Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Prolonged fasting elicits increased hepatic triglyceride accumulation in rats born to dexamethasone-treated mothers.
Pantaleão LC
,
Murata G
,
Teixeira CJ
,
Payolla TB
,
Santos-Silva JC
,
Duque-Guimaraes DE
,
Sodré FS
,
Lellis-Santos C
,
Vieira JC
,
de Souza DN
,
Gomes PR
,
Rodrigues SC
,
Anhe GF
,
Bordin S
.
???displayArticle.abstract???
We investigated the effect of dexamethasone during the last week of pregnancy on glucose and lipid metabolism in male offspring. Twelve-week old offspring were evaluated after fasting for 12-hours (physiological) and 60-hours (prolonged). Physiological fasting resulted in glucose intolerance, decreased glucose clearance after pyruvate load and increased PEPCK expression in rats born to dexamethasone-treated mothers (DEX). Prolonged fasting resulted in increased glucose tolerance and increased glucose clearance after pyruvate load in DEX. These modulations were accompanied by accumulation of hepatic triglycerides (TG). Sixty-hour fasted DEX also showed increased citrate synthase (CS) activity, ATP citrate lyase (ACLY) content, and pyruvate kinase 2 (pkm2), glucose transporter 1 (slc2a1) and lactate dehydrogenase-a (ldha) expressions. Hepatic AKT2 was increased in 60-hour fasted DEX, in parallel with reduced miRNAs targeting the AKT2 gene. Altogether, we show that metabolic programming by prenatal dexamethasone is characterized by an unexpected hepatic TG accumulation during prolonged fasting. The underlying mechanism may depend on increased hepatic glycolytic flux due to increased pkm2 expression and consequent conversion of pyruvate to non-esterified fatty acid synthesis due to increased CS activity and ACLY levels. Upregulation of AKT2 due to reduced miRNAs may serve as a permanent mechanism leading to increased pkm2 expression.
Figure 1. Glucose metabolism in 12-hour fasted rats born to DEX-treated mothers. (A) GTT, (B) ITT and (C) PTT were performed in 12-hour fasted CTL (rats born to untreated mothers) and DEX (rats born to DEX-treated mothers) rats. The AUCs were calculated for glucose tests and PTTs. The KITT was calculated for ITTs. (D) Hepatic determination of pck1 and gcpc mRNA was normalized to rpl37a expression. (E) Hepatic determination of PEPCK and G6Pase was normalized to β actin. Data are shown as the mean ± S.E.M.; *p < 0.05 vs. CTL.
Figure 2. Glucose metabolism in 60-hour fasted rats born to DEX-treated mothers. (A) Blood glucose levels were determined at different time points in CTL (rats born to untreated mothers) and DEX (rats born to DEX-treated mothers) rats during a 72-hour fasting period. (B) GTT, (C) ITT and (D) PTT were performed in 60-hour fasted CTL and DEX rats. The AUCs were calculated for glucose tests and PTTs. The KITT was calculated for ITTs. (E) Hepatic determination of pck1 and gcpc mRNA was normalized to rpl37a expression (F) Hepatic determination of PEPCK and G6Pase was normalized to β actin. (G) Circulating insulin was assessed at specific time points during the GTT. Data are shown as the mean ± S.E.M.; *p < 0.05 vs. CTL.
Figure 3. Parameters related to glucose and lipid metabolism in 60-hour fasted rats born to DEX-treated mothers. (A) Serum levels of TGs, NEFA, cholesterol (Chol) and lactate were determined in CTL (rats born to untreated mothers) and DEX (rats born to DEX-treated mothers) rats subjected to a 60-hour fast. (B) One set of liver samples was used to measure glycogen, TGs, NEFA, Chol and lactate. (C, D and E) A second set of liver samples was processed for the determination of enzymatic activity of (C) β-HAD, (D) LDH and (E) CS. (F) TG content was also assessed by staining liver sections with Oil Red O. (G) Hepatic determination of ACLY was normalized to β actin. Data are shown as the mean ± S.E.M.; *p < 0.05 vs. CTL.
Figure 4. Expression of genes related to lipid metabolism and VLDL production in 60-hour fasted rats born to DEX-treated mothers. (A) Liver samples of CTL (rats born to untreated mothers) and DEX (rats born to DEX-treated mothers) rats subjected to a 60-hour fast were processed for determination of cd36, acc, fasn, scd, dgat2, srebf1, YY1, mttp, apoB and sec. 22 mRNA. Data were normalized to rpl37a. (B) CTL and DEX rats fasted for 60 hours were subjected to tyloxapol injection. The serum TG levels were measured at different time points after injection. Data are shown as the mean ± S.E.M.; *p < 0.05 vs. CTL.
Figure 5. Signaling proteins and miRNAs in the liver of 60-hour fasted rats born to DEX-treated mothers. (A–C) One set of liver samples of CTL (rats born to untreated mothers) and DEX (rats born to DEX-treated mothers) rats subjected to a 60-hour fast was processed for western blot detection of (A) pFoxO1 normalized to FoxO1 and (B) AKT2 and (C) Raptor normalized to β-actin. (D and E) Liver samples of CTL and DEX rats fasted for 60 hours was processed for the determination of (D) pkm2 and (E) slc2a1, ldha and ldhb mRNA normalized to rpl37a expression. (F) In silico analysis using 3 available algorithms (TargetScan, miRanda and microT-CDS) was performed to identify miRNAs likely to physically bind to akt2 mRNA to control its expression. (G) Liver samples were also used for miR-34a-5p, miR-34c-5p, miR-124-3-3p, miR-150-5p and miR-449a determination, and the expression of each is normalized to RNU43 expression. Data are shown as the mean ± S.E.M.; *p < 0.05 vs. CTL.
Agarwal,
Predicting effective microRNA target sites in mammalian mRNAs.
2015,
Pubmed
Alp,
Activities of citrate synthase and NAD+-linked and NADP+-linked isocitrate dehydrogenase in muscle from vertebrates and invertebrates.
1976,
Pubmed
Bernardo,
Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function.
2012,
Pubmed
Carbone,
Prenatal dexamethasone exposure potentiates diet-induced hepatosteatosis and decreases plasma IGF-I in a sex-specific fashion.
2012,
Pubmed
Corominas-Faja,
Chemical inhibition of acetyl-CoA carboxylase suppresses self-renewal growth of cancer stem cells.
2014,
Pubmed
DeBerardinis,
The biology of cancer: metabolic reprogramming fuels cell growth and proliferation.
2008,
Pubmed
Dooley,
A critical role for cAMP response element-binding protein (CREB) as a Co-activator in sterol-regulated transcription of 3-hydroxy-3-methylglutaryl coenzyme A synthase promoter.
1999,
Pubmed
Drake,
Prenatal dexamethasone programs expression of genes in liver and adipose tissue and increased hepatic lipid accumulation but not obesity on a high-fat diet.
2010,
Pubmed
FOLCH,
A simple method for the isolation and purification of total lipides from animal tissues.
1957,
Pubmed
Flaveny,
Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis.
2015,
Pubmed
Fu,
Perifosine inhibits mammalian target of rapamycin signaling through facilitating degradation of major components in the mTOR axis and induces autophagy.
2009,
Pubmed
Garofano,
In utero undernutrition impairs rat beta-cell development.
1997,
Pubmed
Garofano,
Effect of ageing on beta-cell mass and function in rats malnourished during the perinatal period.
1999,
Pubmed
Gomes,
Long-term disruption of maternal glucose homeostasis induced by prenatal glucocorticoid treatment correlates with miR-29 upregulation.
2014,
Pubmed
Hales,
Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis.
1992,
Pubmed
Hara,
Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action.
2002,
Pubmed
Harmon,
Binding of sulfosuccinimidyl fatty acids to adipocyte membrane proteins: isolation and amino-terminal sequence of an 88-kD protein implicated in transport of long-chain fatty acids.
1993,
Pubmed
He,
Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1.
2016,
Pubmed
Huang,
Regulation of FOXO protein stability via ubiquitination and proteasome degradation.
2011,
Pubmed
Jiang,
Estrogen regulates miRNA expression: implication of estrogen receptor and miR-124/AKT2 in tumor growth and angiogenesis.
2016,
Pubmed
Leavens,
Akt2 is required for hepatic lipid accumulation in models of insulin resistance.
2009,
Pubmed
Lithell,
Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50-60 years.
1996,
Pubmed
Mehlem,
Imaging of neutral lipids by oil red O for analyzing the metabolic status in health and disease.
2013,
Pubmed
Nemazanyy,
Role of PI3K, mTOR and Akt2 signalling in hepatic tumorigenesis via the control of PKM2 expression.
2013,
Pubmed
Nyirenda,
Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring.
1998,
Pubmed
Ono,
Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element binding protein involvement.
2003,
Pubmed
Panasyuk,
PPARγ contributes to PKM2 and HK2 expression in fatty liver.
2012,
Pubmed
Phillips,
Thinness at birth and insulin resistance in adult life.
1994,
Pubmed
Phillips,
Fetal growth and insulin secretion in adult life.
1994,
Pubmed
Porstmann,
SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth.
2008,
Pubmed
Postic,
Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice.
2008,
Pubmed
Rodrigues,
Selective regulation of hepatic lipid metabolism by the AMP-activated protein kinase pathway in late-pregnant rats.
2014,
Pubmed
Rui,
Energy metabolism in the liver.
2014,
Pubmed
Sanchez,
Cooperation by sterol regulatory element-binding protein and Sp1 in sterol regulation of low density lipoprotein receptor gene.
1995,
Pubmed
Schwitzgebel,
Modeling intrauterine growth retardation in rodents: Impact on pancreas development and glucose homeostasis.
2009,
Pubmed
Shelness,
Very-low-density lipoprotein assembly and secretion.
2001,
Pubmed
Siddiqi,
The identification of the SNARE complex required for the fusion of VLDL-transport vesicle with hepatic cis-Golgi.
2010,
Pubmed
Sugden,
Maternal glucocorticoid treatment modulates placental leptin and leptin receptor expression and materno-fetal leptin physiology during late pregnancy, and elicits hypertension associated with hyperleptinaemia in the early-growth-retarded adult offspring.
2001,
Pubmed
Sun,
Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth.
2011,
Pubmed
Toledo,
Influence of hepatic steatosis (fatty liver) on severity and composition of dyslipidemia in type 2 diabetes.
2006,
Pubmed
Verschoor,
Glucose and fructose feeding lead to alterations in structure and function of very low density lipoproteins.
1985,
Pubmed
Yang,
Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation.
2011,
Pubmed
Yang,
ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect.
2012,
Pubmed
Yecies,
Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways.
2011,
Pubmed
