Prolonged fasting elicits increased hepatic triglyceride accumulation in rats born to dexamethasone-treated mothers

Lucas Carminatti Pantaleão,Gilson Murata,Gabriel Forato Anhe,Patrícia Rodrigues Gomes,Silvana Bordin,Sandra Campos Rodrigues,Camilo Lellis-Santos,Daniella Esteves Duque-Guimaraes,Caio Jordão Teixeira,Dailson Nogueira De Souza,Junia Carolina Santos-Silva,Juliana Camargo Vieira,Tanyara Baliani Payolla,Frhancielly S Sodré

doi:10.1038/s41598-017-10642-1

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.

Highlights

We investigated the effect of dexamethasone during the last week of pregnancy on glucose and lipid metabolism in male offspring
The present study presents evidence to show that metabolic programming induced by prenatal exposure to dexamethasone-treated mothers (DEX) is characterized by changes in glucose handling that depends on fasting duration
A physiological short-term fast elicits glucose intolerance hallmarked by increased pyruvate conversion into glucose and increased hepatic phosphoenolpyruvate carboxykinase (PEPCK) in rats born to DEX-treated mothers

Summary

Introduction

We investigated the effect of dexamethasone during the last week of pregnancy on glucose and lipid metabolism in male offspring. Physiological fasting resulted in glucose intolerance, decreased glucose clearance after pyruvate load and increased PEPCK expression in rats born to dexamethasone-treated mothers (DEX). Experimental data that support the thrifty phenotype theory have shown that rats born to mothers treated with dexamethasone (DEX) during the last week of pregnancy have impaired glucose tolerance later in life[8, 9]. This effect seems to be relevant for the hepatic metabolic changes found in rats born to DEX-treated mothers, as these animals have increased levels of phosphoenolpyruvate carboxykinase (PEPCK), a limiting enzyme of gluconeogenesis[9]. Data are shown as the mean ± S.E.M.; *p < 0.05 vs. CTL

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Conclusion