurine SAM significance analysis of microarrays TCA tricarboxylic acid Diabetologia (2008) 51:836-845

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

The intrauterine metabolic environment modulates the gene expression pattern in fetal rat islets: prevention by maternal taurine supplementation

et al. 2008

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“…In our previous research, we demonstrated that the metabolism of progeny of dams fed an LP diet during gestation was altered (6,10,31,32,47,57). Although the concept of fetal programming is widely accepted (7,12,45,67), the mechanism is unknown, but the influence of early protein restriction on the pancreatic islet mitochondrial function of offspring may be critical (47,57).…”

Section: Discussionmentioning

confidence: 98%

“…Indeed, taurine is a constituent of mitochondrial tRNAs, and the loss of these tRNAs would explain the molecular pathogenesis of some mitochondrial diseases (24,58). In a proteome analysis of fetal LP islets, we found that the level of proteins involved in the mitochondrial energy transfer, glucose metabolism, and RNA and DNA metabolism, was changed (57). Moreover, we have recently shown that an intrauterine LP diet changed the gene expression pattern in fetal islets among which 10% were genes coding for mitochondrial proteins (47).…”

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confidence: 92%

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

Theys

Bouckenooghe

Ahn

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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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...

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“…Lower IGF levels may be involved in the increased vulnerability of fetal islets, since maternal taurine supplementation, which restores beta cell mass and normalises islet vulnerability, rehabilitates IGF levels in the endocrine pancreas [5]. However, other chaperone proteins and proteins involved in the defence mechanism are altered as well and could contribute to the negative picture [30].…”

Section: Discussionmentioning

confidence: 99%

Effect of maternal low-protein diet and taurine on the vulnerability of adult Wistar rat islets to cytokines

et al. 2004

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Aims/hypothesis. A maternal low-protein diet has been shown to induce an increased susceptibility of fetal islets to cytokines, but this effect can be avoided by maternal taurine supplementation. Here, we question whether these effects persist until adulthood in the offspring, despite the animal having a normal diet after weaning. Methods. Pregnant Wistar rats received a diet of either 20% or 8% protein (control [C group] and recuperated [R group] respectively), which was or was not supplemented with taurine (control treated with taurine [CT group] and recuperated treated with taurine [RT group] respectively) during gestation and lactation. When the female offspring reached adulthood, an OGTT was performed. In a second stage, islets were isolated from these offspring, then pretreated or not with taurine, and subsequently treated with cytokines. Results. Fasting glycaemia was higher (p<0.05) and insulinaemia was lower (p<0.01) in the R group than in the C group. Taurine supplementation decreased insulinaemia in the CT group and tended to increase it in the RT group. After the OGTT, glycaemia in R animals was not different from that in the C group, despite a blunted insulin response (p<0.05) which was restored by taurine. Supplementation in C-group mothers led to a weak glucose intolerance. In vitro, more apoptotic cells were observed in R islets after cytokines treatment (p<0.01). The addition of taurine to the culture medium in the R and C groups protected the islets from the cytokines (p<0.01). Maternal taurine supplementation decreased the sensitivity of islets in the RT group (p<0.01), but increased sensitivity in the CT group (p<0.01). Conclusions/interpretation. The increased vulnerability of islets to cytokines due to a restriction of protein during fetal development was still evident when the offspring reached adulthood. The low-protein diet also induced hyperglycaemia in the presence of lower insulinaemia. Taurine supplementation protected adult islets of the R group from cytokine toxicity and restored the insulinaemia. However, unnecessary supplementation of taurine could have detrimental effects.

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Intrauterine programming of fetal islet gene expression in rats?effects of maternal protein restriction during gestation revealed by proteome analysis

Cited by 48 publications

References 95 publications

The intrauterine metabolic environment modulates the gene expression pattern in fetal rat islets: prevention by maternal taurine supplementation

The intrauterine metabolic environment modulates the gene expression pattern in fetal rat islets: prevention by maternal taurine supplementation

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

Effect of maternal low-protein diet and taurine on the vulnerability of adult Wistar rat islets to cytokines

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