The Obesity Epidemic: Metabolic Imprinting on Genetically Susceptible Neural Circuits

The apparent obesity epidemic in the industrialized world is not explained completely by increased food intake or decreased energy expenditure. Once obesity develops in genetically predisposed individuals, their obese body weight is avidly defended against chronic caloric restriction. In animals genetically predisposed toward obesity, there are multiple abnormalities of neural function that prime them to become obese when dietary caloric density and quantity are raised. Once obesity is fully developed, these abnormalities largely disappear. This suggests that obesity might be the normal state for such individuals. Formation of new neural circuits involved in energy homeostasis might underlie the near permanence of the obese body weight. Such neural plasticity can occur during both nervous system development and in adult life. Maternal diabetes, obesity, and undernutrition have all been associated with obesity in the offspring of such mothers, especially in genetically predisposed individuals. Altered brain neural circuitry and function often accompanies such obesity. This enhanced obesity may then be passed on to subsequent generations in a feed‐forward, upward spiral of increasing body weight across generations. Such findings suggest a form of “metabolic imprinting” upon genetically predisposed neural circuits involved in energy homeostasis. Centrally acting drugs used for obesity treatment lower the defended body weight and alter the function of neural pathways involved in energy homeostasis. But they generally have no permanent effect on body weight or neural function. Thus, early identification of obesity‐prone mothers, infants, and adults and treatment of early obesity may be the only way to prevent the formation of permanent neural connections that promote and perpetuate obesity in genetically predisposed individuals.     

Perinatal nutrition and hormone-dependent programming of food intake

It is increasingly accepted that alterations of the intrauterine and early postnatal nutritional, metabolic and hormonal environment may predispose individuals to development of diseases in later life. Results from studies of the offspring of diabetic mothers strongly support this hypothesis. It has also been suggested that being light at birth leads to an increased risk of the metabolic syndrome (Syndrome X) in later life (the Barker hypothesis). The pathophysiological mechanisms that underlie this programming are unclear. However, hormones are important environment-dependent organizers of the developing neuroendocrine-immune network, which regulates all the fundamental processes of life. Hormones can act as 'endogenous functional teratogens' when present in non-physiological concentrations, induced by alterations in the intrauterine or neonatal environment during critical periods of perinatal life. Perinatal hyperinsulinism is pathognomic in offspring of diabetic mothers. Early hyperinsulinism also occurs as a result of early postnatal overfeeding. In rats, endogenous hyperinsulinism, as well as peripheral or intrahypothalamic insulin treatment during perinatal development, may lead to 'malprogramming' of the neuroendocrine systems regulating body weight, food intake and metabolism. This results in an increased disposition to become obese and to develop diabetes throughout life. Similar malprogramming may occur due to perinatal hypercortisolism and hyperleptinism. With regard to 'small baby syndrome' and the thrifty phenotype hypothesis, we propose that early postnatal overfeeding of underweight newborns may substantially contribute to their long-term risk of obesity and diabetes. In summary, a complex malprogramming of the central regulation of body weight and metabolism may provide a general aetiopathogenetic concept, explaining perinatally acquired disposition to later disease and, thereby, opening a wide field for primary prevention.     

Endocrine disrupting chemicals and the developmental programming of adipogenesis and obesity

Obesity and related disorders are a burgeoning public health epidemic, particularly in the U.S. Currently 34% of the U.S. population is clinically obese (BMI > 30) and 68% are overweight (BMI > 25), more than double the worldwide average and 10-fold higher than Japan and South Korea. Obesity occurs when energy intake exceeds energy expenditure; however, individuals vary widely in their propensity to gain weight and accrue fat mass, even at identical levels of excess caloric input. Clinical, epidemiological, and biological studies show that obesity is largely programmed during early life, including the intrauterine period. The environmental obesogen hypothesis holds that prenatal or early life exposure to certain endocrine disrupting chemicals can predispose exposed individuals to increased fat mass and obesity. Obesogen exposure can alter the epigenome of multipotent stromal stem cells, biasing them toward the adipocyte lineage at the expense of bone. Hence, humans exposed to obesogens during early life might have an altered stem cell compartment, which is preprogrammed toward an adipogenic fate. This results in a higher steady state number of adipocytes and potentially a lifelong struggle to maintain a healthy weight, which can be exacerbated by societal influences that promote poor diet and inadequate exercise. This review focuses on the developmental origins of the adipocyte, the relationship between adipocyte number and obesity, and how obesogenic chemicals may interfere with the highly efficient homeostatic mechanisms regulating adipocyte number and energy balance.     

Early intake of long-chain polyunsaturated fatty acids preserves brain structure and function in diet-induced obesity

Worldwide, the incidence of obesity is increasing at an alarming rate, and the number of children with obesity is especially worrisome. These developments raise concerns about the physical, psychosocial and cognitive consequences of obesity. It was shown that early dietary intake of arachidonic acid (ARA) and docosahexaenoic acid (DHA) can reduce the detrimental effects of later obesogenic feeding on lipid metabolism and adipogenesis in an animal model of mild obesity. In the present study, the effects of early dietary ARA and DHA on cognition and brain structure were examined in mildly obesogenic ApoE*3Leiden mouse model. We used cognitive tests and neuroimaging during early and later life. During their early development after weaning (4–13 weeks of age), mice were fed a chow diet or ARA and DHA diet for 8 weeks and then switched to a high-fat and high-carbohydrate (HFHC) diet for 12 weeks (14–26 weeks of age). An HFHC-diet led to increased energy storage in white adipose tissue, increased cholesterol levels, decreased triglycerides levels, increased cerebral blood flow and decreased functional connectivity between brain regions as well as cerebrovascular and gray matter integrity. ARA and DHA intake reduced the HFHC-diet-induced increase in body weight, attenuated plasma triglycerides levels and improved cerebrovasculature, gray matter integrity and functional connectivity in later life. In conclusion, an HFHC diet causes adverse structural brain and metabolic adaptations, most of which can be averted by dietary ARA and DHA intake early in life supporting metabolic flexibility and cerebral integrity later in life.     

Body mass growth in common marmosets: Toward a model of pediatric obesity

While much is known about adult obesity in nonhuman primates, very little is known regarding development of childhood adiposity. As small monkeys that are easy to handle and have a relatively fast life history, common marmoset monkeys (Callithrix jacchus) offer interesting opportunities to examine the question of fat versus lean mass growth in a nonhuman primate. This article provides an overview of our understanding of early life growth in mass in marmoset monkeys, based primarily upon our past 20 years of research, culminating in our recent findings on early life obesity in this species. Common marmosets display variance in early life growth patterns that is related to both pre‐ and postnatal factors and the marmoset uterine environment is exquisitely designed to reflect resources available for the gestation of multiple offspring, making them an interesting model of developmental programming. We have demonstrated that obesity can be generated in very early life in captive marmosets, with excess adiposity evident by one month of age, making this species a potentially valuable model in which to study pediatric obesity and its sequelae. Birth weight is associated with adiposity in animals vulnerable to obesity. Early life exposure to higher fat diets enhances the chances of postweaning obesity development. However, overall higher food consumption is also associated with obesity development at later ages. One unexpected finding in our studies has been the relatively high body fat percentage of neonatal (12–18%) marmosets suggesting that hypotheses regarding the uniqueness of high human neonatal adiposity merit further examination. Am J Phys Anthropol, 2013. © 2012 Wiley Periodicals, Inc.     

Age- and gender-dependent obesity in individuals with 16p11.2 deletion

Recurrent genomic imbalances at 16p11.2 are genetic risk factors of variable penetrance for developmental delay and autism.Recently,16p11.2 (chr16:29.5 Mb-30.1 Mb) deletion has also been detected in individuals with early-onset severe obesity.The penetrance of 16p11.2deletion as a genetic risk factor for obesity is unknown.We evaluated the growth and body mass characteristics of 28 individuals with 16p11.2(chr16:29.5 Mb-30.1 Mb) deletion originally ascertained for their developmental disorders by reviewing their medical records.We found that nine individuals could be classilied as obese and six as overweight.These individuals generally had early feeding and growth difficulties,and started to gain excessive weight around 5-6 years of age.Thirteen out of the 18 deletion carriers aged 5 years and older (72％) were overweight or obese,whereas only two of 10 deletion carriers (20％) younger than five were overweight or obese.Males exhibited more severe obesity than females.Thus,the obesity phenotype of 16p11.2 deletion carriers is of juvenile onset,exhibited an age.and gender-dependent penetrance.16p11.2 deletion appears to predispose individuals to juvenile onset obesity and in this case are similar to the well-described Prader-Willi syndrome (PWS).Early detection of this deletion will provide opportunity to prevent obesity.     

Early dietary intervention: long-term effects on blood pressure, brain neuropeptide Y, and adiposity markers

Early life nutrition impacts on subsequent risk of obesity and hypertension. Several brain chemicals responsible for both feeding and cardiovascular regulation are altered in obesity. We examined effects of early postnatal overnutrition on blood pressure, brain neuropeptide Y (NPY), and adiposity markers. Rat pup litters were adjusted to either 3 or 12 male animals (overnutrition and control, respectively) on day 1 of life. After weaning, rats were given either a palatable high-fat diet or standard chow. Smaller litter pups were significantly heavier by 17 days of age. By 16 wk, the effect of litter size was masked by that of diet, postweaning. Small and normal litter animals fed a high-fat diet had similar increases in body weight, plasma insulin, leptin, and adiponectin concentrations, leptin mRNA, and fat masses relative to chow-fed animals. An increase in 11beta-hydroxysteroid dehydrogenase-1 mRNA in white adipose tissue, and a decrease in uncoupling protein-1 mRNA in brown adipose tissue in both small litter groups at 16 wk of age, may represent a programming effect of the altered litter size. NPY concentration in the paraventricular nucleus of the hypothalamus was reduced in high fat-fed groups. Blood pressure was significantly elevated at 13 wk in high-fat-fed animals. This study demonstrates that overnourishment during early postnatal development leads to profound changes in body weight at weaning, which tended to abate with maturation. Thus the effects of long-term dietary intervention postweaning can override those of litter size-induced obesity.     

Preventing excessive weight gain in adolescents: interpersonal psychotherapy for binge eating

The most prevalent disordered eating pattern described in overweight youth is loss of control (LOC) eating, during which individuals experience an inability to control the type or amount of food they consume. LOC eating is associated cross-sectionally with greater adiposity in children and adolescents and seems to predispose youth to gain weight or body fat above that expected during normal growth, thus likely contributing to obesity in susceptible individuals. No prior studies have examined whether LOC eating can be decreased by interventions in children or adolescents without full-syndrome eating disorders or whether programs reducing LOC eating prevent inappropriate weight gain attributable to LOC eating. Interpersonal psychotherapy, a form of therapy that was designed to treat depression and has been adapted for the treatment of eating disorders, has shown efficacy in reducing binge eating episodes and inducing weight stabilization among adults diagnosed with binge eating disorder. In this paper, we propose a theoretical model of excessive weight gain in adolescents at high risk for adult obesity who engage in LOC eating and associated overeating patterns. A rationale is provided for interpersonal psychotherapy as an intervention to slow the trajectory of weight gain in at-risk youth, with the aim of preventing or ameliorating obesity in adulthood.     

The developmental origins of obesity and related health disorders--prenatal and perinatal factors

Obesity, and its health-related sequelae (the metabolic syndrome), have recently emerged as a global health crisis. The prevalence of childhood and adult obesity in economically developed and developing countries world-wide has more than doubled over the past decade. While genetic factors, increasingly sedentary lifestyles, and overnutrition have all been cited as important components of the obesity crisis, recent epidemiological and experimental evidence suggests that developmental factors--especially those that occur in utero and during early postnatal life--play a significant role in the pandemic. Research into the 'developmental origins of health and disease' (DOHaD) has now firmly established that pre- and perinatal developmental perturbations which predispose to obesity in adult life can result from a variety of factors, including both nutritional surplus and deficiency, and there is growing evidence that these physiological traits can be passed on epigenetically to subsequent generations. Anthropological perspectives regarding the developmental origins of obesity and its related health problems cannot only shed further light on contemporary ethnic human health disparities, but can offer unique insights into the relevance of the developmental origins of disease to community-based public health interventions.     

A Temperature Hypothesis of Hypothalamus-Driven Obesity

Obesity is a metabolic state in which excess fat is accumulated in peripheral tissues, including the white adipose tissue, muscle, and liver. Sustained obesity has profound consequences on one’s life, which can span from superficial psychological symptoms to serious co-morbidities that may dramatically diminish both the quality and length of life. Obesity and related metabolic disorders account for the largest financial burden on the health care system. Together, these issues make it imperative that obesity be cured or prevented. Despite the increasing wealth of knowledge on the etiology of obesity (see below), there is no successful medical strategy that is available for the vast majority of patients. We suggest that brain temperature control may be a crucial component in obesity development and that shortcutting the brain metabolic centers by hypothalamic temperature alterations in a non-invasive remote manner will provide a revolutionary approach to the treatment of obesity.     

The evolution of human fatness and susceptibility to obesity: an ethological approach

Human susceptibility to obesity is an unusual phenomenon amongst animals. An evolutionary analysis, identifying factors favouring the capacity for fat deposition, may aid in the development of preventive public health strategies. This article considers the proximate causes, ontogeny, fitness value and evolutionary history of human fat deposition. Proximate causes include diet composition, physical activity level, feeding behaviour, endocrine and genetic factors, psychological traits, and exposure to broader environmental factors. Fat deposition peaks during late gestation and early infancy, and again during adolescence in females. As in other species, human fat stores not only buffer malnutrition, but also regulate reproduction and immune function, and are subject to sexual selection. Nevertheless, our characteristic ontogenetic pattern of fat deposition, along with relatively high fatness in adulthood, contrasts with the phenotype of other mammals occupying the tropical savannah environment in which hominids evolved. The increased value of energy stores in our species can be attributed to factors increasing either uncertainty in energy availability, or vulnerability to that uncertainty. Early hominid evolution was characterised by adaptation to a more seasonal environment, when selection would have favoured general thriftiness. The evolution of the large expensive brain in the genus Homo then favoured increased energy stores in the reproducing female, and in the offspring in early life. More recently, the introduction of agriculture has had three significant effects: exposure to regular famine; adaptation to a variety of local niches favouring population-specific adaptations; and the development of social hierarchies which predispose to differential exposure to environmental pressures. Thus, humans have persistently encountered greater energy stress than that experienced by their closest living relatives during recent evolution. The capacity to accumulate fat has therefore been a major adaptive feature of our species, but is now increasingly maladaptive in the modern environment where fluctuations in energy supply have been minimised, and productivity is dependent on mechanisation rather than physical effort. Alterations to the obesogenic environment are predicted to play a key role in reducing the prevalence of obesity.     

Models and mechanisms of metabolic regulation: genes, stress, and the HPA and HPG axes

A variety of models have been developed to better understand the mechanisms underlying individual variation in susceptibility to obesity. This review discusses several of these models and explores their role in understanding individual vulnerability to metabolic disease and the environmental factors around which metabolic perturbations occur. Recently, the focus of models has shifted towards heterogeneous populations, in which individuals characterized by a high vulnerability and individuals that are seemingly resistant can be identified. The use of these heterogeneous studies has lead to the identification of several novel biomarkers predicting obesity. This review therefore focuses on nontraditional factors, which are not directly implicated in metabolic regulation. First, the evidence from rodent knockout models for genetic factors involved in obesity is discussed. Second, the role of a stressful environment, particularly the early life environment is investigated along with a discussion of circadian disruption and metabolic disorders. Finally, the impact of sex-steroids, as exemplified by polycystic ovarian syndrome, is discussed. Overall, the data presented in our review demonstrate that in most cases interplay between genetic and environmental factors best predicts disease development. Our review shows that susceptibility to obesity may be explained by complex interactions between traditional homeostatic mechanisms, such as the hypothalamic peptide, and less studied mechanisms, like steroids and neurotrophic factors.     

Nutritional status, genetic susceptibility, and insulin resistance--important precedents to atherosclerosis

Atherosclerosis is a progressive disease that starts early in life and is manifested clinically as coronary artery disease (CAD), cerebrovascular disease, or peripheral artery disease. CAD remains the leading cause of morbidity and mortality in Western society despite the great advances made in understanding its underlying pathophysiology. The key risk factors associated with CAD include hypercholesterolemia, hypertension, poor diet, obesity, age, male gender, smoking, and physical inactivity. Genetics also play an important role that may interact with environmental factors, including diet, nutritional status, and physiological parameters. Furthermore, certain chronic inflammatory conditions also predispose to the development of CAD. The spiraling increase in obesity rates worldwide has made it more pertinent than ever before to understand the metabolic perturbations that link over nutrition to enhanced cardiovascular risk. Great breakthroughs have been made at the pharmacological level to manage CAD; statins and aspirin have revolutionized treatment of CAD and prolonged lifespan. Nonetheless, lifestyle intervention prior to clinical presentation of CAD symptoms would negate/delay the need for chronic pharmacotherapy in at-risk individuals which in turn would relieve healthcare systems of a costly burden. Throughout this review, we debate the relative impact of nutrition versus genetics in driving CAD. We will investigate how overnutrition affects adipose tissue biology and drives IR and will discuss the subsequent implications for the cardiovascular system. Furthermore, we will discuss how lifestyle interventions including diet modification and weight loss can improve both IR and metabolic dyslipidemia that is associated with obesity. We will conclude by delving into the concept that nutritional status interacts with genetic susceptibility, such that perhaps a more personalized nutrition approach may be more effective in determining diet-related risk as well as response to nutritional interventions.     

The mating brain: early maturing sneaker males maintain investment into the brain also under fast body growth in Atlantic salmon (Salmo salar)

It has been suggested that mating behaviours require high levels of cognitive ability. However, since investment into mating and the brain both are costly features, their relationship is likely characterized by energetic trade-offs. Empirical data on the subject remains equivocal. We investigated if early sexual maturation was associated with brain development in Atlantic salmon (Salmo salar), in which males can either stay in the river and sexually mature at a small size (sneaker males) or migrate to the sea and delay sexual maturation until they have grown much larger (anadromous males). Specifically, we tested how sexual maturation may induce plastic changes in brain development by rearing juveniles on either natural or ad libitum feeding levels. After their first season we compared brain size and brain region volumes across both types of male mating tactics and females. Body growth increased greatly across both male mating tactics and females during ad libitum feeding as compared to natural feeding levels. However, despite similar relative increases in body size, early maturing sneaker males maintained larger relative brain size during ad libitum feeding levels as compared to anadromous males and females. We also detected several differences in the relative size of separate brain regions across feeding treatments, sexes and mating strategies. For instance, the relative size of the cognitive centre of the brain, the telencephalon, was largest in sneaker males. Our data support that a large relative brain size is maintained in individuals that start reproduction early also during fast body growth. We propose that the cognitive demands during complex mating behaviours maintain a high level of investment into brain development in reproducing individuals.     

Animal models of in utero exposure to a high fat diet: A review

The incidence of metabolic disease, including type 2 diabetes and obesity, has increased to epidemic levels in recent years. A growing body of evidence suggests that the intrauterine environment plays a key role in the development of metabolic disease in offspring. Among other perturbations in early life, alteration in the provision of nutrients has profound and lasting effects on the long term health and well being of offspring. Rodent and non-human primate models provide a means to understand the underlying mechanisms of this programming effect. These different models demonstrate converging effects of a maternal high fat diet on insulin and glucose metabolism, energy balance, cardiovascular function and adiposity in offspring. Furthermore, evidence suggests that the early life environment can result in epigenetic changes that set the stage for alterations in key pathways of metabolism that lead to type 2 diabetes or obesity. Identifying and understanding the causal factors responsible for this metabolic dysregulation is vital to curtailing these epidemics. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.     

Pediatric stress: hormonal mediators and human development

Stress activates the central and peripheral components of the stress system, i.e., the hypothalamic-pituitary-adrenal (HPA) axis and the arousal/sympathetic system. The principal effectors of the stress system are corticotropin-releasing hormone (CRH), arginine vasopressin, the proopiomelanocortin-derived peptides alpha-melanocyte-stimulating hormone and beta-endorphin, the glucocorticoids, and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development, and may account for a number of endocrine, metabolic, autoimmune and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors and the timing of the stressful event(s), given that prenatal life, infancy, childhood and adolescence are critical periods characterized by increased vulnerability to stressors. The developing brain undergoes rapid growth and is characterized by high turnover of neuronal connections during the prenatal and early postnatal life. These processes and, hence, brain plasticity, slow down during childhood and puberty, and plateau in young adulthood. Hormonal actions in early life, and to a much lesser extent later, can be organizational, i.e., can have effects that last for long periods of time, often for the entire life of the individual. Hormones of the stress system and sex steroids have such effects, which influence the behavior and certain physiologic functions of individuals for life. Exposure of the developing brain to severe and/or prolonged stress may result in hyperactivity/hyperreactivity of the stress system, with resultant amygdala hyperfunction (fear reaction), decreased activity of the hippocampus (defective glucocorticoid-negative feedback, cognition), and the mesocorticolimbic dopaminergic system (dysthymia, novelty-seeking, addictive behaviors), hyperactivation of the HPA axis (hypercortisolism), suppression of reproductive, growth, thyroid and immune functions, and changes in pain perception. These changes may be accompanied by abnormal childhood, adolescent and adult behaviors, including excessive fear ('inhibited child syndrome') and addictive behaviors, dysthymia and/or depression, and gradual development of components of the metabolic syndrome X, including visceral obesity and essential hypertension. Prenatal stress exerted during the period of sexual differentiation may be accompanied by impairment of this process with behavioral and/or somatic sequelae. The vulnerability of individuals to develop varying degrees and/or components of the above life-long syndrome is defined by as yet unidentified genetic factors, which account for up to 60% of the variance. CRH has marked kindling and glucocorticoids have strong consolidating properties, hence both of these hormones are crucial in development and can alone produce the above syndrome. CRH and glucocorticoids may act in synergy, as in acoustic startle, while glucocorticoids may suppress or stimulate CRH, as in the hypothalamus and amygdala, respectively. A CRH type 1 receptor antagonist, antalarmin, inhibits both the development and expression of conditioned fear in rats, and has anxiolytic properties in monkeys. Profound stressors, such as those from sexual abuse, may elicit the syndrome in older children, adolescents and adults. Most frequently, chronic dysthymia and/or depression may develop in association with gastrointestinal complaints and/or the premenstrual tension syndrome. A lesser proportion of individuals may develop the classic posttraumatic stress disorder, which is characterized by hypocortisolism and intrusive and avoidance symptoms; in younger individuals it may present as dissociative personality disorder.     

Influence of adipose tissue immune dysfunction on childhood obesity

In recent decades, a dramatic rise has been observed in the prevalence of obesity in childhood and adolescence, along with an increase in fetal microsomia rates. The increased risk of obesity during this key period in development negatively affects the health of the individual later in life. Immune cells residing and recruited to white adipose tissue have been highlighted as important factors contributing to the pathogenesis of childhood obesity. Immune dysfunction in the context of obesity begins early in childhood, which is different from the pathological characteristics and influencing factors of adipose immunity in adults. Here, we explore the current understanding of the roles of childhood and early life events that result in high risks for obesity by influencing adipose tissue immune dysfunction under the pathological condition of obesity. Such knowledge will help in determining the mechanisms of childhood and early life obesity in efforts to ameliorate chronic inflammation-related metabolic diseases.     

Hyperleptinemia Is Required for the Development of Leptin Resistance

Leptin regulates body weight by signaling to the brain the availability of energy stored as fat. This negative feedback loop becomes disrupted in most obese individuals, resulting in a state known as leptin resistance. The physiological causes of leptin resistance remain poorly understood. Here we test the hypothesis that hyperleptinemia is required for the development of leptin resistance in diet-induced obese mice. We show that mice whose plasma leptin has been clamped to lean levels develop obesity in response to a high-fat diet, and the magnitude of this obesity is indistinguishable from wild-type controls. Yet these obese animals with constant low levels of plasma leptin remain highly sensitive to exogenous leptin even after long-term exposure to a high fat diet. This shows that dietary fats alone are insufficient to block the response to leptin. The data also suggest that hyperleptinemia itself can contribute to leptin resistance by downregulating cellular response to leptin as has been shown for other hormones.     

Selective Leptin Insensitivity and Alterations in Female-Reproductive Patterns Linked to Hyperleptinemia during Infancy

The dramatic increase in the prevalence of childhood obesity worldwide makes the investigation of its early developmental stages and effective prevention strategies an urgent issue. CCK₁ deficient OLETF rats are a model of obesity previously used to study the early phases of this disorder. Here, we exposed wild type (LETO) females to an early obesogenic environment and genetically obese OLETF females to a lean postnatal environment, to assess long term alterations in leptin sensitivity, predisposition to diet induced obesity and adult female health. We found that genetically lean females reared by obese mothers presented early postnatal hyperleptemia, selectively reduced response to leptin and sensitivity to diet induced obesity when exposed to a high palatable diet as adults. The estrous cycle structure and intake profile were permanently disrupted, despite presenting normal adiposity/body weight/food intake. Genetically obese females reared by lean dams showed normalized early levels of leptin and reduced body weight, food intake and body fat at adulthood; normalized estrous cycle structure and food intake across the cycle, improved hormonal profile and peripheral leptin sensitivity and a remarkable progress in self-control when exposed to a high fat/palatable diet. Altogether, it appears that the early postnatal environment plays a critical role in determining later life coping with metabolic challenges and has an additive effect on the genetic predisposition that makes OLETF females morbidly obese as adults. This work also links, for the first time, alterations in the leptin system during early development to later life abnormalities related to female reproduction and health.