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Michael E Symonds, Mark Pope, Ian Bloor, James Law, Reham Alagal, and Helen Budge

Adipose tissue is usually laid down in small amounts in the foetus and is characterised as possessing small amounts of the brown adipose tissue-specific mitochondrial uncoupling protein (UCP)1. In adults, a primary factor determining the abundance and function of UCP1 is ambient temperature. Cold exposure causes activation and the rapid generation of heat through the free flow of protons across the mitochondria with no requirement to convert ADP to ATP. In rodents, housing at an ambient temperature below thermoneutrality promotes the appearance of beige like adipocytes. These arise as discrete regions of UCP1 containing cells in white fat depots. There is increasing evidence to show that to gain credible translational results on brown and beige fat function in rodent models that they should be housed at thermoneutrality. This not only reflects the type of environment in which humans spend a majority of their time, but is in accord with the rise of global temperature caused by industrialisation and the uncontrolled burning of fossil fuels. There is now good evidence in adult humans, that stimulating brown fat can improve glucose homeostasis which can be achieved either by nutritional or pharmacological interventions. The challenge, therefore, is to establish credible developmental models in animals maintained at thermoneutrality which will elucidate the true impact of nutrition. The primary focus should fall specifically on the components of breast milk and how these modulate long term effects on brown or beige fat development and function.

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Michael E Symonds, Peter Aldiss, Neele Dellschaft, James Law, Hernan P Fainberg, Mark Pope, Harold Sacks, and Helen Budge

Although brown adipose tissue (BAT) is one of the smallest organs in the body, it has the potential to have a substantial impact on both heat production as well as fat and carbohydrate metabolism. This is most apparent at birth, which is characterised with the rapid appearance and activation of the BAT specific mitochondrial uncoupling protein (UCP)1 in many large mammals. The amount of brown fat then gradually declines with age, an adaptation that can be modulated by the thermal environment. Given the increased incidence of maternal obesity and its potential transmission to the mother’s offspring, increasing BAT activity in the mother could be one mechanism to prevent this cycle. To date, however, all rodent studies investigating maternal obesity have been conducted at standard laboratory temperature (21°C), which represents an appreciable cold challenge. This could also explain why offspring weight is rarely increased, suggesting that future studies would benefit from being conducted at thermoneutrality (~28°C). It is also becoming apparent that each fat depot has a unique transcriptome and show different developmental pattern, which is not readily apparent macroscopically. These differences could contribute to the retention of UCP1 within the supraclavicular fat depot, the most active depot in adult humans, increasing heat production following a meal. Despite the rapid increase in publications on BAT over the past decade, the extent to which modifications in diet and/or environment can be utilised to promote its activity in the mother and/or her offspring remains to be established.

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Alison Mostyn, Sylvain Sebert, Jennie C Litten, Katharine S Perkins, John Laws, Michael E Symonds, and Lynne Clarke

Neonatal mortality is greater in commercial porcine genotypes, compared with the ancient Meishan breed that rapidly lay down adipose tissue; this may be related to hormones, such as triiodothyronine (T3) or leptin. Leptin is present in maternal milk; however, the extent to which this supply provides the neonate with leptin is unknown, but may play a role in growth and development. We investigated whether thyroid hormones and leptin concentrations in maternal milk differed between genotypes; and whether this influenced piglet concentrations or expression of genes involved in adipose tissue regulation. Eight Meishan and six commercial sows were entered into the study and milk samples from the day of parturition to day 4 postpartum was taken daily. The median birth weight piglet in each litter had a daily venous blood sample taken and was euthanised on day 4. Gene expressions of IGF-I, IGF-binding protein 3 (IGFBP-3), peroxisome proliferators activated receptor (PPAR)γ and glucocorticoid receptor (GR) were measured in adipose tissue using real-time PCR. T3 was increased in Meishan milk, but not in piglet plasma. Milk thyroxine was similar between breeds but commercial piglet levels were significantly higher. Leptin was higher in commercial sow milk throughout the study. Milk leptin was strongly correlated to plasma leptin during the first postnatal days and also to organ and body weight in Meishan piglets that also had significantly higher expression of GR, but not IGF-I, IGFBP-3 or PPARγ. In conclusion, we have found a significant disparity in the provision of thyroid hormones in Meishan and commercial sow’s milk. These changes are not always translated to plasma concentrations of hormone in the piglet. Leptin appears to have a stronger role in growth and development in the Meishan genotype compared with commercial; along with the increased GR expression, this may also represent a potential mechanism behind the rapid accumulation of adipose tissue in Meishan piglets.

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Neele S Dellschaft, Marie-Cecile Alexandre-Gouabau, David S Gardner, Jean-Philippe Antignac, Duane H Keisler, Helen Budge, Michael E Symonds, and Sylvain P Sebert

Maternal caloric restriction during late gestation reduces birth weight, but whether long-term adverse metabolic outcomes of intra-uterine growth retardation (IUGR) are dependent on either accelerated postnatal growth or exposure to an obesogenic environment after weaning is not established. We induced IUGR in twin-pregnant sheep using a 40% maternal caloric restriction commencing from 110 days of gestation until term (∼147 days), compared with mothers fed to 100% of requirements. Offspring were reared either as singletons to accelerate postnatal growth or as twins to achieve standard growth. To promote an adverse phenotype in young adulthood, after weaning, offspring were reared under a low-activity obesogenic environment with the exception of a subgroup of IUGR offspring, reared as twins, maintained in a standard activity environment. We assessed glucose tolerance together with leptin and cortisol responses to feeding in young adulthood when the hypothalamus was sampled for assessment of genes regulating appetite control, energy and endocrine sensitivity. Caloric restriction reduced maternal plasma glucose, raised non-esterified fatty acids, and changed the metabolomic profile, but had no effect on insulin, leptin, or cortisol. IUGR offspring whose postnatal growth was enhanced and were obese showed insulin and leptin resistance plus raised cortisol. This was accompanied by increased hypothalamic gene expression for energy and glucocorticoid sensitivity. These long-term adaptations were reduced but not normalized in IUGR offspring whose postnatal growth was not accelerated and remained lean in a standard post-weaning environment. IUGR results in an adverse metabolic phenotype, especially when postnatal growth is enhanced and offspring progress to juvenile-onset obesity.

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Alison Mostyn, Linda Attig, Thibaut Larcher, Samir Dou, Pascale Chavatte-Palmer, Monia Boukthir, Arieh Gertler, Jean Djiane, Michael E Symonds, and Latifa Abdennebi-Najar

Intrauterine growth restriction (IUGR) may be accompanied by inadequate thermoregulation, especially in piglets that are not considered to possess any brown adipose tissue (BAT) and are thus entirely dependent on shivering thermogenesis in order to maintain body temperature after birth. Leptin can stimulate heat production by promoting non-shivering thermogenesis in BAT, but whether this response occurs in piglets is unknown. Newborn female piglets that were characterised as showing IUGR (mean birth weight of approximately 0.98 kg) were therefore administered injections of either saline or leptin once a day for the first 5 days of neonatal life. The dose of leptin was 0.5 mg/kg, which is sufficient to increase plasma leptin by approximately tenfold and on the day of birth induced a rapid increase in body temperature to values similar to those of normal-sized ‘control’ piglets (mean birth weight of ∼1.47 kg). Perirenal adipose tissue was then sampled from all offspring at 21 days of age and the presence of the BAT-specific uncoupling protein 1 (UCP1) was determined by immunohistochemistry and immunoblotting. UCP1 was clearly detectable in all samples analysed and its abundance was significantly reduced in the IUGR piglets that had received saline compared with controls, but was raised to the same amount as in controls in those IUGR females given leptin. There were no differences in gene expression between primary markers of brown and white adipose tissues between groups. In conclusion, piglets possess BAT that when stimulated exogenously by leptin can promote increased body temperature.