Abstract
We examined the mechanisms of chronic liver steatosis after prenatal dexamethasone exposure and whether melatonin rescues adult offspring with liver steatosis. Melatonin rescued prenatal dexamethasone-exposed livers with steatosis in young rats. Sprague-Dawley rats pregnant at gestational day 14–21 were administered with intraperitoneal dexamethasone (DEX) or prenatal dexamethasone and melatonin between gestational day 14 and postnatal day ~120 (DEX+MEL). Chronic programming effects in the liver were assessed at day ~120. Liver steatosis increased in the DEX compared with that in the vehicle group and decreased in the DEX+MEL group (p < 0.05), with no changes in cellular apoptosis. Expression of leptin and its receptor decreased in the DEX (p < 0.05) and increased in the DEX+MEL group (p < 0.05), as revealed by RT-PCR and Western blotting. Tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 expression increased in the DEX group compared with that in the vehicle group and decreased in the DEX+MEL group (p < 0.05). Liver DNA methyltransferase activity and leptin methylation increased in the DEX group (p < 0.05) and decreased in the DEX+MEL group (p < 0.05), with no changes in HDAC activity. Thus, prenatal dexamethasone induces liver steatosis at ~120 days via altered leptin expression and liver inflammation without leptin resistance. Melatonin reverses leptin methylation and expression and decreases inflammation and chronic liver steatosis not via apoptosis or histone deacetylation (HDAC).
Highlights
7% of pregnant women are at risk of preterm delivery
We showed that decreased leptin expression levels in mRNA and proteins, leptin receptor mRNA in the DEX group, and leptin methylation are involved in the process of chronic liver steatosis and are important disease-causing factors
We demonstrated that the administration of melatonin beginning at pregnancy can reverse leptin methylation and its expression in prenatal dexamethasone-exposed adult offspring with chronic liver steatosis
Summary
7% of pregnant women are at risk of preterm delivery. In these cases, the women are routinely treated with glucocorticoids in an attempt to improve neonatal outcome [1,2] by accelerating fetal lung maturation [3,4]. Epigenetic regulation during prenatal life has been shown to result in fatty liver disease in adulthood [7]. This may be the result of depot-specific-programmed alterations in fat metabolism transcriptions in adipose tissue [8,9,10].
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