Altered regulation of hepatic glucose output in the male offspring of protein-malnourished rat dams

Ozanne, Susan E.; Smith, Geoffrey D.; Tikerpae, J.; Hales, C. N.

doi:10.1152/ajpendo.1996.270.4.e559

Cited by 137 publications

(136 citation statements)

References 25 publications

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“…In vivo the plasma insulin level was lower in LP offspring in response to an oral glucose challenge but in the presence of a normal glucose concentration. This may be explained by the better sensitivity of the target tissues to insulin (34,35,54).…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Increased expression of the insulin receptor [22,23,24] has been observed and this reversed with age [25] possibly providing part of the explanation of the change from increased to decreased insulin sensitivity with age.…”

Section: Studies In Vitromentioning

confidence: 97%

For Debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure*

2003

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“…For example, Petrik et al (1999) demonstrated a low protein diet during pregnancy and weaning induced a decrease in birth weight and disrupted pancreatic b-cell proliferation in the adult offspring. Other studies have found altered glucagon-stimulated and insulinstimulated hepatic glucose output as well as reduced glucokinase expression and structural modifications in the livers of low protein offspring (Ozanne et al 1996, Burns et al 1997. In addition, Chamson-Reig et al (2009) have demonstrated that low protein offspring have impaired glucose tolerance as early as 130 days of age in rat offspring.…”

Section: Introductionmentioning

confidence: 97%

Maternal protein restriction leads to enhanced hepatic gluconeogenic gene expression in adult male rat offspring due to impaired expression of the liver X receptor

Vo¹,

Revesz²,

Sohi³

et al. 2013

Journal of Endocrinology

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Epidemiological studies demonstrate that the link between impaired fetal development and glucose intolerance in later life is exacerbated by postnatal catch-up growth. Maternal protein restriction (MPR) during pregnancy and lactation in the rat has been previously demonstrated to lead to impaired glucose tolerance in adulthood, however the effects of protein restoration during weaning on glucose homeostasis are largely unknown. Recent in vitro studies have identified that the liver X receptor a (LXRa) maintains glucose homeostasis by inhibiting critical genes involved in gluconeogenesis including G6pase (G6pc), 11b-Hsd1 (Hsd11b1) and Pepck (Pck1). Therefore, we hypothesized that MPR with postnatal catch-up growth would impair LXRa in vivo, which in turn would lead to augmented gluconeogenic LXRa-target gene expression and glucose intolerance. To examine this hypothesis, pregnant Wistar rats were fed a control (20%) protein diet (C) or a low (8%) protein diet during pregnancy and switched to a control diet at birth (LP). At 4 months, the LP offspring had impaired glucose tolerance. In addition, LP offspring had decreased LXRa expression, while hepatic expression of 11b-HSD1 and G6Pase was significantly higher. This was concomitant with decreased binding of LXRa to the putative LXRE on 11b-Hsd1 and G6pase. Finally, we demonstrated that the acetylation of histone H3 (K9,14) surrounding the transcriptional start site of hepatic Lxra (Nr1h3) was decreased in LP offspring, suggesting MPR-induced epigenetic silencing of the Lxra promoter. In summary, our study demonstrates for the first time the important role of LXRa in mediating enhanced hepatic gluconeogenic gene expression and consequent glucose intolerance in adult MPR offspring.

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Altered regulation of hepatic glucose output in the male offspring of protein-malnourished rat dams

Cited by 137 publications

References 25 publications

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

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

For Debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure*

Maternal protein restriction leads to enhanced hepatic gluconeogenic gene expression in adult male rat offspring due to impaired expression of the liver X receptor

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