Endocrine regulation of adipose tissue thermogenesis in the fetal and neonatal sheep
Leptin is produced primarily by white adipose tissue but also by brown adipose tissue (BAT) and the placenta. It has a major physiological role in the control of energy balance. BAT is critically important for the initiation of non-shivering thermogenesis in precocial newborns through the uncoupling protein, UCP1 unique to BAT. This is particularly important in neonatal lambs and infants in which levels of UCP1 peak at birth concomitant with a peak in plasma leptin and a surge in Cortisol. Other mitochondrial proteins may contribute to this effect e.g. VDAC which is located in the outer mitochondrial membrane. The aim of this thesis was to: 1. investigate the role of the late gestation Cortisol surge on BAT development 2. investigate the effect of route of delivery on subsequent neonatal plasma leptin concentrations 3. assess the effect of leptin administration to neonatal lambs on thermoregulation Late gestation fetuses were infused with Cortisol or saline or underwent adrenalectomy or sham operation. BAT was sampled at 129 and 144 days of gestation, respectively. UCPl abundance was significantly increased in the animals receiving Cortisol treatment compared to controls and was significantly reduced in adrenalectomised animals. Plasma leptin was analysed from lambs delivered vaginally or near term by caesarean section (CS). Cord plasma leptin decreased significantly after birth, an adaptation that was delayed by CS delivery. Acute and chronic administration of leptin to neonatal lambs improved thermoregulation by preventing a decline in body temperature. Chronic leptin treatment over 7 days (lOOp-g daily) promoted the loss of UCP1 mRNA and protein, but had no deleterious effects on body temperature. Polyclonal antibodies were developed against mitchondrial voltage-dependent anion channel (VDAC). The postnatal ontogeny of VDAC was found to be similar to that of UCP1 and cytochrome c, with abundance peaking around one day of age. VDAC was found in high abundance in organs with high metabolic requirements such as heart, muscle and BAT. These results suggest that VDAC is involved in ensuring BAT maintains a maximal rate of thermogenesis after birth. In conclusion, I have shown for the first time that leptin has an important role in thermogenesis during the transition from fetal to neonatal life. This is attenuated in CS animals, possibly linked to a reduced sympathetic nervous system activity. The rapid loss of UCP1 mRNA, which occurs within the first few days of life, appears to be modulated by leptin, possibly stimulating the development of white adipose tissue and generation of body heat through mechanisms other than nonshivering thermogenesis in BAT. VDAC may be important during this period in ensuring adequate substrate delivery to BAT. Intact adrenal glands are also necessary for the increase in UCP1 abundance during late gestation, an effect mediated in part by Cortisol. NB. This ethesis has been created by scanning the typescript original and may contain inaccuracies. In case of difficulty, please refer to the original text.