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One of the fundamental challenges in obesity research is to identify subjects prone to gain weight so that obesity and its comorbidities can be promptly prevented or treated. The principles of thermodynamics as applied to human body energetics demonstrate that susceptibility to weight gain varies among individuals as a result of inter-individual differences in energy expenditure and energy intake, two factors that counterbalance one another and that together determine daily energy balance and, ultimately, bodyweight change. This review focuses on the variability among individuals in human metabolism that determines weight change. Conflicting results have been reported about the role of inter-individual differences in energy metabolism during energy balance in relation to future weight change. However, recent studies show that metabolic responses to acute, short-term dietary interventions that create energy imbalance, such as low-protein overfeeding or fasting for 24 hours, may reveal the underlying metabolic phenotype that determines the degree of resistance to diet-induced weight loss or the propensity to spontaneous weight gain over time. Metabolically “thrifty” individuals, characterized by a predilection for saving energy in settings of undernutrition and dietary protein restriction, display a minimal increase in plasma Fibroblast Growth Factor 21 (FGF21) concentrations in response to a low-protein overfeeding diet and tend to gain more weight over time as compared to metabolically “spendthrift” individuals. Similarly, inter-individual variability in the causal relationship between energy expenditure and energy intake (“energy sensing”) and in the metabolic response to cold exposure (e.g., brown adipose tissue activation) seems to some extent to be indicative of individual propensity to weight gain. Thus, an increased understanding and the clinical characterization of phenotypic differences in energy metabolism among individuals (metabolic profile) may lead to new strategies to prevent weight gain or improve weight loss interventions by targeted therapies on the basis of metabolic phenotype and susceptibility to obesity in individual persons.

Objectives Plasticity in the growth of body segments between populations has been researched in relation to migration, temporal change and high‐altitude studies. We study the within population variation in body segments, thus controlling for some of the environmental and genetic differences that could be at play in between populations studies. We test a version of the thrifty phenotype hypothesis, where the growth of head‐trunk and hand are prioritized due to their functional significance over height and leg growth. Materials and methods A total of 3913 Guatemalan, rural, semi‐urban and urban, Maya and Ladino children 6 to 15 years old were studied. Height, sitting height, leg length, and metacarpal length were studied in relation to three proxies for living conditions: height‐ and leg length‐for‐age, and maternal education. Estimation statistics and null hypothesis significance testing were used to analyze the data. Results Metatarsal length and sitting height values were higher than height and leg length respectively. Relative metacarpal length was conserved across height‐for‐age groups. Females were less affected than males for metacarpal length and sitting height, but more affected for leg length. Conclusion Our results agree with the thrifty phenotype hypothesis, where metacarpal and sitting height growth would be prioritized over height and leg length due to greater functional significance.

As heifer rearing is a costly investment, dairy farmers have been stimulated to maximize early growth of their calves, mainly by enhanced liquid feeding. However, the long-term effects of this "accelerated growth" are largely unknown. Studies recently performed at Ghent University indicate that in dairy cattle, certain maternal factors (such as young age and high milk yield) and environmental factors (such as high ambient temperatures) create a suboptimal environment for the developing foetus, altering the phenotype of the newborn calf. According to the "thrifty phenotype hypothesis," these metabolic alterations prepare the newborn for similar ("matching") conditions after birth, enhancing its survival during periods of limited feeding. Yet, when an abundance of nutrients is available in post-natal life (e.g., during periods of enhanced feeding), the "mismatch" between pre- and post-natal environment results in an early catch-up growth, with potential negative consequences. The aim of the article was to discuss this mismatch between pre- and post-natal environment in dairy calves. Previous studies, especially in human medicine, have shown catch-up growth to be associated with obesity, fertility problems, metabolic diseases and a reduced lifespan. Hence, we hypothesize that, by applying programs of accelerated growth, our current management system accentuates the mismatch between the pre- and post-natal environment in dairy calves. We can conclude that, although more research is necessary, the current findings point towards a more individual approach when rearing dairy heifers.

Early-life conditions can drive ageing patterns and life history strategies throughout the lifespan. Certain social, genetic and nutritional developmental conditions are more likely to produce high-quality offspring: those with good likelihood of recruitment and productivity. Here, we call such conditions "favoured states" and explore their relationship with physiological variables during development in a long-lived seabird, the black-legged kittiwake (Rissa tridactyla). Two favoured states were experimentally generated by manipulation of food availability and brood size, while hatching order and sex were also explored as naturally generating favoured states. Thus, the favoured states we explored were high food availability, lower levels of sibling competition, hatching first and male sex. We tested the effects of favoured developmental conditions on growth, stress, telomere length (a molecular marker associated with lifespan) and nestling survival. Generation of favoured states through manipulation of both the nutritional and social environments furthered our understanding of their relative contributions to development and phenotype: increased food availability led to larger body size, reduced stress and higher antioxidant status, while lower sibling competition (social environment) led to lower telomere loss and longer telomere lengths in fledglings. Telomere length predicted nestling survival, and wing growth was also positively correlated with telomere length, supporting the idea that telomeres may indicate individual quality, mediated by favoured states.

Obesity has more than doubled in children and tripled in adolescents in the past 30 yr. The association between metabolic disorders in offspring of obese mothers with diabetes has long been known; however, a growing body of research indicates that fathers play a significant role through presently unknown mechanisms. Recent observations have shown that changes in paternal diet may result in transgenerational inheritance of the insulin-resistant phenotype. Although diet-induced epigenetic reprogramming via paternal lineage has recently received much attention in the literature, the effect of paternal physical activity on offspring metabolism has not been adequately addressed. In the current study, we investigated the effects of long-term voluntary wheel-running in C57BL/6J male mice on their offspring’s predisposition to insulin resistance. Our observations revealed that fathers subjected to wheel-running for 12 wk produced offspring that were more susceptible to the adverse effects of a high-fat diet, manifested in increased body weight and adiposity, impaired glucose tolerance, and elevated insulin levels. Long-term paternal exercise also altered expression of several metabolic genes, including Ogt, Oga, Pdk4, H19, Glut4, and Ptpn1, in offspring skeletal muscle. Finally, prolonged exercise affected gene methylation patterns and micro-RNA content in the sperm of fathers, providing a potential mechanism for the transgenerational inheritance. These findings suggest that paternal exercise produces offspring with a thrifty phenotype, potentially via miRNA-induced modification of sperm.—Murashov, A. K., Pak, E. S., Koury, M., Ajmera, A., Jeyakumar, M., Parker, M., Williams, O., Ding, J., Walters, D., Neufer, P. D. Paternal long-term exercise programs offspring for low energy expenditure and increased risk for obesity in mice.

Though indigenous communities have undergone rapid economic integration in the last few decades as a result of neoliberal reforms and increased migration, these communities experience a complex epidemiological profile that includes fetal and childhood undernutrition and adult obesity and diabetes. We argue here that the interaction of these burdens and the social conditions that have dismantled local food systems and propelled out-migration best explain the growing rate of diabetes in this region. We contrast this syndemic approach with the Thrifty Genotype Hypothesis, which attributes the high rate of diabetes among Native American populations to presumed genetic predisposition, triggered by lifestyle changes. We find the Thrifty Phenotype Hypothesis useful for explaining links between fetal and postnatal nutrition interruptions and chronic diseases in later life in certain populations and that a syndemics framework is useful for modeling the complex social causes of this pattern. While the syndemics model has largely been used to understand infectious diseases and addiction, social scientists have yet to use the framework to investigate the complex interactions between chronic malnutrition, metabolic syndrome, and political economy in rural Oaxacan communities. The most effective efforts to reduce diabetes will be those that address the social determinants of diabetes in this and other similar populations, rather than programs that address individual behaviors and lifestyle.

Intrauterine growth-restricted (IUGR) newborns have increased risk of adult metabolic syndrome, including fatty liver. However, it is unclear whether the fatty liver development is "programmed" or secondary to the accompanying obesity. In this study, we examined hepatic lipid accumulation and lipid-regulatory factors (sterol regulatory element-binding protein-1c and fatty acid synthase) in IUGR and Control fetal (embryonic day 20; e20) and newborn (postnatal day 1; p1) rat pups. Notably, despite of in utero undernutrition state, IUGR fetuses demonstrated "fatty liver" with upregulation of these lipogenic indices at as early as e20. Both IUGR and Control newborns exhibited the same extent of massive increase in hepatic lipid content, whereas IUGR newborns continued to exhibit upregulated lipogenic indices. The persistent upregulation of the lipogenic indices in fetal and newborn IUGR suggests that fatty liver is gestationally programmed. Our study suggested that IUGR offspring were born with an altered metabolic life strategy of increased fuel/lipid storage which could be a distinct metabolic pathway of the thrifty phenotype.

In this review, we consider the role of endocannabinoids and cannabinoid-1 (CB1) cannabinoid receptors in metabolic regulation and as mediators of the thrifty phenotype that underlies the metabolic syndrome. We survey the actions of endocannabinoids on food intake and body weight, as well as on the metabolic complications of visceral obesity, including fatty liver, insulin resistance and dyslipidemias. Special emphasis is placed on weighing the relative importance of CB1 receptors located in peripheral tissues versus the central nervous system in mediating the metabolic effects of endocannabinoids. Finally, we review recent observations that indicate that peripherally restricted CB1 receptor antagonists retain efficacy in reducing weight and improving metabolic abnormalities in mouse models of obesity without causing behavioural effects predictive of neuropsychiatric side effects in humans. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7

Human diseases in adulthood are increasingly associated with growth patterns in early life, implicating early-life nutrition as the underlying mechanism. The thrifty phenotype hypothesis proposed that early-life metabolic adaptations promote survival, with the developing organism responding to cues of environmental quality by selecting an appropriate trajectory of growth. Recently, some authors have proposed that the thrifty phenotype is also adaptive in the longer-term, by preparing the organism for its likely adult environment. However, windows of plasticity close early during human development, and subsequent environmental changes may result in the selected trajectory becoming inappropriate, leading to adverse effects on health. This paradox generates uncertainty as to whether the thrifty phenotype is indeed adaptive for the offspring in humans. The thrifty phenotype should not be considered a dichotomous concept, rather it refers to the capacity of all offspring to respond to environmental information during early ontogenetic development. This article argues that the thrifty phenotype is the consequence of three different adaptive processes - niche construction, maternal effects, and developmental plasticity - all of which in humans are influenced by our large brains. While developmental plasticity represents an adaptation by the offspring, both niche construction and parental effects are subject to selection on parental rather than offspring fitness. The three processes also operate at different paces. Human offspring do not become net calories-producers until around 18 years of age, such that the high energy costs of the human brain are paid primarily by the mother, even after weaning. The evolutionary expansion of human brain volume occurred in environments characterised by high volatility, inducing strong selective pressure on maternal capacity to provision multiple offspring simultaneously. The thrifty phenotype is therefore best considered as a manipulation of offspring phenotype for the benefit of maternal fitness. The information that enters offspring phenotype during early development does not predict the likely future environment of the offspring, but rather reflects the mother's own developmental experience and the quality of the environment during her own maturation. Offspring growth trajectory thus becomes aligned with long-term maternal capacity to provision. In contemporary populations, the sensitivity of offspring development to maternal phenotype exposes the offspring to adverse effects, through four distinct pathways. The offspring may be exposed to (1) poor maternal metabolic control (e.g. gestational diabetes), (2) maternally derived toxins (e.g. maternal smoking), or (3) low maternal social status (e.g. small size). Adverse consequences of these effects may then be exacerbated by (4) exposure either to the "toxic" western environment in postnatal life, in which diet and physical activity levels are mismatched with metabolic experience in utero, or at the other extreme to famine. The rapid emergence of the epidemic of the metabolic syndrome in the 20th Century reflects the rapid acceleration in the pace of niche construction relative to the slower physiological combination of developmental plasticity and parental effects.

Aim: To discuss a hypothesis regarding the impact and possible side effects of glutamate in paediatric parenteral nutrition. Results: Published evidence suggests that the arcuate nucleus, which is a potent site of leptin action, is severely damaged by elevated glutamate levels. Early administration of glutamate (GLU) to the neonatal rat disrupts the hypothalamic signalling cascade of leptin action. Conclusion: We are concerned that GLU-containing parenteral nutrition may not only increase the risk of hypothalamic damage in neurosurgical patients with an impaired blood–brain barrier, and in patients with periventricular leukomalacia, but may also permanently damage the arcuate nucleus neurones in the very immature infant. This may result in later impairment of feeding regulation, obesity, hyperleptinaemia, and other symptoms that characterize the “thrifty phenotype” and the dysmetabolic syndrome. We strongly suggest reconsidering the recommended daily allowances of amino acids, particularly the use of GLU, in current paediatric parenteral nutrition.

High concentrations of glucose induce insulin resistance and impair insulin secretion in a manner that mirrors type 2 diabetes, a phenomenon known as glucose toxicity. High concentrations of hexosamines mimic these effects, leading to the hypothesis that cells use hexosamine flux as a glucose- and satiety-sensing pathway. Overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine:fructose-6-phosphate amidotransferase, GFA) in muscle and fat results in insulin resistance and hyperleptinemia. GFA overexpression targeted to liver results in hyperlipidemia and to the beta cell in increased insulin secretion. Thus, excess hexosamine flux leads to a coordinated response whereby fuel is shunted toward long-term storage, mirroring the "thrifty phenotype". The results suggest a mechanism by which chronic overnutrition leads to the phenotype of type 2 diabetes.

Insulin resistance has been recognized as the fundamental underlying metabolic defect in the pathogenesis of metabolic syndrome, a clustering of cardiovascular risk factors such as diabetes, hypertension, dyslipidemia, and obesity. Recent studies established that mitochondrial dysfunction is involved in insulin resistance in general and fetal origin of this state in particular. Because genes are the fundamental molecular basis of inheritance—and thus the cornerstones of evolution—a model explaining insulin resistance is based at the gene level at best. Since a certain mtDNA polymorphism, 16189T>C, is associated with insulin resistance, mtDNA has to be a basic component of the gene-based model. We developed a mitochondria-based model that explains insulin resistance in terms of quantitative and qualitative change of the mitochondrion and its DNA. This model can accommodate several important hypotheses, such as thrifty genotype hypothesis, thrifty phenotype hypothesis, fetal insulin hypothesis, contribution of metabolic imprinting by epigenetic changes, and many other features associated with insulin resistance. We will discuss mechanisms that indicate why the perturbed initial condition of mitochondrial function should lead to the reduced insulin sensitivity.

Studies in both humans and experimental animals addressing the ‘Fetal Origins of Adult Disease’ hypothesis have established a relationship between an adverse intrauterine environment and offspring disease in adult life. This phenomenon, termed ‘fetal programming’ describes a process whereby a stimulus in utero establishes a permanent response in the fetus leading to enhanced susceptibility to later disease. However, the environment, during periods of developmental plasticity in postnatal life, can also ‘programme’ function. Thus, the terms ‘developmental programming’ and the ‘Developmental Origins of Adult Health and Disease’ are preferentially utilized. The ‘Thrifty Phenotype’ hypothesis explained the association between insufficient in utero nutrition and the later development of Type 2 diabetes. Most recently the ‘Predictive Adaptive Response’ hypothesis proposes that the degree of mismatch between the pre- and postnatal environments is an important determinant of subsequent disease. Epidemiological studies have indicated that fetal growth restriction correlates with later disease, implying that fetal nutritional deprivation is a strong programming stimulus. This prompted the development of experimental animal models using controlled maternal calorie, protein or macronutrient deficiency during key periods of gestation. However, in many societies, maternal and postnatal nutrition are either sufficient or excessive. Here, we examine findings from a range of nutritional studies examining maternal and/or postnatal nutritional excess. There is supportive evidence from a limited number of studies to test the ‘Predictive Adaptive Response’ hypothesis. These suggest that maternal over-nutrition is deleterious to the health of offspring and can result in a phenotype of the offspring that is characteristic of metabolic syndrome.

The sections in this article are: 1 Beginnings 1.1 Endocrine Nature of the Pancreas 2 Action Mechanisms 2.1 Landmarks in Protein Phosphorylation: Mechanism of Action of Glucagon 3 Insulin 3.1 Early Development of Ideas About the Mechanism of Action of Insulin 3.2 Insulin Secretion and Biosynthesis 4 Fuels: Consumption and Selection—The Glucose Fatty Acid Cycle and the Role of the PDH Complex 4.1 Fuel Consumption and Selection 4.2 The Glucose Fatty Acid Cycle 4.3 Role of the Pyruvate Dehydrogenase Complex 4.4 Physiopathological Significance of Pyruvate Dehydrogenase Kinase Regulation in Humans 5 The Thrifty Phenotype Hypothesis in Relation to Insulin Secretion, Insulin Insensitivity, and the Origins of Non-Insulin-Dependent Diabetes Mellitus 6 Where Next?

BACKGROUND Inverse correlations have been reported between birth weight and the Metabolic Syndrome (abdominal obesity, insulin resistance, hyperinsulinemia, glucose intolerance, dyslipidemia, and hypertension). These correlations are thought to reflect primarily nutritional inadequacies during fetal and early life. We explored familial influences on these correlations. METHODS Using birth weight data on 602 subjects from 65 pedigrees, we partitioned phenotypic correlations into familial and non-familial. The former are usually regarded as reflecting primarily genetic influences, although they may also reflect environmental influences that are shared by family members, and the latter reflect random environmental influences. RESULTS A consistent pattern of positive familial and inverse non-familial correlations were observed. The strongest familial correlations were between birth weight and fasting insulin (r = 0.58, p = 0.002), leptin (r = 0.48, p = 0.021), split proinsulin (r=0.51, p = 0.090), and heart rate (r = 0.39, p = 0.037). An inverse familial correlation was observed with HDL cholesterol (r = -0.28, p = 0.018). Non-familial correlations were weaker and only two-- subscapular-to-triceps skinfold ratio and fasting insulin--were statistically significant. CONCLUSION Since the familial and non-familial correlations were in opposite directions, we attribute the former to the pleiotropic effects of genes. Specifically, we conclude that genes that increase birth weight also worsen the Metabolic Syndrome in adult life. Since the inverse correlations reported in the literature reflect mainly cohorts born in the early part of the 20th century, improved maternal nutrition since then may have allowed the expression of genetic influences in our participants, all of whom were born after 1950.

Objectives The paper tests the thrifty phenotype hypothesis, according to which nonharmonious growth trajectories are costly for adult health. Methods The American surge in the prevalence of type 2 diabetes is concentrated in the South, a region characterized by a long history of poverty followed by rapid economic growth beginning in the 1960s. Civil rights legislation further accelerated income growth for African-Americans in the region. The paper investigates the hypothesis by using per capita income at the state level as a proxy for net nutritional conditions. Results Regressions at the state level explain 56% of the variation in the prevalence rate of type 2 diabetes in 2009 using two explanatory variables: the ratio of per capita income in 1980 to that in 1950 and the share of the population that was African-American. The paper discusses ways that rapid economic growth may have translated into weight gain and type 2 diabetes. Conclusions If the thrifty phenotype hypothesis is correct, future rates in the prevalence of type 2 diabetes are predictable based on income history. The forecast for rapidly developing countries such as India and China are ominous. Am. J. Hum. Biol. 25:508–515, 2013. © 2013 Wiley Periodicals, Inc.

The 'thrifty phenotype' hypothesis states that impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) are the result of adaptation to undernutrition in the fetal and infant environment. In adapting the fetus and infant have to be nutritionally 'thrifty'. If poor nutrition continues throughout life these adaptations are not detrimental. However, if adult nutrition is better, the ability of the pancreas to maintain homeostasis is exceeded, with resulting diabetes. The hypothesis has been tested by a series of longitudinal studies which relate early growth with IGT and NIDDM in adult life. The studies show that babies who are small at birth or during infancy have increased rates of IGT and NIDDM. These relations are independent of social class and are seen at all levels of current body mass. More detailed anthropometric measurements at birth show that the baby at risk of glucose intolerance is characterized by disproportionate fetal growth, particularly relative thinness. Direct measurements have shown that this is a function of insulin resistance rather than deficiency. Reduced fetal growth is also associated with higher levels of plasma glucose in children. The aetiology of IGT and NIDDM may lie in undernutrition in utero or during infancy. This has major implications for their prevention.

Type 2 diabetes has in the past been claimed to be genetically determined. However, nongenetic metabolic effects including complex social determinants better explain the current epidemic of obesity and diabetes worldwide. Keywords: thrifty gene hypothesis; epidemiology; type 2 diabetes mellitus; thrifty phenotype hypothesis

In this issue of The Journal of Physiology, Rumball et al. publish an important article on the impact of periconceptional undernutrition on maternal and fetal metabolism with special emphasis on the glucose–insulin axis function and fetal growth in twin versus singleton ovine pregnancies (Rumball et al. 2008). The authors previously showed that periconceptional undernutrition leads to altered maternal metabolism and fetal growth in sheep with singleton pregnancies during late gestation, and they therefore hypothesized that the periconceptional circumstances associated with twinning might affect late pregnancy metabolism and fetal growth in a similar way as that of periconceptional undernutrition. This was, however, not the case. Thus, twins were characterized by a more severe growth retardation as opposed to singleton fetuses during late gestation when exposed to both normal feeding as well as in particular to fasting of the mothers (ewes). Whereas twin fetuses displayed an exaggerated plasma insulin response to a glucose challenge in late gestation, singleton fetuses of periconceptional undernourished ewes showed reduced glucose excursions in response to the glucose challenges at the same time point of gestation, indicating increased glucose effectiveness, metabolism or perhaps even insulin sensitivity. Taken together, these data add to mounting evidence of twins being exposed to a unique and different intrauterine environment from conception to birth as compared with singletons, and given the fact that this period in early life may play a (or the) key role for the risk of developing the metabolic syndrome including type 2 diabetes, hypertension, dyslipidaemia and abdominal obesity many decades later, known as the ‘thrifty phenotype hypothesis’ (Hales & Barker, 2001), it does give rise to many layers of reflection regarding twins and how they may be used – or not used – in studies on the aetiology and pathophysiology of diseases and states inherent in the metabolic syndrome. The authors conclude that the data indicate that twins and singletons must be examined separately in any study of fetal and postnatal physiology. Indeed, these findings along with others warrant caution extrapolating data obtained in twins to singletons and vice versa, but they do not indicate that twins cannot be used to study the early (periconceptional and fetal) origin of the metabolic syndrome. In that respect, studies using identical twins discordant for both type 2 diabetes (Poulsen et al. 1997) as well as hypertension (Bergvall et al. 2007) provided conclusive evidence that these key components of the metabolic syndrome are associated with low birth weight and an adverse intrauterine environment in a non-genetic manner. Interestingly, as also discussed in the article by Rumball et al., intra-pair differences of birth weights in twins are much more predictive of later metabolic health as compared with absolute birth weights, and the reason for that may be explained by the very special early life conditions and intrauterine growth trajectories associated with twinning (Rumball et al. 2008). As for the absolute birth weights, an argument used against the ‘thrifty phenotype hypothesis’ has been that low birth weight in twins does not predict an excess risk of premature death from especially cardiovascular disease (Christensen et al. 1995), the unfortunate ultimate risk or consequence of having the metabolic syndrome. Although we need to know more about the specific disease patterns and causes of mortality in twins versus singletons, the data from Rumball et al. provide some of the first physiological evidence for altered and distinct intrauterine programming mechanisms and intrauterine growth trajectories in twins compared with singletons, supporting the notion that birth weight in twins may not necessarily predict later metabolic health in the same way – and to the same extent – as birth weight in singletons. The findings by Rumball et al. may also provide additional concerns about the validity of heritability estimates, disease concordance rates and thus genetic contributions to various states of disease obtained from studies of monozygotic and dizygotic twins, as discussed recently (Vaag & Poulsen, 2007). An additional lesson that can be learned from the study by Rumball et al., as well as from previous studies from the same group (Oliver et al. 2005), is that periconceptional undernutrition may influence maternal and fetal metabolism during late gestation without influencing weight at birth per se after correction for gestational age. Indeed, this finding supports the view that birth weight represents only a (although surprisingly predictive) proxy of risk of later metabolic disease, and that we need to find other and even more precise markers of factors linking an adverse intrauterine environment with later risk of disease. Another very recent study documented that periconceptional dietary restriction of vitamin B12 and folate within the physiological range of mature female sheep led to adult offspring that were both fatter, more insulin resistant and had higher blood pressures, but without any significant alterations of birth weights, as compared with control animals (Sinclair et al. 2007). Interestingly, the offspring displayed widespread alterations of the methylation pattern of a number of DNA CpG islands in liver cells, providing the first evidence of epigenetic mechanisms linking physiologically relevant periconceptional micronutrient manipulations to distinct adult features of the metabolic syndrome in the offspring. Altogether, the scene has been set to a new area of understanding the molecular mechanisms linking periconceptional and intrauterine nutrition – as well as fetal growth – to relevant outcomes of metabolic health in late gestation, after birth and throughout the entire life course from detailed physiological studies of twins and singletons, separately or in comparisons when appropriate.

Intra-uterine development and early-life malnutrition The ‘thrifty phenotype’ hypothesis suggests metabolic adaptations occur in the undernourished foetus. These adaptations confer a susceptible phenotype impacting on insulin sensitivity and secretion mechanisms. Such a hypothesis might explain the rising type 2 diabetes prevalence in developing ‘Westernised’ countries. Many studies demonstrate a correlation between low birth weight, insulin resistance and development of type 2 diabetes. In the Preston study, men and women who were thin at birth were found to be insulin resistant in later life.

Postnatal early overnutrition (EO) is a risk factor for obesity in adult life. Rats raised in a small litter can develop hyperinsulinaemia, hyperphagia, hyperleptinaemia and hypertension as adults. Since leptin regulates the hypothalamic–pituitary–thyroid axis and the metabolism of thyroid hormones, we studied the leptin signalling pathway in pituitary and thyroid glands of the postnatal EO model. To induce EO, at the third day of lactation the litter size was reduced to three pups per litter (SL group). In control litters (NL group), the litter size was adjusted to 10 pups per litter. Body weight and food intake were monitored. Rat offspring were killed at 21 (weaning) and 180 days old (adulthood). Plasma thyroid hormones, thyroid-stimulating hormone (TSH) and leptin were measured by radioimmunoassay. Proteins of the leptin signalling pathway were analysed by Western blotting. Body weight of offspring in the SL group was higher from the seventh day of lactation (+33%, P < 0.05) until 180 days old (+18%, P < 0.05). Offspring in the SL group showed higher visceral fat mass at 21 and 180 days old (+176 and +52%, respectively, P < 0.05), but plasma leptin was higher only at 21 days (+88%, P < 0.05). The SL offspring showed higher plasma TSH, 3,5,3′-triiodothronine (T3) and thyroxine (T4) at 21 days (+60, +91 and +68%, respectively, P < 0.05), while the opposite was observed at 180 days regarding thyroid hormones (T3, −10%; and T4, −30%, P < 0.05), with no difference in TSH levels. In hypothalamus, no change was observed in the leptin signalling pathway at 21 days. However, lower janus thyrosine kinase 2 (JAK2) and phosphorilated-signal transducer and activator of transcription-3 (p-STAT3) content were detected in adulthood. In pituitary, the SL group presented higher leptin receptors (Ob-R), JAK2 and p-STAT3 content at 21 days and lower JAK2 and STAT3 content at 180 days old. In contrast, in thyroid, the Ob-R expression was lower in young SL rats, while the adult SL group presented higher Ob-R and JAK2 content. We showed that postnatal EO induces short- and long-term effects upon the hypothalamic–pituitary–thyroid axis. These changes may help to explain future development of metabolic and endocrine dysfunctions, such as metabolic syndrome and hypothyroidism.

This themed issue of The Journal of Physiology was developed to include a group of cutting edge articles that discuss recent research into the interplay between the fetal and maternal cardiovascular and endocrine systems and developmental programming. These articles are the result of a meeting of basic and clinical scientists actively involved in research directly related to cardiovascular perinatal biology during pregnancy. The group met in Tucson, AZ on August 14–19, 2004 for the Third Federation of American Societies for Experimental Biology Summer Research Conference on ‘Molecular and Cellular Signalling in the Perinatal Cardiovascular System’. The overall rationale for the meeting was that the mechanisms that control the fetal and maternal cardiovascular, endocrine and metabolic systems during pregnancy are extremely important topics of basic and clinical research with significant health implications. Recent research in this area has emphasized the extraordinary and lifelong consequences of nutritional and pathophysiological influences during early development, which may occur through perturbation of maternal and fetal cardiovascular/endocrine systems. Several major themes emerged from this meeting, too numerous to be adequately covered in detail here. One was the major role of in utero stress or ‘stressors’ in altering the development and function of the fetal and neonatal cardiovascular and metabolic systems. Stress was broadly defined to include environmental factors, hypoxia, maternal over-nutrition and malnutrition, physical factors including shear stress or pressure-induced forces. Particularly interesting was the concept of how NO synthesis, and its products (peroxynitrate, nitrosylated tyrosine residues) and growth factors are profoundly affected by in utero stress. We discussed the concept of developmental ‘windows’ in time, at which these stressor influences produce greater or lesser effects at certain stages of development and pregnancy. A second major and sequentially related theme was the ‘Developmental Origins of Adult Disease’, appropriately introduced by the originator of this concept, Professor David Barker (Barker 1995, 1998, 2000). Discussions focused on the concept that in utero stress ‘predisposes’ the individual to develop cardiovascular and metabolic diseases as an adult (Armitage et al. 2005; Hanson & Gluckman, 2005; McMillen et al. 2005). For example, the offspring of mothers that were nutritionally compromised in utero develop an earlier onset of cardiovascular disease (as evidenced by high blood pressure and cardiac mortality indices), as well as Type 2 diabetes and increased adiposity. These risk factors have been identified in small for gestational age babies, although it now appears that subtle developmental disturbances, rather than birth weight per se, are the major effectors of these critical developmental abnormalities (Barker, 1995, 1998). There was also lively discussion regarding the concept of ‘Predictive Adaptive Responses’, an extension of the ‘Thrifty Phenotype’ hypothesis. The theory suggests that the developing fetus can, through signals from the maternal ‘milieu’, anticipate its future environment and make necessary adaptation for survival in that environment whether rich or poor, but that if the actual environment is outside the limits of expectation, then the predictive adaptive responses can be positively disadvantageous, and disease may ensue (Armitage et al. 2005; Wallace et al. 2005; Hanson & Gluckman, 2005). The articles in this themed issue of The Journal of Physiology provide reviews and original papers which reflect the themes highlighted in the meeting and provide insight into the cardiovascular adaptation to pregnancy, and its consequences for the offspring, both short and long term, or perturbation of the maternal and fetal environment (Davis et al. 2005; Reynolds et al. 2005; Wallace et al. 2005). Notably we have included topical reviews and original research papers demonstrating the effects of distinct perturbations during gestation (nutritional restriction, energy rich exposure, preconception nutrition, fetal anaemia, hypoxia, high altitude and even cocaine exposure) and the utility of various animal models (e.g. rats, sheep, guinea pigs, etc.) on developmental programming (Armitage et al. 2005; McMillen et al. 2005; Reynolds et al. 2005; Wallace et al. 2005). Also included are articles on normal developmental changes related to cardiovascular development, placental angiogenesis (via VEGF, bFGF, etc.), nitric oxide regulation via alterations in steroid hormone receptors (e.g. oestrogen) and the renin–angiotensin system (Reynolds et al. 2005; Zheng et al. 2005). The 7 reviews and 11 research papers reflect the diversity of the research endeavours from numerous labs in what we believe will spawn new and exciting directions. The participants of this meeting and the authors of the articles hope that the questions and discussions in this themed issue of The Journal of Physiology will serve as a model, not only to those who are attempting to unravel developmental regulation of the perinatal cardiovascular and endocrine systems, but to scientists who wish to understand mechanistically how environmental influences can permanently affect the developing fetus and neonate, to increase the risk of later cardiovascular disease. The improved understanding of the basic developmental physiology of the cardiovascular system and the clinical implications that arise from this themed issue also should further justify this important multidisciplinary work.