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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
.
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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.
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