Prolonged fasting elicits increased hepatic triglyceride accumulation in rats born to dexamethasone-treated mothers
Lucas Carminatti Pantaleão1, Gilson Murata1, Caio Jordão Teixeira2
1Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Insights
Prenatal dexamethasone exposure alters offspring metabolism, causing glucose intolerance under short fasting and improved tolerance with hepatic triglyceride accumulation during prolonged fasting, impacting key metabolic enzymes and pathways.
Area of Science:
- Endocrinology
- Metabolic Research
- Developmental Programming
Background:
- Prenatal exposure to glucocorticoids like dexamethasone can influence offspring development.
- Understanding the long-term metabolic consequences of such exposures is crucial for public health.
Purpose of the Study:
- To investigate the effects of maternal dexamethasone administration during late pregnancy on glucose and lipid metabolism in adult male offspring.
- To examine metabolic responses under both physiological (12-hour) and prolonged (60-hour) fasting conditions.
Main Methods:
- Male offspring from dexamethasone-treated and control rats were assessed at 12 weeks of age.
- Metabolic parameters including glucose tolerance, glucose clearance, and hepatic gene/enzyme expression were measured after fasting periods.
- Analysis included key metabolic enzymes (PEPCK, CS, ACLY, PKM2, LDHA), glucose transporters (GLUT1), and signaling molecules (AKT2) along with miRNA profiling.
Main Results:
- Physiological fasting induced glucose intolerance and impaired glucose clearance in offspring of dexamethasone-treated mothers (DEX).
- Prolonged fasting led to increased glucose tolerance and clearance in DEX offspring, accompanied by significant hepatic triglyceride accumulation.
- DEX offspring exhibited altered expression of genes involved in glycolysis, gluconeogenesis, and lipid metabolism, including increased hepatic AKT2, potentially mediated by reduced targeting miRNAs.
Conclusions:
- Prenatal dexamethasone exposure results in lasting metabolic adaptations in male offspring, characterized by paradoxical responses to fasting durations.
- Hepatic triglyceride accumulation during prolonged fasting in DEX offspring suggests a shift towards lipid utilization and storage.
- The observed metabolic reprogramming, involving key enzymes and signaling pathways like AKT2, highlights the potential for permanent alterations in metabolic regulation due to early-life environmental exposures.
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.
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