Early foetal programming of hepatic gluconeogenesis: glucocorticoids strike back

McCurdy, Carrie E.; Friedman, Jacob E.

doi:10.1007/s00125-006-0256-x

Cited by 10 publications

(4 citation statements)

References 43 publications

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“…Substrate availability was not the problem, because lactate and most of the free amino acids (J. Steinhoff-Wagner, S. Görs, C. C. Metges, and H. M. Hammon, Nutritional Physiology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany, unpublished data) were higher in PT than in T calves. Probably, the low cortisol status in PT calves delayed maturation of endocrine regulation of eGP, which supports previous findings (Seckl, 2004;McCurdy and Friedman, 2006). On the other hand, hyperglycemia in TC calves on d 4 after feeding was combined with the highest postprandial plasma insulin concentrations.…”

Section: Ontogenic Changes Of Hormones and Additional Metabolitessupporting

confidence: 88%

Maturation of endogenous glucose production in preterm and term calves

Steinhoff‐Wagner

Görs

Junghans

et al. 2011

Journal of Dairy Science

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Glucose disposability is often impaired in neonatal calves and even more in preterm calves. The objective of this study was to investigate ontogenic maturation of endogenous glucose production (eGP) in calves and its effects on postnatal glucose homeostasis. Calves (n = 7 per group) were born preterm (PT; delivered by section 9 d before term) or at term (T; spontaneous vaginal delivery), or spontaneously born and fed colostrum for 4 d (TC). Blood samples were taken immediately after birth and before and 2h after feeding at 24h after birth (PT; T) or on d 4 of life (TC) to determine metabolic and endocrine changes. After birth (PT and T) or on d 3 of life (TC), fasted calves were gavaged with deuterium-labeled water to determine gluconeogenesis (GNG) and intravenously infused with [U(13)C]-glucose to measure eGP and glucose oxidation (GOx) in blood plasma. After slaughter at 26h after birth (PT, T) or on d 4 of life (TC), glycogen concentrations in liver and hepatic mRNA concentrations and enzyme activities of pyruvate carboxylase, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase were measured. Preterm calves had the lowest plasma concentrations of cortisol and 3,5,3'-triiodothyronine at birth. Plasma glucose concentrations from d 1 to 2 decreased more, but plasma concentrations of lactate and urea and glucagon:insulin ratio were higher in PT than in T and TC calves. The eGP, GNG, GOx, as well as hepatic glycogen concentrations and PEPCK activities, were lowest in PT calves. Results indicate impaired glucose homeostasis due to decreased eGP in PT calves and maturation of eGP with ontogenic development.

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Section: Ontogenic Changes Of Hormones and Additional Metabolitessupporting

confidence: 88%

Maturation of endogenous glucose production in preterm and term calves

Steinhoff‐Wagner

Görs

Junghans

et al. 2011

Journal of Dairy Science

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“…This has been attributed primarily to the low expression of rate-limiting gluconeogenic enzymes such as G6PC and PEPCK, and their regulatory transcriptional factors, including HNF4 α . 29 , 30 However, premature activation of the gluconeogenic pathway, especially an increase in expression of Hnf4α and Pck1/Pck2 , in fetuses exposed in utero to dexamethasone or to maternal HFD, has been associated with adulthood diabetic symptoms in both rodents and monkeys. 9 , 31 , 32 This suggests that gluconeogenic gene activation before birth may be a common underlying mechanism for fetal programming of adult metabolic diseases.…”

Section: Discussionmentioning

confidence: 99%

H19 lncRNA alters methylation and expression of Hnf4α in the liver of metformin-exposed fetuses

et al. 2017

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Metformin is the most widely used anti-diabetic medication worldwide. However, human and animal studies suggest that prenatal metformin exposure may increase the risk of metabolic disorders in adult offspring, yet the underpinning mechanism remains unclear. Here we report that metformin-exposed mouse fetuses exhibit elevated expression of the H19 long noncoding RNA, which induces hypomethylation and increased expression of hepatocyte nuclear factor 4α (HNF4α). As a transcription factor essential for morphological and functional differentiation of hepatocytes, HNF4α also has an indispensable role in the regulation of expression of gluconeogenic genes. Consistently, H19 overexpression in a human liver cell line leads to decreased methylation and increased expression of Hnf4α, with concomitant activation of the gluconeogenic program. Mechanistically, we show that the methylation change of Hnf4α is induced by H19-mediated regulation of S-adenosylhomocysteine hydrolase. We also provide evidence that altered H19 expression is a direct effect of metformin in the fetal liver. Our results suggest that metformin from the mother can directly act upon the fetal liver to modify Hnf4α expression, a key factor for both liver development and function, and that perturbation of this H19/Hnf4α-mediated pathway may contribute to the fetal origin of adult metabolic abnormalities.

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“…Chronic maternal HFD feeding reprograms the fetal hepatic gluconeogenic pathway. Hepatic gluconeogenesis is normally absent during fetal development, which is primarily attributed to the appearance of the rate-limiting enzyme phosphoenolpyruvate carboxykinase (PCK1) at the time of birth (58)(59)(60)(61)(62). Quantitative PCR demonstrated increased expression in 4 key enzymes in the gluconeogenic pathway in the O-HFD group: glucose 6 phosphatase (G6P), fructose 1,6-bisphosphatase 1 (FBP1), PPARγ coactivator 1α (PGC1A, which encodes PGC1α), and PCK1 (2-tailed Student's t test, Figure 4, A-D).…”

Section: Figurementioning

confidence: 99%

Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates

McCurdy¹,

Bishop²,

Williams³

et al. 2009

J. Clin. Invest.

422

562

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Maternal obesity is thought to increase the offspring's risk of juvenile obesity and metabolic diseases; however, the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Here, we investigated in nonhuman primates the effect of chronic high-fat diet (HFD) on the development of fetal metabolic systems. We found that fetal offspring from both lean and obese mothers chronically consuming a HFD had a 3-fold increase in liver triglycerides (TGs). In addition, fetal offspring from HFD-fed mothers (O-HFD) showed increased evidence of hepatic oxidative stress early in the third trimester, consistent with the development of nonalcoholic fatty liver disease (NAFLD). O-HFD animals also exhibited elevated hepatic expression of gluconeogenic enzymes and transcription factors. Furthermore, fetal glycerol levels were 2-fold higher in O-HFD animals than in control fetal offspring and correlated with maternal levels. The increased fetal hepatic TG levels persisted at P180, concurrent with a 2-fold increase in percent body fat. Importantly, reversing the maternal HFD to a low-fat diet during a subsequent pregnancy improved fetal hepatic TG levels and partially normalized gluconeogenic enzyme expression, without changing maternal body weight. These results suggest that a developing fetus is highly vulnerable to excess lipids, independent of maternal diabetes and/or obesity, and that exposure to this may increase the risk of pediatric NAFLD.

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Early foetal programming of hepatic gluconeogenesis: glucocorticoids strike back

Cited by 10 publications

References 43 publications

Maturation of endogenous glucose production in preterm and term calves

Maturation of endogenous glucose production in preterm and term calves

H19 lncRNA alters methylation and expression of Hnf4α in the liver of metformin-exposed fetuses

Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates

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