Differential effects of leptin on thermoregulation and uncoupling protein abundance in the neonatal lamb

Abstract

As the role of leptin in energy balance in neonate is unknown, we investigated the effect of acute (2 h) and chronic (7 days) administration of leptin (100 microg/day) on thermoregulation and mitochondrial protein abundance in adipose tissue. The concentration of uncoupling protein (UCP)1 and voltage-dependent anion channel (VDAC) located on the inner and outer mitochondrial membranes, respectively, were measured. Administration of leptin prevented the normal decline in colonic temperature over the first few hours and days after birth. It subsequently accelerated the loss of both mRNA and protein for UCP1 but had no effect on VDAC abundance. At seven days of age, colonic temperature was correlated strongly with both mRNA abundance and thermogenic potential of UCP1 in leptin-treated but not control lambs, indicating more effective use of UCP1 for heat production following leptin administration. Leptin had no effect on weight gain or adipose tissue deposition; at one day of age only, leptin mRNA was correlated positively with adipose tissue weight. In conclusion, leptin administration to neonatal lambs improves thermoregulation and promotes the loss of UCP1 in brown adipose tissue.

UCP1 is present in porcine adipose tissue and is responsive to postnatal leptin

“…This could either be a direct response or by promoting the conversion of T 4 to triiodothyronine by the enzyme 5 0 -monodeiodinase within BAT (Hall et al 2010). The effect of leptin on perirenal adipose tissue in piglets appears to persist well after its administration had ceased and the magnitude of responses both acutely on body temperature and in the longer term on UCP1 were much greater than those observed previously in neonatal sheep that were normal sized and female (Mostyn et al 2002). This could be because, in young sheep, the rate of loss of BAT and its subsequent replacement with white adipose tissue are possibly much more rapid when compared with pigs, due in part to the concomitant growth of wool, widening of the thermoneutral zone (Symonds 2013) and replacement of non-shivering with shivering thermogenesis as the dominant response to acute cold exposure (Symonds et al 1989).…”

“…When administered to female postnatal sheep, leptin improves thermoregulation in the newborn and then subsequently promotes the normal loss of UCP1 in the main fat depot (i.e. perirenal) over the first week of life (Mostyn et al 2002). Daily administration of leptin to piglets showing intrauterine growth restriction (IUGR) between day 2 and day 10 after birth can partially rectify this adverse metabolic phenotype although its effects on adipose tissue appear to be confined to white adipocytes (Attig et al 2008).…”

Tissue-specific effects of leptin administration on the abundance of mitochondrial proteins during neonatal development

“…In the human fetus, plasma leptin concentrations increase with gestational age (Yuen et al 1999, Cetin et al 2000. In the newborn sheep, plasma leptin concentrations decline during the immediate 6 h after birth to then increase up to 7 days of age (Bispham et al 2002). These temporal changes in leptin coincide with development of the hypothalamic-pituitary-adrenal axis with respect to the regulation of cortisol production coincident with the rapid activation of uncoupling protein (UCP)-1, which is unique to brown adipose tissue (BAT) (Clarke et al 1997a, Ricquier & Bouillaud 2000, and is followed by the gradual loss of UCP1 (Clarke et al 1997b).…”

“…These temporal changes in leptin coincide with development of the hypothalamic-pituitary-adrenal axis with respect to the regulation of cortisol production coincident with the rapid activation of uncoupling protein (UCP)-1, which is unique to brown adipose tissue (BAT) (Clarke et al 1997a, Ricquier & Bouillaud 2000, and is followed by the gradual loss of UCP1 (Clarke et al 1997b). In the neonatal sheep, leptin administration results in reduced UCP1 mRNA and protein abundance, in conjunction with maintained colonic temperature and plasma non-esterified fatty acid (NEFA) concentration, therefore not affecting thermogenic potential (Mostyn et al 2002). The peak in UCP1 abundance at birth is accompanied by parallel increases in other mitochondrial proteins including the voltage-dependent anion channel (VDAC) located on the outer mitochondrial membrane, and cytochrome c, present within the inter-membrane space (Mostyn et al 2003).…”

“…These changes in body temperature have been linked to increased abundance of UCP1 (Scarpace et al 1997) andUCP2 (Gong et al 1997) in BAT by some studies, but not by others (Memon et al 2000). Moreover, these changes appear to be unique to rodents, as leptin treatment of large mammals, such as sheep and pigs, has been found to have a minor role in thermogenesis (Mostyn et al 2002, Litten et al 2004.…”