L. Clarke

ADIPOSE TISSUE DEVELOPMENT DURING EARLY POSTNATAL LIFE IN EWE-REARED LAMBS

This study examines the precise time course that brown adipose tissue (BAT) takes to adopt the characteristics of white adipose tissue in postnatal lambs. Perirenal adipose tissue was sampled from ewe‐reared lambs within 1 h of birth and at 1, 2, 4, 7, 14, 21 and 30 days of age and analysed for the amount of mRNA for uncoupling protein (UCP), the amount and activity of UCP, and protein, mitochondrial protein and lipid content. This was combined with measurements of colonic temperature and jugular venous plasma concentrations of thyroid hormones and insulin‐like growth factor‐1 (IGF‐1). Over the first 4‐7 days of age, large quantities of UCP mRNA were associated with a peak in plasma triiodothyronine concentration at 2 days of age followed by a maximal amount and activity of UCP at 4 days and a basal colonic temperature of 39.3 degrees C. Between 7 and 30 days there was a large increase in lipid deposition as the amount and activity of UCP and the amount of UCP mRNA declined to basal values and colonic temperature was maintained at 40 degrees C. A significant positive relationship between perirenal adipose tissue lipid content and plasma IGF‐1 concentration was observed throughout the study period. It is concluded that ovine adipose tissue maturation occurs in two distinct phases over the first month of life. The precise time scale of this process could be regulated in part by the lambs body temperature which determines whether adipose tissue is required for heat production (i.e. BAT) or as an endogenous energy source (i.e. white adipose tissue).

The influence of maternal nutrient restriction in early to mid-pregnancy on placental and fetal development in sheep

Placental weight is a primary factor determining size at birth in many species. In sheep, placental weight peaks at approximately mid-gestation, with structural remodelling occurring over the second half of pregnancy to meet the increasing nutritional demands of the growing fetus. Numerous factors influence placental growth and development in sheep, and many workers (see Kelly, 1992) have investigated the role of maternal nutrition as a regulator of placental and fetal size. We have studied the effects of feeding ewes approximately 50% of their recommended energy requirements during early to mid-pregnancy on fetal and placental indices measured at mid-gestation (i.e. 80 d) and close to term (i.e. 145 d). Maternal nutrient restriction is associated with a reduction in placental weight at 80 d, but an increase in placental weight at 145 d of gestation, compared with ewes fed adequately in early pregnancy. No significant effect on fetal weight was observed at either 80 or 145 d gestation, although differences in body dimensions and the insulin-like growth factor-1 axis were found in lambs from nutrient-restricted ewes delivered close to term. Maternal nutrition during pregnancy plays a pivotal role in the regulation of fetal and placental development in sheep, and therefore has the potential to influence both short- and longer-term health outcomes.

Nutrition, temperature and homeostasis during perinatal development

Introduction 907 The maternal environment and fetal development 908 Maternal nutrition and fetal lung growth 911 Fetal metabolism 913 Placetal inhibitory factors 915 Adenosine 915 Prostaglandin E2 916 Fetal stimulatory factors 917 Thyroid hormones 917 Catecholamines 917 Ontogeny of fetal brown adipose tissue 918 Birth 920 Caesarean section delivery 922 Environmental temperature and metabolic adaptation after birth 923 Postnatal development 925 Thyroid hormones and the control of metabolism during postnatal life 926 Nutritional and environmental influences on postnatal metabolism and growth 929 Postnatal metabolism and breathing control 931 Conclusion 932 References 933

Maternal dexamethasone administration and the maturation of perirenal adipose tissue of the neonatal sheep

Maternal dexamethasone administration promotes fetal maturation such that thermoregulation is improved following premature delivery and is thus comparable with a full term birth. In the present study we determined the impact of dexamethasone on both the mothers’ metabolic status together with adipose tissue function in the newborn. Glucocorticoid action, adipokine gene expression and mitochondrial protein abundance were measured in perirenal adipose tissue of neonatal sheep that were born into either a warm (30oC) or cool (15oC) ambient temperature at 140 days of gestation (dGA; term ~147 dGA), either two days after maternal dexamethasone administration, or at 146 dGA for controls. Dexamethasone administration resulted in a reduction in maternal food intake in conjunction with raised plasma cortisol and free triiodothyronine. In offspring of dexamethasone administered mothers, plasma cortisol was lower and non-esterified fatty acids (NEFA) higher than controls. Glucocorticoid receptor (GR), 11β-hydroxysteroid dehydrogenase (11β-HSD1), interleukin-6 and uncoupling protein (UCP)1 and 2 mRNA together with voltage dependent anion channel, cytochrome c protein and UCP1 abundance were all increased by dexamethasone administration and being born into a cool ambient temperature. Gene expression of tumor necrosis factor α, adiponectin and peroxisome proliferator-activated receptor transcription factor γ were unaffected by dexamethasone. The abundance of mRNA for the GR, 11β-HSD1, UCP1 and 2 mRNA together with each protein were positively correlated to plasma NEFA and negatively correlated to plasma cortisol. In conclusion, despite reduced maternal food intake dexamethasone promotes maturation of glucocorticoid action and mitochondrial protein abundance in the newborn, an adaptation dependent on delivery temperature.

EFFECT OF REARING TEMPERATURE ON PERIRENAL ADIPOSE TISSUE DEVELOPMENT AND THERMOREGULATION FOLLOWING METHIMAZOLE TREATMENT OF POSTNATAL LAMBS

This study examined the effect of ambient temperature on perirenal adipose tissue development and thermoregulation over the first month of postnatal life in lambs treated with a drug that reduces thyroid hormone synthesis (methimazole; at a dose of 50 mg day‐1 (kg body weight)‐1). Twin lambs were hand‐reared at a fixed level of nutrition in either a warm (WR; 25 degrees C) or cool (CR; 10‐15 degrees C) ambient temperature. Oxygen consumption, heart rate and colonic temperature were measured during non‐rapid eye movement sleep in different ambient temperatures (6, 15, 25 and 34–36 degrees C) at 7, 14 and 28 days of age. Plasma thyroid hormone concentrations decreased with postnatal age and were higher in CR than in WR lambs. All lambs increased plasma thyroid hormone concentrations and O2 consumption during cold exposure but this was associated with a mean increase in colonic temperature in WR lambs at 7 or 28 days. Colonic temperature increased with the onset of panting at all ages when lambs were exposed to 34–36 degrees C, a response that was greatest at 28 days in CR lambs. An increase in colonic temperature with age was observed in CR but not WR lambs. Heart rate declined with age only in the WR group. At 8 and 29 days there were no significant differences between WR and CR groups in the occurrence of shivering or in the thermogenic activity (i.e. GDP binding to mitochondria) of perirenal adipose tissue. At 29 days WR lambs possessed more adipose tissue with a higher lipid and DNA content. It is concluded that modest changes in rearing temperature can have a large influence on the control of body temperature and thyroid hormone response to methimazole treatment. CR lambs are able to maintain higher plasma thyroid hormone concentrations and exhibit improved thermoregulation compared with WR lambs without any detectable differences in brown adipose tissue function.

Effect of maternal nutrient restriction in early to mid gestation and thyrotrophin-releasing hormone on lamb survival following Caesarean section delivery near to term

We investigated the influence of restricted maternal nutrition between 28 and 77 days gestation on survival and thermoregulatory adaptation following Caesarean section delivery near to term. This study was designed to examine the hypothesis that adaptation after birth would be compromised in those lambs born to nutrient restricted ewes. We further hypothesised that this would be due in part to inadequate hypothalamic-pituitary-thyroidal function. Lambs born to nutrient restricted ewes were untreated (RU) or treated with thyrotrophin-releasing hormone (TRH; RT) immediately prior to umbilical cord clamping. Single bearing ewes consumed either 6.60 MJ x day(-1) (controls, n = 4) or 3.00 MJ x day(-1) (nutrient restricted, n = 15) from 28-77 days gestation, after which all ewes consumed 7.20 MJ x day(-1). All lambs born to control ewes commenced continuous breathing and began to shiver following Caesarean section delivery and survived to 6 h after birth. Only 4 out of 9 RU lambs established continuous breathing and survived to 6 h after birth compared with all RT lambs. Six hours after birth, RT lambs possessed perirenal brown adipose tissue with a higher thermogenic activity than 6 h old RU or control lambs. Lamb birth weight was similar in all groups. In conclusion, near-term lambs born to ewes nutrient restricted in early to mid gestation are at increased risk of death following Caesarean section delivery. Survival after birth can be significantly enhanced if TRH is administered to the lambs immediately before delivery.

Influence of Thyrotrophin‐Releasing Hormone on Thermoregulatory Adaptation after Birth in Near‐Term Lambs Delivered by Caesarean Section

We investigated the hypothesis that exogenous stimulation with thyrotrophin‐releasing hormone (TRH) immediately prior to umbilical cord clamping can improve thermoregulatory adaptation after birth in near‐term lambs delivered by Caesarean section. Lambs received an umbilical vein injection of saline ± TRH (8 μg) prior to cord clamping. The rate of change in colonic temperature and oxygen consumption after birth were not influenced by TRH, but TRH‐treated lambs exhibited a greater incidence of shivering compared with controls over the first hour of neonatal life. Two and a half hours after birth, TRH‐treated lambs possessed brown adipose tissue (BAT) with a higher thermogenic activity (i.e. GDP binding to mitochondrial protein), but their BAT had a reduced DNA content and they had less hepatic glycogen than control lambs. TRH administration had no effect on iodothyronine 5′ deiodinase activity in BAT and liver, or on plasma concentrations of total triiodothyronine, thyroxine, cortisol or free fatty acids. Three TRH‐treated but no control lambs, failed to establish continuous breathing, so tissues from these treated lambs together with time‐matched controls were sampled 25 min after birth. These ‘non‐surviving’ TRH‐treated lambs had very high plasma catecholamine concentrations, but their lung weights were similar to controls. ‘Surviving’ TRH‐treated lambs possessed lungs with less DNA than non‐surviving TRH‐treated lambs. It is concluded that umbilical vein injection of TRH prior to umbilical cord clamping increases the recruitment of both shivering and non‐shivering thermogenesis after birth.