Impact of Maternal Melatonin Suppression on Amount and Functionality of Brown Adipose Tissue (BAT) in the Newborn Sheep

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.

Melatonin multiple effects on brown adipose tissue molecular machinery

“…The results seen in Ucp1 gene and protein expressions in PINX animals are possibly due to time disorganization of the transcription factors Pgc1α and Cidea expression, which presented rhythmicity in this group, differently from the observed in the other groups. Studies showed Ucp1, Pgc1α, and melatonin interaction in WAT browning and BAT fetal programming . Although using different models, our data reinforce the possibility of melatonin regulating role on Pgc1α and, consequently, Ucp1 expression.…”

“…Studies showed Ucp1, Pgc1α, and melatonin interaction in WAT browning 82 and BAT fetal programming. 89 Although using different models, our data reinforce the possibility of melatonin regulating role on Pgc1α and, consequently, Ucp1 expression.…”

Simulated shift work disrupts maternal circadian rhythms and metabolism, and increases gestation length in sheep

“…) and reduces the amount of brown adipose tissue and impairs thermoregulation in newborn lambs (Seron‐Ferre et al . ).…”

“…There may also be consequences for SSW lambs immediately after birth. A lack of rhythmic maternal melatonin secretion affects the phase of newborn temperature rhythms in capuchin monkeys (Serón-Ferré et al 2013) and reduces the amount of brown adipose tissue and impairs thermoregulation in newborn lambs (Seron-Ferre et al 2014). J Physiol 597.7 Melatonin concentrations measured during the dark decreased across pregnancy, independent of treatment group.…”

60 YEARS OF NEUROENDOCRINOLOGY: Regulation of mammalian neuroendocrine physiology and rhythms by melatonin

“…Melatonin became a focus of research on maternal-foetal signalling, due to its robust circadian rhythm and its lipophilic nature, which allows it to cross the placenta (Reppert et al 1979, Yellon & Longo 1987, Zemdegs et al 1988) and even pass into milk (Reppert & Klein 1978, Illnerova et al 1993. In addition to the following examples, evidence indicates effects of maternal melatonin on foetal and neonatal endocrine physiology outside of the scope of this review, including the regulation of adrenal gland (Torres-Farfan et al 2011) and adipose tissue (Seron-Ferre et al 2014) function.…”