Abstract
In human and sheep newborns, brown adipose tissue (BAT) accrued during fetal development is used for newborn thermogenesis. Here, we explored the role of maternal melatonin during gestation on the amount and functionality of BAT in the neonate. We studied BAT from six lambs gestated by ewes exposed to constant light from 63% gestation until delivery to suppress melatonin (LL), six lambs gestated by ewes exposed to LL but receiving daily oral melatonin (12 mg at 1700 h, LL + Mel) and another six control lambs gestated by ewes maintained in 12 h light:12 h dark (LD). Lambs were instrumented at 2 days of age. At 4–6 days of age, they were exposed to 24°C (thermal neutrality conditions) for 1 h, 4°C for 1 h, and 24°C for 1 h. Afterward, lambs were euthanized and BAT was dissected for mRNA measurement, histology, and ex vivo experiments. LL newborns had lower central BAT and skin temperature under thermal neutrality and at 4°C, and higher plasma norepinephrine concentration than LD newborns. In response to 4°C, they had a pronounced decrease in skin temperature and did not increase plasma glycerol. BAT weight in LL newborns was about half of that of LD newborns. Ex vivo, BAT from LL newborns showed increased basal lipolysis and did not respond to NE. In addition, expression of adipogenic/thermogenic genes (UCP1, ADBR3, PPARγ, PPARα, PGC1α, C/EBPβ, and perilipin) and of the clock genes Bmal1, Clock, and Per2 was increased. Remarkably, the effects observed in LL newborns were absent in LL + Mel newborns. Thus, our results support that maternal melatonin during gestation is important in determining amount and normal functionality of BAT in the neonate.
Highlights
The unusual profile of melatonin in fetal circulation, provided by the mother during fetal life – and its absence in the early newborn – suggests that maternal melatonin contributes to modulate several functions of key importance in fetal physiology or in preparation for extrauterine life
MELATONIN DEPRIVED NEWBORNS WERE COLDER THAN light:12 h dark (LD) NEWBORNS UNDER THERMAL NEUTRALITY CONDITIONS AND RESPONDED ABNORMALLY TO COLD We measured central, skin, and perirenal fat temperature under thermal neutrality conditions (24°C), and under exposure to 4°C to stimulate facultative thermogenesis. These three temperatures were lower in LL newborns than in LD and LL + Mel newborns under thermal neutrality conditions, suggesting that melatonin deprivation during fetal life affected some mechanisms of thermoregulation in the newborns (Figure 2)
The present experiments investigated the role of maternal melatonin during gestation on preparing the perirenal adipose tissue of newborns lambs for postnatal thermogenesis
Summary
The unusual profile of melatonin in fetal circulation, provided by the mother during fetal life – and its absence in the early newborn – suggests that maternal melatonin contributes to modulate several functions of key importance in fetal physiology or in preparation for extrauterine life. Along these lines, several studies demonstrate a role of maternally derived melatonin in fetal adrenal function, fetal hippocampus, and fetal heart gene expression, and importantly, its prenatal absence has long-term effects in the offspring [1,2,3,4,5]. Since the 24-h mean of the temperature rhythm represents the balance between heat production and heat loss, we speculated that some of these mechanisms were altered by fetal melatonin deprivation
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