Helen Budge

Nutritional programming of the metabolic syndrome

The primary markers of the metabolic syndrome are central obesity, insulin resistance and hypertension. In this review, we consider the effect of changes in maternal nutrition during critical windows in fetal development on an individuals subsequent predisposition to the metabolic syndrome. The fetal origins of obesity, cardiovascular disease and insulin resistance have been investigated in a wide range of epidemiological and animal studies; these investigations highlight adaptations made by the nutritionally manipulated fetus that aim to maintain energy homeostasis to ensure survival. One consequence of such developmental plasticity may be a long term re-setting of cellular energy homeostasis, most probably via epigenetic modification of genes involved in a number of key regulatory pathways. For example, reduced maternal–fetal nutrition during early gestation to midgestation affects adipose tissue development and adiposity of the fetus by setting an increased number of adipocyte precursor cells. Importantly, clinically relevant adaptations to nutritional challenges in utero may only manifest as primary components of the metabolic syndrome if followed by a period of accelerated growth early in the postnatal period and/or if offspring become obese.

LONG-TERM EFFECTS OF NUTRITIONAL PROGRAMMING OF THE EMBRYO AND FETUS: MECHANISMS AND CRITICAL WINDOWS

The maternal nutritional and metabolic environment is critical in determining not only reproduction, but also long-term health and viability. In the present review, the effects of maternal nutritional manipulation at defined stages of gestation coinciding with embryogenesis, maximal placental or fetal growth will be discussed. Long-term outcomes from these three developmental windows appear to be very different, with brain and cardiovascular function being most sensitive to influences in the embryonic period, the kidney during placental development and adipose tissue in the fetal phase. In view of the similarities in fetal development, number and maturity at birth, there are close similarities in these outcomes between findings from epidemiological studies in historical human cohorts and nutritional manipulation of large animals, such as sheep. One key nutrient that may modulate the long-term metabolic effects is the supply of glucose from the mother to the fetus, because this is sensitive to both global changes in food intake, maternal glucocorticoid status and an increase in the carbohydrate content of the diet. The extent to which these dietary-induced changes may reflect epigenetic changes remains to be established, especially when considering the very artificial diets used to induce these types of effects. In summary, the maintenance of a balanced and appropriate supply of glucose from the mother to the fetus may be pivotal in ensuring optimal embryonic, placental and fetal growth. Increased or decreased maternal plasma glucose alone, or in conjunction with other macro- or micronutrients, may result in offspring at increased risk of adult diseases.

Thermal Imaging to Assess Age-Related Changes of Skin Temperature within the Supraclavicular Region Co-Locating with Brown Adipose Tissue in Healthy Children

OBJECTIVE To establish the feasibility of infrared thermal imaging as a reproducible, noninvasive method for assessing changes in skin temperature within the supraclavicular region in vivo. STUDY DESIGN Thermal imaging was used to assess the effect of a standard cool challenge (by placement of the participants feet or hand in water at 20°C) on the temperature of the supraclavicular region in healthy volunteer participants of normal body mass index in 3 age groups, 3-8, 13-18, and 35-58 years of age. RESULTS We demonstrated a highly localized increase in temperature within the supraclavicular region together with a significant age-related decline under both baseline and stimulated conditions. CONCLUSION Thermogenesis within the supraclavicular region can be readily quantified by thermal imaging. This noninvasive imaging technique now has the potential to be used to assess brown adipose tissue function alone, or in combination with other techniques, in order to determine the roles of thermogenesis in energy balance and, therefore, obesity prevention.

Adipose tissue and fetal programming

Adipose tissue function changes with development. In the newborn, brown adipose tissue (BAT) is essential for ensuring effective adaptation to the extrauterine environment, and its growth during gestation is largely dependent on glucose supply from the mother to the fetus. The amount, location and type of adipose tissue deposited can also determine fetal glucose homeostasis. Adipose tissue first appears at around mid-gestation. Total adipose mass then increases through late gestation, when it comprises a mixture of white and brown adipocytes. BAT possesses a unique uncoupling protein, UCP1, which is responsible for the rapid generation of large amounts of heat at birth. Then, during postnatal life some, but not all, depots are replaced by white fat. This process can be utilised to investigate the physiological conversion of brown to white fat, and how it is re-programmed by nutritional changes in pre- and postnatal environments. A reduction in early BAT deposition may perpetuate through the life cycle, thereby suppressing energy expenditure and ultimately promoting obesity. Normal fat development profiles in the offspring are modified by changes in maternal diet at defined stages of pregnancy, ultimately leading to adverse long-term outcomes. For example, excess macrophage accumulation and the onset of insulin resistance occur in an adipose tissue depot-specific manner in offspring born to mothers fed a suboptimal diet from early to mid-gestation. In conclusion, the growth of the different fetal adipose tissue depots varies according to maternal diet and, if challenged in later life, this can contribute to insulin resistance and impaired glucose homeostasis.

Effect of Maternal Nutrition on Brown Adipose Tissue and Its Prolactin Receptor Status in the Fetal Lamb

We investigated the influence of maternal nutritional enhancement during the second half of gestation on prolactin receptor (PRLR) abundance in fetal brown adipose tissue (BAT) and liver close to term (i.e. 141–144 d gestation). Ewes were provided with 100% (i.e. control;n = 8) or 150% (i.e. well-fed;n = 7) of their metabolic requirements from 80 to 144 d gestation. Crude plasma membranes were prepared from fetal BAT and hepatic tissue, and individual molecular weight isoforms for the long and short forms of the PRLR were detected by immunoblotting. Mitochondrial preparations were prepared from BAT to measure the amount of the BAT-specific mitochondrial uncoupling protein-1 and its thermogenic activity (i.e. guanosine 5′-diphosphate binding). Fetuses sampled from well-fed ewes were heavier (controls, 3927 ± 196 g; well-fed, 4783 ± 219 g;p = 0.01) but possessed less BAT per kilogram body weight (controls, 5.92 ± 0.43 g/kg; well-fed, 3.85 ± 0.19 g/kg;p = 0.001), which had a greater uncoupling protein-1 abundance (controls, 56 ± 5% of reference; well-fed, 78 ± 9% of reference;p < 0.01) and higher thermogenic activity (controls, 157 ± 41 pmol guanosine 5′-diphosphate per milligram mitochondrial protein; well-fed, 352 ± 36 pmol guanosine 5′-diphosphate per milligram mitochondrial protein;p < 0.01) than controls. Multiple isoforms of the long and short forms of the PRLR were detected in all tissues. BAT from well-fed fetuses had a higher abundance of the 15-kD isoform of the long form of the PRLR (controls, 1.6 ± 0.4 densitometric units; well-fed, 16.3 ± 2.0 densitometric units;p < 0.001). This isoform was not detected in hepatic tissue. Maternal nutrient intake had no effect on any other isoforms of the PRLR in BAT or liver. In conclusion, increasing the quantity of feed provided in late gestation acts to promote fetal weight and BAT maturation, the combination of which will enhance neonatal viability.

Adult Epicardial Fat Exhibits Beige Features

CONTEXT Human epicardial fat has been designated previously as brown-like fat. The supraclavicular fat depot in man has been defined as beige coexistent with classical brown based on its gene expression profile. OBJECTIVE The aim of the study was to establish the gene expression profile and morphology of human epicardial and visceral paracardial fat compared with sc fat. SETTING The study was conducted at a tertiary care hospital cardiac center. PATIENTS Epicardial, visceral paracardial, and sc fat samples had been taken from middle-aged patients with severe coronary atherosclerosis or valvular heart disease. INTERVENTIONS Gene expression was determined by reverse transcription-quantitative PCR and relative abundance of the mitochondrial uncoupling protein-1 (UCP-1) by Western blotting. Epicardial tissue sections from patients were examined by light microscopy, UCP-1 immunohistochemistry, and cell morphometry. MAIN OUTCOME MEASURES We hypothesized that epicardial fat has a mixed phenotype with a gene expression profile similar to that described for beige cell lineage. RESULTS Immunoreactive UCP-1 was clearly measurable in each epicardial sample analyzed but was undetectable in each of the 4 other visceral and sc depots. Epicardial fat exhibited high expression of genes for UCP-1, PRDM16, PGC-1α, PPARγ, and the beige adipocyte-specific marker CD137, which were also expressed in visceral paracardial fat but only weakly in sternal, upper abdominal, and lower extremity sc fat. Histology of epicardial fat showed small unilocular adipocytes without UCP-1 immunostaining. CONCLUSION UCP-1 is relatively abundant in epicardial fat, and this depot possesses molecular features characteristic of those found in vitro in beige lineage adipocytes.

Maternal nutrient restriction during pregnancy differentially alters the unfolded protein response in adipose and renal tissue of obese juvenile offspring

Maternal diet during pregnancy can program an offsprings risk of disease in later life. Obesity adversely alters renal and adipose tissue function, resulting in chronic kidney disease and insulin resistance, respectively, the latter associated with dysregulation of the unfolded protein response (UPR). In view of the current obesity epidemic, we explored the combined effects of in utero early‐ to midgestational nutrient restriction and postnatal obesity on the UPR in ovine juvenile offspring. Nutrient restriction was coincident with fetal kidney development but prior to exponential adipose tissue deposition. Nutrient restricted (NR) and normal diet (control) offspring were exposed to an obesogenic environment throughout adolescence, resulting in similar degrees of juvenile obesity. NR offspring showed enhanced adipose tissue dysregulation characterized by activation of the UPR, perturbed insulin signaling, and marked inflammation, as demonstrated by increased abundance of crownlike structures and proinflammatory genes. Conversely, in renal tissue NR offspring had marked attenuation of cellular stress and inflammation evident as reduced activation of the UPR, down‐regulation of proinflammatory genes, and less histological damage. In conclusion, obesity‐related activation of the UPR can be determined by the in utero nutritional environment, demonstrating organ‐specific effects dependent on the developmental phase targeted within the fetus.— Sharkey, D., Gardner, D. S., Fainberg, H. P., Sebert, S., Bos, P., Wilson, V., Bell, R., Symonds, M. E., Budge, H. Maternal nutrient restriction during pregnancy differentially alters the unfolded protein re‐sponse in adipose and renal tissue of obese juvenile offspring. FASEBJ. 23, 1314–1324 (2009)

Nutritional Manipulation of Fetal Adipose Tissue Deposition and Uncoupling Protein 1 Messenger RNA Abundance in the Sheep: Differential Effects of Timing and Duration

Abstract A range of epidemiological and experimental studies have indicated that suboptimal nutrition at different stages of gestation is associated with an increased prevalence of adult hypertension, cardiovascular disease, and obesity. The timing of prenatal nutrient restriction is important in determining postnatal outcomes—including obesity. The present study, aimed to determine the extent to which fetal adiposity and expression of the key thermogenic protein, uncoupling protein (UCP)1, are altered by restriction of maternal nutrient intake imposed during four different periods, starting from before conception. Maternal nutrient intake was restricted from 60 days before until 8 days after mating (periconceptional nutrient restriction; R-C), from 60 days before mating and throughout gestation (R-R), from 8 days gestation until term (C-R), or from 115 days gestation until term. Fetal perirenal adipose tissue (PAT) was sampled near to term at ∼143 days. UCP1 mRNA, but not protein, abundance in PAT was increased in fetuses in the R-R group (C‐C 63 ± 18; R-C 83 ± 43; C-R 103 ± 38; R-R 167 ± 50 arbitrary units (P < 0.05)). In contrast, the abundance of UCP1 mRNA, but not protein, in fetal PAT was decreased when maternal nutrition was restricted from 115 days gestation. The major effect of maternal nutrient restriction on adipose tissue deposition occurred in the C-R group, in which the proportion of fetal fat was doubled, whereas maternal nutrient restriction from 115 days gestation reduced fetal fat deposition. In conclusion, there are differential effects of maternal and therefore fetal nutrient restriction on UCP1 mRNA expression and fetal fat mass and these effects are dependent on the timing and duration of nutrient restriction.

The impact of diet during early life and its contribution to later disease: critical checkpoints in development and their long-term consequences for metabolic health.

Changes in maternal diet at different stages of reproduction can have pronounced influences on the health and well-being of the resulting offspring, especially following exposure to an obesogenic environment. The mechanisms mediating adaptations in development of the embryo, placenta, fetus and newborn include changes in the maternal metabolic environment. These changes include reductions in a range of maternal counter-regulatory hormones such as cortisol, leptin and insulin. In the sheep, for example, targeted maternal nutrient restriction coincident with the period of maximal placental growth has pronounced effects on the development of the kidney and adipose tissue. As a consequence, the response of these tissues varies greatly following adolescent-onset obesity and ultimately results in these offspring exhibiting all the symptoms of the metabolic syndrome earlier in young adult life. Leptin administration to the offspring after birth can have some long-term differential effects, although much higher amounts are required to cause a response in small compared with large animal models. At the same time, the responsiveness of the offspring is gender dependent, which may relate to the differences in leptin sensitivity around the time of birth. Increasing maternal food intake during pregnancy, either globally or of individual nutrients, has little positive impact on birth weight but does impact on liver development. The challenge now is to establish which components of the maternal diet can be sustainably modified in order to optimise the maternal endocrine environment through pregnancy, thus ensuring feto-placental growth is appropriate in relation to an individuals gender and body composition.

Ontogeny and nutritional manipulation of mitochondrial protein abundance in adipose tissue and the lungs of postnatal sheep

The present study examined the ontogeny of mitochondrial protein abundance in adipose tissue and lungs over the first month of life in the sheep and the extent to which this may be altered by maternal undernutrition during the final month of gestation. The ontogeny of uncoupling protein (UCP), voltage-dependent anion channel (VDAC) and cytochrome c abundance were determined in adipose tissue and lungs sampled from near-term fetuses and young sheep aged 4 h, 1, 7 and 30 d. In adipose tissue, the abundance of UCP1, VDAC and cytochrome c all peaked at 1 d of age and then decreased by 30 d of age, at which stage the brown adipose tissue-specific UCP1 was no longer detectable but UCP2 was clearly abundant. For the lungs, however, UCP2 and VDAC abundance both peaked 7 d after birth and then decreased by 30 d of age. During postnatal development, therefore, a marked change in mitochondrial protein abundance occurs within both adipose tissue and lungs. Maternal nutrient restriction had no effect on lamb growth or tissue weights at 30 d of age but was associated with increased abundance of UCP2 and VDAC but not cytochrome c in both adipose tissue and lungs. These mitochondrial adaptations within both adipose tissue and the lungs of offspring born to previously nutrient-restricted mothers may compromise adipose tissue and lung function during periods of environmental stress.