Early life programming of obesity and metabolic disease

It is becoming increasingly apparent that conditions experienced in early life play an important role in the long-term health of individuals. Alterations in development due to impaired, excessive or imbalanced growth, both in utero and during critical periods of relative plasticity beyond birth, can lead to the permanent programming of physiological systems. The regulation of energy balance is one area that is receiving particular attention, as rates of obesity and associated metabolic and cardiovascular disease continue to rise. Over recent decades, much progress has been made toward understanding the way in which metabolic tissues and physiological systems develop, and the impact of early life events and nutrition on these processes. It is apparent within human populations that some individuals are better able to maintain an appropriate body weight in the face of an obesogenic environment. Animal models have been widely used for the investigation of differential susceptibility to diet-induced obesity (DIO) and impaired energy balance regulation, and are shedding light on key pathways that may be involved. Alterations in pathways mediating energy homeostasis, outlined below, are likely candidates for programming effects following disturbed growth in early life.     

On the waterfront: predictive and reactive regulatory descriptions of thirst and sodium appetite

The concepts of homeostasis and regulation are discussed and examples are given in which current regulatory models of ingestive behavior inadequately predict or explain the observed phenomena. The implications of this for the choice of experimental paradigms, and the interpretation of neurobiological data obtained therein, are discussed. Paradigms that allow the expression of behavioral strategies and learned responses may be biologically more relevant than the more popular but highly constrained "physiologic" paradigms.     

Developmental origins of the metabolic syndrome: prediction, plasticity, and programming

The "fetal" or "early" origins of adult disease hypothesis was originally put forward by David Barker and colleagues and stated that environmental factors, particularly nutrition, act in early life to program the risks for adverse health outcomes in adult life. This hypothesis has been supported by a worldwide series of epidemiological studies that have provided evidence for the association between the perturbation of the early nutritional environment and the major risk factors (hypertension, insulin resistance, and obesity) for cardiovascular disease, diabetes, and the metabolic syndrome in adult life. It is also clear from experimental studies that a range of molecular, cellular, metabolic, neuroendocrine, and physiological adaptations to changes in the early nutritional environment result in a permanent alteration of the developmental pattern of cellular proliferation and differentiation in key tissue and organ systems that result in pathological consequences in adult life. This review focuses on those experimental studies that have investigated the critical windows during which perturbations of the intrauterine environment have major effects, the nature of the epigenetic, structural, and functional adaptive responses which result in a permanent programming of cardiovascular and metabolic function, and the role of the interaction between the pre- and postnatal environment in determining final health outcomes.     

Developmental programming of obesity in mammals

Converging lines of evidence from epidemiological studies and animal models now indicate that the origins of obesity and related metabolic disorders lie not only in the interaction between genes and traditional adult risk factors, such as unbalanced diet and physical inactivity, but also in the interplay between genes and the embryonic, fetal and early postnatal environment. Whilst studies in man initially focused on the relationship between low birth weight and risk of adult obesity and metabolic syndrome, evidence is also growing to suggest that increased birth weight and/or adiposity at birth can also lead to increased risk for childhood and adult obesity. Hence, there appears to be increased risk of obesity at both ends of the birth weight spectrum. Animal models, including both under- and overnutrition in pregnancy and lactation lend increasing support to the developmental origins of obesity. This review focuses upon the influence of the maternal nutritional and hormonal environment in pregnancy in permanently programming appetite and energy expenditure and the hormonal, neuronal and autocrine mechanisms that contribute to the maintenance of energy balance in the offspring. We discuss the potential maternal programming 'vectors' and the molecular mechanisms that may lead to persistent pathophysiological changes resulting in subsequent disease. The perinatal environment, which appears to programme subsequent obesity, provides a potential therapeutic target, and work in this field will readily translate into improved interventional strategies to stem the growing epidemic of obesity, a disease which, once manifest, has proven particularly resistant to treatment.     

The role of peptide YY in appetite regulation and obesity

The last decade has witnessed a marked increase in our understanding of the importance of gut hormones in the regulation of energy homeostasis. In particular, the discovery that the gut hormone peptide YY 3–36 (PYY3–36) reduced feeding in obese rodents and humans fuelled interest in the role of PYY3–36 in body weight regulation. Pharmacological and genetic approaches have revealed that the Y2-receptor mediates the anorectic effects of PYY3–36 whilst mechanistic studies in rodents identified the hypothalamus, vagus and brainstem regions as potential sites of action. More recently, using functional brain imaging techniques in humans, PYY3–36 was found to modulate neuronal activity within hypothalamic and brainstem, and brain regions involved in reward processing. Several lines of evidence suggest that low circulating PYY concentrations predispose towards the development and or maintenance of obesity. Subjects with reduced postprandial PYY release exhibit lower satiety and circulating PYY levels that correlate negatively with markers of adiposity. In addition, mice lacking PYY are hyperphagic and become obese. Conversely, chronic PYY3–36 administration to obese rodents reduces adiposity, and transgenic mice with increased circulating PYY are resistant to diet-induced obesity. Moreover, there is emerging evidence that PYY3–36 may partly mediate the reduced appetite and weight loss benefits observed post-gastric bypass surgery. Taken together these findings, coupled with the retained responsiveness of obese subjects to the effects of PYY3–36, suggest that targeting the PYY system may offer a therapeutic strategy to help treat obesity.     

Maternal obesity and the developmental programming of hypertension: a role for leptin

Mother–child cohort studies have established that both pre‐pregnancy body mass index (BMI) and gestational weight gain are independently associated with cardio‐metabolic risk factors in young adult offspring, including systolic and diastolic blood pressure. Animal models in sheep and non‐human primates provide further evidence for the influence of maternal obesity on offspring cardiovascular function, whilst recent studies in rodents suggest that perinatal exposure to the metabolic milieu of maternal obesity may permanently change the central regulatory pathways involved in blood pressure regulation. Leptin plays an important role in the central control of appetite, is also involved in activation of efferent sympathetic pathways to both thermogenic and non‐thermogenic tissues, such as the kidney, and is therefore implicated in obesity‐related hypertension. Leptin is also thought to have a neurotrophic role in the development of the hypothalamus, and altered neonatal leptin profiles secondary to maternal obesity are associated with permanently altered hypothalamic structure and function. In rodent studies, maternal obesity confers persistent sympathoexcitatory hyper‐responsiveness and hypertension acquired in the early stages of development. Experimental neonatal hyperleptinaemia in naive rat pups provides further evidence of heightened sympathetic tone and proof of principle that hyperleptinaemia during a critical window of hypothalamic development may directly lead to adulthood hypertension. Insight from these animal models raises the possibility that early‐life exposure to leptin in humans may lead to early onset essential hypertension. Ongoing mother–child cohort and intervention studies in obese pregnant women provide a unique opportunity to address associations between maternal obesity and offspring cardiovascular function. The goal of the review is to highlight the potential importance of leptin in the developmental programming of hypertension in obese pregnancy.     

Pathogenesis and pharmacologic treatment of obesity: the role of energy regulatory mechanism

Obesity has become a worldwide public health problem affecting millions of people. This is a chronic, stigmatized, and costly disease, rarely curable and is increasing in prevalence to a point today where we define obesity as an epidemic disease that not only in developed but also on developing countries. The pathogenesis of obesity is largely unknown, especially about energy regulatory mechanism that involved wide area of neuroendocrinology that is very interesting but very complex and makes internists "refuse" to learn. Obesity occurs through a longstanding imbalance between energy intake and energy expenditure, influenced by a complex biologic system that regulates appetite and adiposity. Obesity influences the pathogenesis of hypertension, type 2 diabetes, dyslipidemia, kidney, heart, and cerebrovascular disease. It is very wise for every internist to learn the pathogenesis and treatment of this worldwide diseases. Until now, the available treatments, including drugs, are palliative and are effective only while the treatment is being actively used; and besides so many side effects reported.     

Perinatal undernutrition-induced obesity is independent of the developmental programming of feeding

Protein or calorie restriction during gestation and/or suckling induces hyperphagia and increases the susceptibility to develop obesity, glucose intolerance and hypertension in adulthood. The mechanisms by which early nutrient restriction affects the normal physiological regulation of feeding as well as to what extent the metabolic programming of hyperphagia contributes to the long-term risk of obesity and insulin resistance remain, however, to be determined. Here the temporal pattern of food intake and the behavioural satiety sequence were investigated in the offspring of Sprague-Dawley rats fed a control (C) or a low-protein (LP) diet throughout pregnancy and lactation. During the first two months of their post-natal life, protein-restricted animals exhibited hyperphagia characterized by a delayed appearance of satiety, an increase in meal size and reduced latency to eat. Protein-restricted pups also exhibited an enhanced expression of the orexigenic peptides Agouti-related protein and neuropeptide Y and decreased hypothalamic levels of the anorexigenic peptide pro-opiomelanocortin. At 8 months, LP rats still consumed larger meals than their control counterparts but they ingested daily the same amount of food as control offspring and exhibited enhanced abdominal fat and increased levels of triglycerides and fatty acids in serum. These observations indicate that the hyperphagia observed in young LP rats results from a decreased action of negative feedback signals critical to meal termination and an enhanced function of the positive signals that initiate and maintain eating. These results also suggest that perinatal malnutrition programmes obesity through a mechanism independent of its effects on feeding behaviour.     

Evolutionary origins of the purinergic signalling system

Purines appear to be the most primitive and widespread chemical messengers in the animal and plant kingdoms. The evidence for purinergic signalling in plants, invertebrates and lower vertebrates is reviewed. Much is based on pharmacological studies, but important recent studies have utilized the techniques of molecular biology and receptors have been cloned and characterized in primitive invertebrates, including the social amoeba Dictyostelium and the platyhelminth Schistosoma, as well as the green algae Ostreococcus, which resemble P2X receptors identified in mammals. This suggests that contrary to earlier speculations, P2X ion channel receptors appeared early in evolution, while G protein‐coupled P1 and P2Y receptors were introduced either at the same time or perhaps even later. The absence of gene coding for P2X receptors in some animal groups [e.g. in some insects, roundworms (Caenorhabditis elegans) and the plant Arabidopsis] in contrast to the potent pharmacological actions of nucleotides in the same species, suggests that novel receptors are still to be discovered.     

Alcohol, appetite and energy balance: Is alcohol intake a risk factor for obesity?

The increased recognition that the worldwide increase in incidence of obesity is due to a positive energy balance has lead to a focus on lifestyle choices that may contribute to excess energy intake, including the widespread belief that alcohol intake is a significant risk factor for development of obesity. This brief review examines this issue by contrasting short-term laboratory-based studies of the effects of alcohol on appetite and energy balance and longer-term epidemiological data exploring the relationship between alcohol intake and body weight. Current research clearly shows that energy consumed as alcohol is additive to that from other dietary sources, leading to short-term passive over-consumption of energy when alcohol is consumed. Indeed, alcohol consumed before or with meals tends to increase food intake, probably through enhancing the short-term rewarding effects of food. However, while these data might suggest that alcohol is a risk factor for obesity, epidemiological data suggests that moderate alcohol intake may protect against obesity, particularly in women. In contrast, higher intakes of alcohol in the absence of alcohol dependence may increase the risk of obesity, as may binge-drinking, however these effects may be secondary to personality and habitual beverage preferences.     

Perinatal programming and functional teratogenesis: impact on body weight regulation and obesity

It is increasingly accepted that alterations of the intrauterine and early postnatal nutritional, metabolic, and hormonal environment may cause predispositions for the development of diseases in later life. Studies in the offspring of diabetic mothers have decisively contributed to this perception. Alterations of the fetal and neonatal environment which offspring of diabetic mothers 'experience' seem to program a disposition to develop obesity, diabetes mellitus and Syndrome X-like alterations throughout later life. Underweight at birth is also suggested to lead to an increased risk of Syndrome X in later life ('Barker hypothesis'). Pathophysiological mechanisms are unclear. Hormones are important environment-dependent organizers of the developing neuro-endocrine-immune network, which finally regulates all fundamental processes of life. When present in non-physiological concentrations during 'critical periods' of perinatal life, induced by alterations in the intrauterine or neonatal environment, hormones can act as 'endogenous functional teratogens'. Perinatal hyperinsulinism is pathognomonic in the offspring of diabetic mothers. Early hyperinsulinism also occurs as a result of early postnatal overfeeding. In rats, endogenous hyperinsulinism, as well as peripheral or only intrahypothalamic insulin treatment during perinatal development, may lead to 'malprogramming' of neuroendocrine systems regulating body weight, food intake and metabolism. This results in an increased disposition to become obese and to develop diabetes throughout life. In conclusion, a complex malprogramming of the central regulation of body weight and metabolism may provide a general etiopathogenetic concept, explaining perinatally acquired dispositions, thereby opening a wide field of primary prevention.     

Thirst and sodium appetite after colloid treatment in rats: role of the renin-angiotensin-aldosterone system

Recent experiments indicated that rats usually develop sodium appetite 5 hr after subcutaneous injection of polyethylene glycol (PEG) solution. However, sodium appetite appeared within 30 to 60 min if the rats had been maintained on sodium-deficient diet instead of Purina chow for 2-4 days previously. Elevated levels of aldosterone paralleled the appearance of NaCl consumption in both circumstances. In the present experiments, sodium appetite was no longer potentiated by pretreatment maintenance on sodium-deficient diet when the hypersecretion of aldosterone after PEG administration was prevented by prior hypophysectomy. Conversely, sodium appetite was enhanced in PEG-treated rats when angiotensin II (AII) was produced in unusually large amounts in the brain, owing to the systemic administration of captopril. This latter effect occurred even when drinking water was withheld and plasma sodium concentrations were markedly elevated. These and other findings raise the possibility that the normal secretion of aldosterone in rats after PEG treatment might permit physiological amounts of AII to be effective in stimulating sodium appetite. Such actions would complement the accepted physiological role of the renin-angiotension-aldosterone system in the maintenance of blood pressure and sodium balance.     

B-cell-derived lymphokines: regulatory effects on the immune system

While both regulatory and effector functions within the T cell lineage have been extensively studied, B lymphocytes have been considered merely a source of humoral antibodies until recently. With the exception of antibody feedback, only a limited number of investigations have been designed to explore the possibility that B cells may exert regulatory activity. The purpose of this review is to analyze how B cells can modulate themselves by generating signals (lymphokines), which under certain circumstances may initiate a chain of regulatory events. Only factors exclusively produced by B cells are considered. While, for the most part, this review is dedicated to recent studies on nonimmunoglobulin B cell factors, the role played by Ig molecules as immunoregulatory linker molecules, independently of their antigenic specificity, will be briefly examined. Furthermore, some basic questions regarding the biological significance of these regulatory mechanisms will be raised.     

Description and evaluation of a Newton-based electronic appetite rating system for temporal tracking of appetite in human subjects

This study assessed the reliability and validity of a palm-top-based electronic appetite rating system (EARS) in relation to the traditional paper and pen method. Twenty healthy subjects [10 male (M) and 10 female (F)] - mean age M=31 years (S.D.=8), F=27 years (S.D.=5); mean BMI M=24 (S.D.=2), F=21 (S.D.=5) - participated in a 4-day protocol. Measurements were made on days 1 and 4. Subjects were given paper and an EARS to log hourly subjective motivation to eat during waking hours. Food intake and meal times were fixed. Subjects were given a maintenance diet (comprising 40% fat, 47% carbohydrate and 13% protein by energy) calculated at 1.6xResting Metabolic Rate (RMR), as three isoenergetic meals. Bland and Altman's test for bias between two measurement techniques found significant differences between EARS and paper and pen for two of eight responses (hunger and fullness). Regression analysis confirmed that there were no day, sex or order effects between ratings obtained using either technique. For 15 subjects, there was no significant difference between results, with a linear relationship between the two methods that explained most of the variance (r(2) ranged from 62.6 to 98.6). The slope for all subjects was less than 1, which was partly explained by a tendency for bias at the extreme end of results on the EARS technique. These data suggest that the EARS is a useful and reliable technique for real-time data collection in appetite research but that it should not be used interchangeably with paper and pen techniques.     

Endogenous opioids and cannabinoids: system interactions in the regulation of appetite, grooming and scratching

Growing evidence suggests substantial crosstalk between endogenous opioid and cannabinoid systems in the regulation of appetite. Not only is cannabinoid-induced hyperphagia abolished by opioid receptor antagonists (and vice versa), but several laboratories have reported supra-additive anorectic responses following co-administration of opioid and CB1 receptor antagonists. In the present study, videoanalysis has been used to characterise the acute effects of sub-anorectic doses of rimonabant (0.25, 0.75 mg/kg) and naloxone (0.1 mg/kg), alone and in combination, on mash intake, ingestive and non-ingestive behaviour, and post-treatment weight gain in male rats. The results confirmed that, when administered alone, none of these treatments significantly altered mash consumption, various measures of feeding behaviour, or weight gain. Although most non-ingestive behaviours were also unaffected, 0.75 mg/kg rimonabant induced compulsive scratching and grooming. However, when naloxone was given in combination with either dose of rimonabant, both food intake and time spent feeding were significantly decreased while the behavioural satiety sequence (BSS) was accelerated. On further analysis, the co-treatment reductions in food intake and feeding behaviour were found to be of an additive rather than supra-additive nature. Intriguingly, the co-administration of naloxone also virtually abolished the compulsive scratching response to the higher dose of rimonabant. Findings are discussed in relation to current views on the molecular bases of opioid-cannabinoid system interactions and the unexpected 'dual' advantage (reduction in appetite plus attenuation of side-effect) of low-dose combinations of opioid and cannabinoid CB1 receptor antagonists.     

Telescoping the origins of obesity to women's bodies: How gender inequalities are being squeezed out of Barker's hypothesis

Aim: This paper traces the genealogy of the Barker hypothesis and its intersections with popular representations of scientific discourses about pregnancy and maternal obesity.

Method: Drawing on Foucault's genealogical method, this study examines the historical ‘descent’ of the developmental origins of adult disease and its initial grounding in structural factors of gender inequality and low socioeconomic status.

Results: In the more recent reproductive medicine literature, Barker's hypothesis has been used to understand the causes and consequences of foetal over-nutrition and has shifted its focus from social determinants to individual, gendered bodies. The print media has gainfully employed this conceptualization of obesity and, in doing so, placed women, and mothers in particular, as causal agents in the reproduction of obesity across generations. Such a ‘common sense’ understanding of obesity production and reproduction means that both the scientific literature and the public understanding of science has inadvertently assisted in putting women forward as the transmitters of obesity across generations.

Conclusions: This powerful telescoping of the origins of obesity to women's bodies and their appetites is in stark contrast to earlier foci on gender inequalities and changing women's circumstances.     

Early trauma and adult obesity: Is psychological dysfunction the mediating mechanism?

Several studies have shown that physical and/or sexual abuse during childhood may lead to the development of obesity later in life. Despite these consistent findings, the mechanism for the increased risk of obesity following developmental trauma is unknown. It has been suggested that psychological dysfunction, including the presence of disordered eating behavior, may account for the added risk of adult obesity. To test this hypothesis, we analyzed the prevalence and severity of different types of early traumatic life events, assessed the presence of co-existing psychiatric disorders and measured adult attachment style in a sample of 200 subjects including non-obese healthy volunteers and obese participants undergoing a psychiatric assessment to determine suitability for bariatric surgery. Participants who scored higher on a scale measuring the severity of traumatic events experienced during the first 15 years of their lives were more likely to be obese at the time of testing. The exclusion of the participants who experienced physical and/or sexual abuse did not change the results of statistical analysis. Severity of early trauma remained a significant predictor of adult obesity when the influence of psychiatric diagnosis and anxious attachment was taken into account. These findings suggest that: (1) not only sexual or physical abuse but also less severe forms of early-life stress are linked to the development of obesity later in life; and (2) psychological dysfunction is not the only mechanism mediating the elevated risk of obesity in persons exposed to early-life trauma.