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

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.

Fructose Consumption by Adult Rats Exposed to Dexamethasone In Utero Changes the Phenotype of Intestinal Epithelial Cells and Exacerbates Intestinal Gluconeogenesis

“…As reported by us in previous studies [ 16 , 33 ], rats born to DEX-treated mothers displayed reduced birth weight (18% lower than CTL; p = 0.033) ( Figure 1 A). The body weights of the 40 h fasted offspring with 160 days of age were influenced by both in utero exposure to DEX and treatment with 10% fructose ( p < 0.0001 and p = 0.0002, respectively).…”

“…In utero exposure to DEX is well known for programming metabolic changes in the adult offspring of rats. The metabolic imprinting caused by excessive exposure to DEX during fetal life is hallmarked by glucose intolerance, increased whole-body gluconeogenesis, and upregulation of PEPCK expression in the liver [ 17 , 33 , 34 ]. Recently, we have also described that in utero exposure to DEX exacerbates hepatic steatosis caused by fructose consumption during adult life [ 16 ].…”

In Utero Dexamethasone Exposure Exacerbates Hepatic Steatosis in Rats That Consume Fructose During Adulthood

“…Although the DOHaD concept has initially focused on the nutritional status during pregnancy, fetal overexposure to glucocorticoids—a common feature of maternal undernutrition, maternal stress, and poor fetal blood supply—has also been shown to play a central role in the metabolic programming of the offspring [15]. For example, previous studies demonstrated that in utero dexamethasone (DEX) exposure favors hepatic steatosis in the adult offspring subjected to either food deprivation or excess fat intake [16,17,18]. It is also worth noting that exposure to antenatal glucocorticoids is far from being an exclusively experimental condition, since its use is a common medical approach for increasing the pre-term survival rate [19].…”

Maternal Obesity in Mice Exacerbates the Allergic Inflammatory Response in the Airways of Male Offspring

“…RNA purity (260/280 and 260/230 ratios) and concentration were calculated using a NanoDrop 2000 spectrophotometer (Thermo Scientific, Waltham, MA, USA) and subjected to poly(A) tailing and reverse transcription with an annealed adaptor (5 -GGCCACGCGTCGACTAGTAC(T)12-3 ) as previously described [21]. PCRs were conducted using KAPA SYBR ® FAST qPCR Master Mix (Kapa Biosystems, Inc., Boston, MA, USA) in a StepOnePlus Real-Time PCR System (Applied Biosystems, Foster City, CA, USA), using adhesive-sealed plates.…”