Selenium promotes adipogenic determination and differentiation of chicken embryonic fibroblasts with regulation of genes involved in fatty acid uptake, triacylglycerol synthesis and lipolysis.

Selenium (Se) has been utilized in the differentiation of primary pig and rat preadipocytes, indicating that it may have proadipogenic potential; however, some studies have also demonstrated that Se has antiadipogenic activity. In this study, chicken embryonic fibroblasts (CEFs) were used to investigate the role of Se in adipogenesis in vitro and in ovo. Se supplementation increased lipid droplet accumulation and inhibited proliferation of cultured CEFs isolated from 6-day-old embryos dose-dependently. This suggests that Se may play a role in cell cycle inhibition, thereby promoting the differentiation of fibroblasts to adipocytes. Se did not stimulate adipogenic differentiation of CEFs isolated from 9- to 12-day-old embryos, implying a permissive stage of adipogenic determination by Se at earlier embryonic ages. Microarray analysis comparing control and Se treatments on CEFs from 6-day-old embryos and confirmatory analysis by quantitative real-time polymerase chain reaction revealed that genes involved in adipocyte determination and differentiation, fatty acid uptake and triacylglycerol synthesis were up-regulated. In addition, up-regulation of an anti-lipolytic G0/G1 switch gene 2 and down-regulation of a prolipolytic monoglyceride lipase may lead to inhibition of lipolysis by Se. Both osteogenic and myogenic genes were down-regulated, and several genes related to oxidative stress response during adipogenesis were up-regulated. In ovo injection of Se at embryonic day 8 increased adipose tissue mass by 30% and caused adipocyte hypertrophy in 17-day-old chicken embryos, further supporting the proadipogenic role of Se during the embryonic development of chickens. These results suggest that Se plays a significant role in several mechanisms related to adipogenesis.

Transcriptional profiling of hypothalamus during development of adiposity in genetically selected fat and lean chickens.

The hypothalamus integrates peripheral signals to regulate food intake, energy metabolism, and ultimately growth rate and body composition in vertebrates. Deviations in hypothalamic regulatory controls can lead to accumulation of excess body fat. Many regulatory genes involved in this process remain unidentified, and comparative studies may be helpful to unravel evolutionarily conserved mechanisms controlling body weight and food intake. In the present study, divergently selected fat (FL) and lean (LL) lines of chickens were used to characterize differences in hypothalamic gene expression in these unique genetic lines that develop differences in adiposity without differences in food intake or body weight. Hypothalamic transcriptional profiles were defined with cDNA microarrays before and during divergence of adiposity between the two lines. Six differentially expressed genes identified in chickens are related to genes associated with control of body fat in transgenic or knockout mice, supporting the importance of these genes across species. We identified differences in expression of nine genes involved in glucose metabolism, suggesting that alterations in hypothalamic glycolysis might contribute to differences in levels of body fat between genotypes. Expression of the sweet taste receptor (TAS1R1), which in mammals is involved in glucose sensing and energy uptake, was also higher in FL chickens, suggesting that early differences in glucose sensing might alter the set point for subsequent body composition. Differences in expression of genes associated with tumor necrosis factor (TNF) signaling were also noted. In summary, we identified alterations in transcriptional and metabolic processes within the hypothalamus that could contribute to excessive accumulation of body fat in FL chickens in the absence of differences in food intake, thereby contributing to the genetic basis for obesity in this avian model.

Impacts of amino acid nutrition on pregnancy outcome in pigs: mechanisms and implications for swine production.

Pigs suffer up to 50% embryonic and fetal loss during gestation and exhibit the most severe naturally occurring intrauterine growth retardation among livestock species. Placental insufficiency is a major factor contributing to suboptimal reproductive performance and reduced birth weights of pigs. Enhancement of placental growth and function through nutritional management offers an effective solution to improving embryonic and fetal survival and growth. We discovered an unusual abundance of the arginine family of AA in porcine allantoic fluid (a reservoir of nutrients) during early gestation, when placental growth is most rapid. Arginine is metabolized to ornithine, proline, and nitric oxide, and these compounds possess a plethora of physiological functions. Nitric oxide is a vasodilator and angiogenic factor, whereas both ornithine and proline are substrates for placental synthesis of polyamines, which are key regulators of protein synthesis and angiogenesis. Additionally, arginine, leucine, glutamine, and proline activate the mammalian target of rapamycin cell-signaling pathway to enhance protein synthesis and cell proliferation in placentae. To translate basic research on AA biochemistry and nutrition into application, dietary supplementation with 0.83% l-arginine to gilts on d 14 to 28 or d 30 to 114 of gestation increased the number and litter birth weight of live-born piglets. In addition, supplementing the gestation diet with 0.4% l-arginine plus 0.6% l-glutamine enhanced the efficiency of nutrient utilization, reduced variation in piglet birth weight, and increased litter birth weight. By regulating syntheses of nitric oxide, polyamines, and proteins, functional AA stimulate placental growth and the transfer of nutrients from mother to embryo or fetus to promote conceptus survival, growth, and development.

Maternal vitamin D in pregnancy may influence not only offspring bone mass but other aspects of musculoskeletal health and adiposity.

Osteoporotic fractures, falls and obesity are major health problems in developed nations. Evidence suggests that there are antenatal factors predisposing to these conditions. Data are emerging from Australia and elsewhere to suggest that maternal vitamin D status in pregnancy affects intrauterine skeletal mineralisation and skeletal growth together with muscle development and adiposity. Given that low levels of vitamin D have been documented in many urbanised populations, including those in countries with abundant sunlight, an important issue for public health is whether maternal vitamin D insufficiency during pregnancy has adverse effects on offspring health. The developing fetus may be exposed to low levels of vitamin D during critical phases of development as a result of maternal hypovitaminosis D. We hypothesise that this may have adverse effects on offspring musculoskeletal health and other aspects of body composition. Further research focused on the implications of poor gestational vitamin D nutrition is warranted as these developmental effects are likely to have a sustained influence on health during childhood and in adult life. We suggest that there is a clear rationale for randomised clinical trials to assess the potential benefits and harmful effects of vitamin D supplementation during pregnancy.

Metabolic syndrome: effects of n-3 PUFAs on a model of dyslipidemia, insulin resistance and adiposity.

Both genetic and environmental factors (e.g. nutrition, life style) contribute to the development of the plurimetabolic syndrome, which has a high prevalence in the world population. Dietary n-3 PUFAs specially those from marine oil (EPA and DHA) appear to play an important role against the adverse effects of this syndrome. The present work examined the effectiveness of fish oil (FO) in reversing or improving the dyslipidemia, insulin resistance and adiposity induced in rats by long-term feeding a sucrose-rich diet (SRD). We studied several metabolic and molecular mechanisms involved in both lipid and glucose metabolisms in different tissues (liver, skeletal muscle, fat pad) as well as insulin secretion patterns from perifused islets under the stimulation of different secretagogues. Dietary FO reverses dyslipidemia and improves insulin action and adiposity in the SRD fed rats. FO reduces adipocytes cell size and thus, the smaller adipocytes are more insulin sensitive and the release of fatty acids decreases. In muscle, FO normalizes both the oxidative and non-oxidative glucose pathways. Moreover, FO modifies the fatty acid composition of membrane phospholipids. In isolated beta cells, lipid contents and glucose oxidation return to normal. All these effects could contribute to the normalization of glucose-stimulated insulin secretion and muscle insulin insensitivity.

Long-term hypoxia increases leptin receptors and plasma leptin concentrations in the late-gestation ovine fetus.

This study was designed to test the hypothesis that long-term hypoxia (LTH) increases fetal plasma leptin and fetal adipose or placental leptin expression and alters hypothalamic and adrenocortical leptin receptor (OB-R) expression. Pregnant ewes were maintained at high altitude (3,820 m) from day 30 to approximately 130 days of gestation. Reduced Po2 was maintained in the laboratory by nitrogen infusion through a maternal tracheal catheter. On day 132, normoxic control and LTH fetuses underwent surgical implantation of vascular catheters (n=6 for each group). Five days after surgery, maternal and fetal arterial blood samples were collected for leptin, insulin, and glucose analysis. Placental tissue, periadrenal fat, and fetal hypothalami and adrenal glands were collected from additional control (n=7) and LTH (n=8) fetuses for analysis of leptin mRNA by quantitative, real-time, RT-PCR (qRT-PCR). There was a significant (P<0.03) elevation in fetal plasma leptin in the LTH fetuses (3.5+/-0.7 ng/ml) vs. control (1.1+/-0.1 ng/ml). There were no differences in either glucose or insulin concentrations between the two groups. Periadrenal adipose leptin mRNA was significantly higher in the LTH group compared with control, as was placental leptin expression. The levels of leptin mRNA in adipose were approximately 70 times higher vs. placenta. LTH significantly reduced expression of OB-Ra (short-isoform) in the hypothalamus (P=0.0156), while resulting in a significant increase in adrenal OB-Rb (long-form) expression (P<0.03). Our data suggest that leptin is a hypoxia-inducible gene in the ovine fetus and OB-R expression is altered by LTH. These changes may be responsible in part, for our previously observed alterations in fetal hypothalamic-pituitary-adrenal function following LTH.

Impact of glucose infusion on the structural and functional characteristics of adipose tissue and on hypothalamic gene expression for appetite regulatory neuropeptides in the sheep fetus during late gestation.

In the present study, our aim was to determine whether intrafetal glucose infusion increases fetal adiposity, synthesis and secretion of leptin and regulates gene expression of the 'appetite regulatory' neuropeptides neuropepetide Y (NPY), agouti-related peptide (AGRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) and receptors (leptin receptor (OB-Rb) and melancortin 3 receptor (MC3R)) within the fetal hypothalamus. Glucose (50% dextrose in saline) or saline was infused (7.5 ml h(-1)) into fetal sheep between 130 and 140 days gestation (term = 150 +/- 3 days gestation). Glucose infusion increased circulating glucose and insulin concentrations, mean lipid locule size (532.8 +/- 3.3 microm2 versus 456.7 +/- 14.8 microm2) and total unilocular fat mass (11.7 +/- 0.6 g versus 8.9 +/- 0.6 g) of the perirenal fat depot. The expression of OB-Rb mRNA was higher in the ventromedial nucleus compared to the arcuate nucleus of the hypothalamus in both glucose and saline infused fetuses (F= 8.04; P < 0.01) and there was a positive correlation between expression of OB-Rb and MC3R mRNA in the arcuate nucleus (r= 0.81; P < 0.005). Glucose infusion increased mRNA expression for POMC, but not for the anorectic neuropeptide CART, or the orexigenic neuropeptides NPY and AGRP, in the arcuate nucleus of the fetal hypothalamus. These findings demonstrate that increased circulating glucose and insulin regulate gene expression of the neuropeptides within the fetal hypothalamus that are part of the neural network regulating energy balance in adult life.

Obesity in young men after famine exposure in utero and early infancy.

In a historical cohort study of 300,000 19-year-old men exposed to the Dutch famine of 1944-45 and examined at military induction, we tested the hypothesis that prenatal and early postnatal nutrition determines subsequent obesity. Outcomes were opposite depending on the time of exposure. During the last trimester of pregnancy and the first months of life, exposure produced significantly lower obesity rates (P less than 0.005). This result is consistent with the inference that nutritional deprivation affected a critical period of development for adipose-tissue cellularity. During the first half of pregnancy, however, exposure resulted in significantly higher obesity rates (P less than 0.0005). This observation is consistent with the inference that nutritional deprivation affected the differentiation of hypothalamic centers regulating food intake and growth, and that subsequent increased food availability produced an accumulation of excess fat in an organism growing to its predetermined maximum size.