These include the immune system leptin, the MCs , bone formation and remodeling leptin, NPY, CART, MCH , blood pressure and cardiovascular regulation leptin, NPY , kidney function NPY , reproduction NPY, MCH , stress NPY, CART, CRH, MCH , pigmentation and pain sensation the MCs , reward and addiction CART, MCH , anxiety MCH , and the wake-sleep cycle MCH and ORX , , , — This section is not meant to be exhaustive, but intends merely to give an impression of the complexity of the regulation of energy balance summarized in Fig.

However, despite the many interconnections, the main pathway is believed to be from the peripheral input to the ARC with NPY, AgRP, POMC, and CART , via the PVN CRH and TRH and LHA MCH and ORX , to the output systems as depicted in Fig.

Although at first sight these peptides all seem to fulfill one of two functions orexigenic or anorexigenic , subtle differences between these peptides are revealed upon closer inspection.

We have concentrated on evidence from rodents. Although some variation in the details exists 38 , , the regulation of energy balance is very similar in different animal species, including humans.

Simplified diagrams of the hypothalamic regulation of energy balance. Besides the main pathway see Fig. Note that in A, the connection to the LHA does not contact MCH or ORX neurons directly. To program a certain system or function, an environmental stimulus must occur during a period in development when the system or function is still plastic.

In rodents, the energy balance-regulating system is structurally and functionally immature at the start of postnatal life. The basic anatomy of the rat hypothalamus is established prenatally, with its nuclei expressing specific neuropeptides being recognizable before birth , but the majority of connections between the hypothalamus and its input and output systems , , and those within the hypothalamus itself 27 , , develop only in the first weeks after birth.

This rapid postnatal development is also reflected in overall brain growth: in neonatal rats, total brain weight increases by a factor 5 between birth and weaning Developing rat pups go through some major transitions.

Whereas the fetus receives mainly glucose, lactate, and amino acids via the placenta, at birth the source of energy changes to high-fat mother's milk Only a few weeks later, the pups are weaned and make a more gradual transition to the high-carbohydrate, low-fat adult diet , At the same time, the pups have to make the transition from obtaining all energy and fluids from the dam by suckling to the two separate processes of feeding and drinking As will be described below, different mechanisms appear to regulate these different types of ingestive behavior.

Rat pups as young as 1 d old already regulate their milk intake according to how deprived they are , The only cue that suckling rats have been shown to use to regulate their milk intake is the distension by gastrointestinal fill , This response is mediated primarily by vagus nerve activity , , and hence by the brainstem rather than by the hypothalamus.

Other signals that influence food intake in adult rats, such as the nutritional value of the stomach contents, serum leptin levels, and manipulations of levels of glucose and free fatty acids, do not affect intake in suckling rats , , It appears that the regulation of energy balance in the suckling pup is limited to optimizing energy intake for growth, and intake is only restricted by a full stomach to prevent gross overeating.

Therefore, in suckling pups there seems to be only short-term regulation of milk intake, with no long-term regulation Thermoregulation and the regulation of adult forms of ingestion then develop in the early postnatal period.

From d 1 on, pups can already regulate their temperature by moving toward or away from a heat source , whereas mechanisms for thermogenesis develop over the first 2 wk of life In the first 10 d of life, gastric distension is the only cue that terminates intake.

From then on, the nutritive value of the gastric content starts to play a role reviewed in Refs. At this same age, pups first start to adjust their intake according to their level of fatty acids reviewed in Ref.

Another major development event is the differentiation between feeding and drinking; young pups simply increase their intake when they are dehydrated, and only from around the age of 20 d they will reduce their milk intake when dehydrated, a phenomenon called dehydration anorexia reviewed in Refs.

The development of the regulation of energy balance is accompanied by changes in mRNA and protein levels of the reviewed peptides. The ontogeny of these peptides is summarized in Sections III. In rats, leptin can be detected in fetal plasma on d 19 of gestation In nearly full-term fetuses d 20—21 , leptin levels strongly resembled those of the pregnant dams , Leptin mRNA is already expressed by rat adipose tissue at birth, and its expression and serum levels are immediately regulated by the nutritional status of the neonatal pup In addition, Ob-Rb, the leptin receptor, has been shown to be expressed in the fetal brain as early as d 14 of gestation , During the lactation period, leptin undergoes some major changes.

A first, relatively small increase in serum leptin levels can be detected in rat pups 1 to 2 d old , , followed by a second and larger peak around d 7 to 12 — Interestingly, this leptin surge is unrelated to changes in body weight and fat content in the neonatal period , The high leptin levels do coincide with elevated leptin mRNA in neonatal adipose tissue, suggesting that the peak originates from the pups' own leptin production Both the neonatal pituitary, which has high leptin expression during this period , and the dam's milk may contribute to the leptin surge.

In concert with the changes in leptin levels, hypothalamic levels of Ob-Rb and its mRNA rise significantly between birth and weaning , Leptin's functionality in the regulation of energy balance appears to be partial in the neonatal period.

In rats as young as 1 wk old, leptin injections are found to reduce gain in body weight and especially in fat mass, without any effect on milk intake , — Instead, these effects seem to be the result of an increase in energy expenditure , Leptin is effective in increasing POMC and decreasing NPY mRNA in the ARC of rats in this neonatal period , and a robust positive relation between leptin levels and fat mass has been reported on d 10 The exact timing of the development of this system seems to differ between mice and rats.

In mice, serum leptin levels were not altered after milk deprivation on d 8 , energy expenditure was not yet increased by leptin injections on d 9 , and daily leptin injections in the second week of postnatal life were not found to affect hypothalamic neuropeptide expression During the period of partial functionality in energy balance regulation, leptin has a neurotrophic role.

In the absence of leptin, general brain development and that of the hypothalamic circuitry specifically are impaired , Leptin shares this property with insulin, which is also implicated in brain development.

The neurotrophic actions of insulin include stimulation of neurite outgrowth, protein synthesis, and neuronal survival — Furthermore, the lining of the third ventricle has been shown to contain neural progenitor cells that can be induced by neurotrophic factors to proliferate and differentiate into functional hypothalamic neurons , This residual plasticity of the hypothalamic circuitry in adulthood provides an additional route by which environmental signals including leptin can regulate energy balance The four reviewed peptides that are expressed by the ARC NPY, AgRP, POMC, and CART are already expressed in the prenatal rat brain However, ARC projections to other hypothalamic nuclei only develop during the early postnatal period During this period, there are also dynamic changes in the levels of the peptides and their gene expression.

NPY peptide is detected in the rat fetal midbrain as early as d 13 or 14 of gestation — NPY mRNA levels rise during gestation to reach near adult levels around birth 75 , Like leptin, NPY gene expression is elevated during the lactation period, with a peak around d 16 , At the same time, NPY mRNA is transiently expressed in hypothalamic areas that do not produce NPY in adulthood.

Suckling rat pups express NPY mRNA in the DMN, PVN, LHA, and perifornical area, albeit at lower levels than in the ARC , Alongside the developmental changes in NPY mRNA, NPY peptide levels show a rapid postnatal rise and in the ARC reach adult levels by the time of weaning , Immunohistochemistry studies have shown that the number of cell bodies containing NPY peptide rises gradually until birth, with declining numbers afterward , After d 10, NPY cell bodies can only be visualized when axonal transport is chemically blocked by colchicine administration—a finding that is consistent with the simultaneous increase in NPY-immunoreactive fibers throughout the hypothalamus — In a more recent study, by staining for NPY and AgRP peptide simultaneously, the origin of these postnatally developing fibers was proven to be the ARC Indeed, the developmental pattern of AgRP resembles that of NPY, with increasing expression during the first postnatal weeks and a peak around d 16 , In the neonatal period, NPY and AgRP already appear to have some functionality.

Maternal deprivation has been shown to increase expression in the ARC already on d 2 NPY and at least from d 11 AgRP , Furthermore, NPY injections into the PVN increased intake of water and milk as early as d 2; on d 15 the pups showed a preferential increase in milk intake As mentioned, intrahypothalamic fibers in the neonatal rat are still incomplete, and NPY is expressed in several hypothalamic nuclei.

Therefore, NPY may exert most of its actions locally at the site of expression, rather than after being axonally transported from the ARC to other hypothalamic regions. POMC mRNA is first detected in the midbrain on d 13 of gestation During the lactation period, hypothalamic POMC expression is either stable or increases toward weaning ARC POMC expression then increases significantly between weaning and young adulthood , Hypothalamic POMC peptide has been detected as early as d 12 of gestation , , with α-MSH, the cleaved product, only appearing between d 15 and d Postnatally, POMC and α-MSH protein in the ARC go through a rapid increase, to peak around d 21 to 28 , There is only limited information about early CART ontogeny.

One study in mice has reported low levels of hypothalamic mRNA on postnatal d 5, with near adult levels on d 10 and 22 However, the developmental patterns reported by this study for NPY, AgRP, and POMC were different from those found in most other studies.

In contrast to NPY, α-MSH does not seem to have much functionality early in life. In 1-wk-old rat pups, many PVN neurons are responsive to NPY, whereas only a few show a response after administration of an α-MSH agonist At the age of 4 to 5 wk, however, the number of PVN neurons responsive to NPY has decreased, whereas the number of neurons responsive to melanotan II has increased dramatically This phenomenon may ensure a high intake in neonatal life by minimizing anorexigenic signaling in early life.

Less detailed information is available about the development of the peptides of interest in the PVN and the LHA: CRH, TRH, MCH, and ORX. Gene expression is detected in the fetal rat brain for all four peptides — The peptide is generally also detected in the hypothalamus before birth , — Neonatally, there is a gradual increase in expression and protein levels of most peptides, and adult levels are generally reached around the time of weaning , — , — , although ORX and TRH peptide levels may keep on rising between weaning and young adulthood , Functional tests are reported for ORX.

In the neonatal period, leptin administration increases ORX mRNA in the LHA , where the normal effect in adults would be inhibition of expression Interestingly, the neonatal leptin administration that increases ORX expression does not affect body weight and blood glucose levels, whereas 24 h of milk deprivation reduces body weight and blood glucose levels but does not affect ORX expression levels Therefore, the neonatal leptin effect on ORX mRNA may be interpreted to reflect a developmental role, rather than an effect on energy balance regulation If we want to extrapolate data and conclusions from animal studies to the human situation, it is important to consider the respective timing of the ontogeny of the relevant systems in humans and rats.

At birth, humans are further in their development, and many developmental events that occur in the early postnatal period in rats take place in the third trimester of human pregnancy 27 , — Therefore, caution is needed in extrapolating findings from one species to another.

As has been shown in Section III. G , a large part of the development of the energy balance-regulating system occurs in the perinatal period in both man and rat, although the exact timing of developmental events differs between the two species. With the knowledge of the previous section, one can imagine that the perinatal period with its rapid development may be a critical period and that during this critical time-window, the organism is vulnerable to environmental influences.

One can also imagine that different timing of an external stimulus, relative to the stage of development of the organism, can produce different outcomes. Also, different types of stimulus e. overnutrition, global vs. specific nutrients, maternal vs.

Therefore, in this section, we will discuss developmental programming of energy balance according to the type and timing of the stimulus. To identify programming of energy balance, different approaches have been taken.

There are basically three types of outcome that can be measured to investigate this phenomenon. An indirect way of looking at energy balance is to measure body dimensions and body composition. Because positive energy balance results in fat deposition and allows growth, these measurements can give an indication of enduring positive or negative energy balance in the recent past.

Relevant parameters are body weight, body length, body mass index BMI , fat mass and lean mass, and whether or not there is complete catch-up growth. These parameters are most apparent, and in humans are often the first indication that energy balance may be disturbed.

Another way of investigating energy balance programming is to examine components of energy balance directly. Energy intake, resting energy expenditure, and activity-related energy expenditure together determine energy balance.

These parameters may be somewhat less explicit in everyday life, but they can be studied relatively easily, also in the human situation. The third approach to investigate energy balance programming is to study the peptides and hormones that are responsible for the regulation of energy balance.

Properties like gene expression, peptide levels, epigenetic modifications, and functional changes can be studied.

Because these measurements require invasive techniques, this approach is less suitable for use in the human situation. Naturally, a combination of the three approaches will generate the most complete description of the phenomenon of developmental programming of energy balance.

With many new studies on the subject, our understanding of this phenomenon has much advanced in recent years. Now, various influences of the perinatal environment on energy balance parameters will be discussed—first, briefly for the human situation, and then in different rat models.

Epidemiological evidence suggests that the early environment can have a profound influence on energy balance. With these studies, it must be kept in mind, however, that in the human situation, the underlying cause of low birth weight or restricted fetal growth varies and is often unknown 25 , In addition, there are many confounding factors e.

Although higher adult body weight and BMI have repeatedly been reported with increasing birth weight 13 , 16 — 19 , the notion that low birth weight and impaired fetal growth may also program increased adiposity is gaining recognition. Over the last decade or so, researchers have increasingly investigated effects on more refined indicators of obesity, such as body composition lean vs.

fat mass and fat distribution e. These studies have shown that the positive relationship between birth weight and adult BMI results mostly from a positive relationship with lean mass, but not with fat mass 18 , — Moreover, low birth weight and impaired fetal growth have now been shown to be associated with a higher fat percentage in later life 10 , — and with a detrimental distribution of fat i.

The fact that these studies were performed in diverse populations [from different European countries Belgium, Finland, France, The Netherlands, Spain, and the United Kingdom , the United States non-Hispanic white, non-Hispanic black, and Mexican-American , Brazil, Guatemala, and Jamaica], with different ages from young children to old age , and in both sexes underlines the robustness of these associations.

It is becoming more and more clear that low birth weight is not always a reliable proxy for impaired fetal growth.

When, for example, early-gestation growth impairment is followed by prenatal catch-up growth, adult health can be affected without an effect on birth weight see Ref. Furthermore, the significance of the rapid postnatal catch-up that often follows perinatal undernutrition, rather than that of the undernutrition per se , has been stressed in recent years.

Several studies have shown that rapid early growth with the definition of early ranging from the first week of postnatal life to about 3 yr increases the risk for later adiposity and obesity , — This at least partly removes the apparent paradox of the association of both low and high birth weight with metabolic syndrome and obesity.

When both situations are characterized by perinatal overfeeding even if this is postnatal-only in the case of SGA subjects and may be both pre- and postnatal after maternal obesity , the underlying mechanisms may also share some similarities. Maternal obesity and gestational diabetes are increasingly common problems , The newborns of those affected usually have greater birth weights than infants born to control mothers — Greater gestational weight gain is also associated with higher birth weight , Even when their birth weight is not altered, the offspring of diabetic mothers often have an increased fat percentage In older children, ranging from 2 to 10 yr of age in the different studies, more obesity was found in those that were born to obese or diabetic mothers , — Interestingly, this obesity-prone profile improved dramatically after bariatric weight loss surgery.

Children that were born to obese mothers with substantial weight loss after surgery had lower birth weights without a higher risk for SGA, and their obesity rates in the ages of 2 to 25 yr were reduced to normal population levels To summarize, more obese phenotypes with detrimental adiposity have been found after both prenatal undernutrition and overnutrition.

Relatively few studies have directly assessed energy balance parameters in low- and high-birth-weight subjects. For energy expenditure, mostly neonatal data are available. These suggest that infants that are born SGA have higher energy expenditure than both premature appropriate-for-gestational-age very low-birth-weight infants — and at-term appropriate-for-gestational-age infants , In a study on prepubertal children on the other hand, SGA subjects were reported to have reduced resting energy expenditure compared with at-term appropriate-for-gestational-age children Energy intake was generally similar to that of premature infants of the same body weight , , One study reported a higher intake per kilogram body weight in SGA infants, whereas those large for gestational age had a lower relative intake compared with control infants of the same postnatal age In a more long-term study, a sample of prepubertal SGA children that did not catch up had a food intake below the recommended energy intake for their age After gestational famine exposure, middle-aged subjects had a higher energy intake, consumed diets with a higher fat density, and had lower levels of physical activity than nonexposed persons , In humans, measurements of the third category that of the peptides and hormones that are involved in the regulation of energy balance have largely been limited to the circulating hormones.

Serum leptin levels have been investigated most thoroughly. In neonates, several studies have found positive correlations of leptin with birth weight, birth length, and BMI — Because the strongest correlation was usually found with BMI, these associations most likely reflect the deficit in fat deposition in low-birth-weight infants and the excess in those born after fetal hypernutrition, respectively.

However, a programming effect is suggested by the fact that subjects that were born with a low birth weight were found to have high leptin levels with respect to their BMI at several different ages ranging from 4 months to adulthood — Another report that suggests programming of leptin levels studied the influence of early nutrition in preterm infants It was shown that adolescents that had received preterm formula had more leptin per kilogram fat mass than adolescents that had received a control diet in infancy Besides altered leptin levels, a few studies have shown increased ghrelin levels in SGA subjects at birth , , but not at the age of 1 yr In contrast, high-birth-weight newborns were reported to have normal ghrelin levels Children 2 to 25 yr of age that were born to obese mothers after bariatric weight loss surgery had higher ghrelin levels and lower leptin levels than those born before such surgery, a beneficial profile that corresponded to their improved body composition Lastly, there is also some evidence in neonates and children that the HPT axis may be disturbed in SGA subjects , Summarizing, there is quite some evidence that the early nutritional environment can have a permanent effect on the body dimensions of humans.

The long-term effects observed at both sides of the birth weight spectrum seem to share their general direction: after the initial period of catch-up growth after perinatal undernutrition, both are associated with more obese phenotypes.

Although direct measurements of energy balance and its regulation are still scarce, disturbances have been found, some of which seem to persist into adult life.

Because these kinds of measurements are more invasive and some can only be performed postmortem, they are obviously not employed in humans on a large scale. That is why different animal models were designed to study these effects more closely. The use of experimental animal models has some substantial advantages over studies in humans.

In contrast to the human situation, with animal models for perinatal restriction of growth and nutrition, the exact cause of the observed symptoms is known, and the degree of control over the subsequent environment is far greater.

In addition, animal models permit the use of more invasive methods than in humans. Experimental animal models for developmental programming have been designed in various species, including primates, sheep, guinea pigs, and rats 28 , 31 , , In this review, we will focus on studies in the rat, although a few studies in mice are also included.

In rats, both prenatal and postnatal manipulations of nutrition have been used to induce developmental programming of energy balance, including ligation of the uterine arteries; maternal diets with altered protein, fat, or energy content; and manipulations of litter size 28 , 31 , , These different models produce different phenotypes.

Here, we will first describe effects on the body dimensions and body composition of the major models that have been used in rodents. Then, the effects on energy balance and its regulation will be discussed. Prenatal manipulations of fetal nutrition, via the diet of the pregnant dam, exert long-term effects on the body dimensions of the offspring, with or without an immediate effect on birth weight of the pups.

Perinatal overfeeding, on the other hand, can be induced by feeding the dams high-fat or high-energy high on both fat and sugar diets. Whether a maternal low-protein diet actually reduces birth weight of the pups appears to depend on the exact composition of the diet and other details in the methodology because some studies mostly using a low-protein Hope Farms diet report lower birth weights — , whereas others mostly using the Southampton diet have reported normal birth weight after maternal low-protein diet during gestation — After a maternal low-protein diet, body weight either stays reduced or normalizes to control levels, with the outcome apparently independent of birth weight and the experimental diet used during pregnancy — , — Two studies have reported rapid catch-up growth with increased body weight , Adult body composition after a maternal low-protein diet has mostly been reported to be normal — , although some of these studies did report an altered fat percentage in either males or females.

One study found increased leptin and triglyceride levels in males, but not females, with otherwise normal body weight and fat mass This suggests that, although the body composition may be normal, its regulation can still be disturbed in these animals.

After maternal food restriction, rats show either complete or incomplete catch-up growth — , , so that in rats with a low birth weight, adult body weight was reduced, normal, or elevated compared with that of controls , , , Several studies have found normal body composition after prenatal maternal food restriction , — , — , — However, increased and decreased adiposity has also been reported.

Within studies, these different outcomes can be attributed to sex differences, different effects at different ages, strain differences, and timing of the food restriction , , , , , Between studies, the method of determining body composition e.

Leptin levels usually reflected body composition , , , — , , , , although in one study increased leptin levels appeared to precede the increased fat percentage In summary, although studies using the Vickers model present a constant exception, most studies have found normal body composition after prenatal maternal food restriction.

Because a considerable part of the developmental events that occur in utero in humans take place after birth in rats, postnatal manipulations are also frequently used as a model. When the same maternal dietary manipulations that are used prenatally are either started or continued in the lactation period, the reductions in body weight are generally longer lasting, and less catch-up growth is reported 15 , , , , — , — Concomitantly, an obese phenotype is observed less frequently than with strictly prenatal manipulations , , — , — There may be less catch-up growth after these postnatal manipulations because the condition is too severe to recover from especially when prenatal and postnatal malnutrition are combined , or at weaning the animals may have reached the end of the time-window in which complete catch-up is possible.

Besides maternal underfeeding paradigms, maternal overfeeding and gestational diabetes have also been induced in rodents. Interestingly, one study reported a lower birth weight specifically after a pregestational-only cafeteria diet With maternal overfeeding continued into lactation, a substantial number of studies reported increased body weight by the time of weaning — , , — , although a reduced body weight was found in a study where the high-fat-fed dams lost more weight during lactation than the control dams In later life, animals born to overfed dams had normal , , , or elevated , , , , , , body weight when fed on chow.

A higher body weight was usually accompanied by increased adiposity — , , , , , In one study, the development of overweight was specific to animals that were born to control dams but then cross-fostered to dams fed on hypercaloric diets When transferred to an obesogenic diet themselves, some , , , , but not all , , , , of these animals showed an increased susceptibility to diet-induced obesity.

In the studies by Levin and colleagues , , the adverse consequences of the maternal diet were mostly specific to animals from a strain bred for diet-induced obesity, demonstrating the importance of the interaction between perinatal nutrition and genetic factors.

In rodents, gestational diabetes can be induced by glucose injections in early pregnancy or injections of the pancreatic islet toxin streptozotocin, but it also occurs in the female offspring of rats that underwent uterine artery ligation see Section IV.

Mostly, birth weight is found to be increased in these models , , , although normal birth weight has been reported after maternal streptozotocin injections Around weaning, body weight remained higher in the offspring of ligated dams , remained normal, or increased slightly after streptozotocin injections , Cross-fostering to normal dams after birth did not influence growth , but normal pups that were cross-fostered to diabetic dams had lower body weights Offspring of diabetic mothers was reported to be overweight with increased adiposity in adulthood , , Uterine artery ligation in the pregnant dam reduces the blood flow to the fetuses and is frequently used as a model for placental insufficiency, the most common cause of low birth weight in westernized countries To approach the human IUGR situation as closely as possibly, often only pups that are growth restricted according to similar criteria as those used in humans are selected for studies This obviously results in a birth weight that is by definition reduced — Nevertheless, studies that did not use pup selection have also reported a lower birth weight in rats born after uterine artery ligation , — The long-term effects on body weight seem to be dependent on the exact timing of the ligation.

When performed on d 17 of gestation, the weight deficit is usually persistent , — , whereas after ligation on d 19 of gestation, complete catch-up growth has been reported , , Some studies also found a return to normal body weight after ligation on d 16 or 17 , Newborn pups that were growth restricted by uterine artery ligation were shown to have a fat percentage that was either reduced or comparable to that of control pups , Juveniles and adults that do not completely catch up in body weight have been shown to have normal BMI, fat percentage, and serum leptin levels , The ones that do catch up to control body weight also have normal leptin levels when young at an age when their body weight is still reduced , Rats that stay at the same body weight as control rats after catch-up have elevated leptin levels and increased fat mass in adulthood The group that reported overweight in adulthood found normal or increased fat mass at the age that body weights were similar to those of controls , and increased fat mass afterward , In summary, when there is complete or even overcomplete catch-up in body weight, the animals' body composition is disturbed and shifted toward a more obese phenotype.

If the catch-up growth stays limited, however, body composition remains normal. A method to manipulate early postnatal nutrition that targets the offspring directly rather than indirectly via the diet of the dam is to manually adjust the number of pups nursed in a litter , In this way, both neonatal under- and overnutrition can be achieved.

By definition, birth weight is not affected by these manipulations because they take place after birth. Shortly after redistribution into litters of different sizes, differences in body weight become apparent. Rats that are raised in a small litter of only two to five pups receive more milk, resulting in a higher growth rate and body weight before weaning , — Although a few studies report normalization of body weight , , — , this elevated body weight is generally found to persist into adulthood and middle-age , , , , , , — The opposite is true for rats that are raised in a large litter of 14 to 24 pups, which has less milk available per pup.

These rats grow much slower during the lactation period and have a significantly lower body weight , , — , , Again, some studies report normalization , , , but most researchers find that body weight is persistently reduced , , , — , , , , , , , , , Already during the lactation period, the two models show marked effects on body composition: overfed small-litter pups have an increased fat percentage and leptin levels, whereas these are both decreased in underfed large-litter pups , , , , , , Thus, a disproportionate part of the added growth in small-litter pups can be ascribed to adipose tissue.

After weaning, when all animals are transferred to a normal feeding regime, body composition remains disturbed. In most small- and large-litter rats with persistent changes in body weight, fat percentage and leptin levels also remain altered into adulthood and middle-age , , , , , , , — , , , — , One study even reported an increased fat percentage in small-litter rats at an age when their body weight was no longer elevated Apart from a few exceptions, the effects of neonatal litter manipulations are long-lasting and also rather consistent between studies.

Neonatal overfeeding by raising rats in small litters causes an immediate rise in growth velocity, with persistent higher body weight and fat mass in adulthood, resulting in an obese phenotype. Neonatal underfeeding by raising rats in large litters, on the other hand, acutely reduces growth rate and causes a permanently lower body weight and fat mass, resulting in a leaner phenotype.

This section has demonstrated that diverse manipulations of perinatal nutrition can bring forth different phenotypes. Even seemingly comparable manipulations have been shown to generate different long-term effects on body dimensions and body composition. What's more, some of these manipulations have been shown to alter the animals' susceptibility to diet-induced obesity which is induced by feeding a hypercaloric diet, usually a high-fat diet.

Again, there is considerable variation in the reports on this effect. A maternal low-protein diet either did not affect or increased 15 , , the susceptibility to diet-induced obesity when the manipulation was prenatal. When the manipulation was restricted to the lactation period, less obesity was observed on a highly palatable diet Several studies have reported a higher susceptibility to diet-induced obesity after prenatal maternal food restriction , , , , , , , , but unchanged obesity has also been reported , , , , , Here, there seems to be a difference in susceptibility between the sexes, although this sex difference may be strain-dependent; Jones , , reported increased diet-induced obesity in Sprague-Dawley males but not females, whereas Vickers , , , , , , found higher susceptibility in Wistar females but not males.

In rats that were neonatally overfed or underfed by raising them in small or large litters, conflicting results have also been reported. In rats with persistent differences in body weight, some studies found no difference between the two models in their susceptibility to diet-induced obesity , One study, however, reported that diet-induced obesity was augmented in small-litter rats and diminished in large-litter rats From these data, we can conclude that the effects of a dietary challenge are mostly consistent with the general phenotype.

More diet-induced obesity is observed in those models that under baseline conditions showed more catch-up growth and increased adiposity. In the above-mentioned rodent models, energy intake and energy expenditure have been studied using a range of different parameters.

Expenditure-related parameters include resting and total energy expenditure, locomotor activity, body temperature, and measurements of thyroid function and cellular metabolism. For energy intake, the variety is more in how the data are represented. Daily food intake is given per animal raw data , per kilogram body weight or some other approximation of body size , or adjusted for body size in a statistical test.

The results of these different representations are not always easily compared. Especially when intake is divided by body size, the results can be distorted. Because energy requirements per kilogram body weight fall with increasing body size, this calculation systematically underestimates energy utilization by larger individuals Therefore, such studies are excluded from this review; only studies that report raw food intake data or intake adjusted for body size in a statistical test are included.

One study that induced prenatal underfeeding by a maternal low-protein diet reported normal food intake in the adult offspring The same study found reduced food intake when the underfeeding was continued during the lactation period.

This was confirmed by others , , although some have also reported normal levels of food intake in these prenatally and postnatally malnourished rats , , These data suggest a subtle decrease in food intake after protein malnutrition in the lactation period, whereas prenatal-only malnutrition probably does not affect long-term energy intake.

On the expenditure side, in rats with postnatal exposure, increased thyroid function pointing to increased basal metabolism was found , , and normal-to-low activity levels have been reported after prenatal exposure Taken together, these studies suggest that in prenatally malnourished animals normal levels of intake and reduced activity may lead to positive energy balance, whereas in postnatally malnourished animals a negative balance may result from their lower food intake and increased basal metabolism.

After maternal food restriction, food intake was usually found to be similar to that of control animals.

However, when body size is taken into account, the effects on energy intake differ according to the timing of the malnutrition: prenatally or postnatally.

When pups were exposed to the maternal diet postnatally, they often had reduced body size combined with normal food intake , , , , which results in an elevated relative energy intake.

With prenatal-only maternal food restriction, both body size and food intake were usually normal , , — , , leading to a normal relative food intake. In a few cases, both body size and food intake were elevated , , , which also may point to a fairly normal relative energy intake. Measurements of energy expenditure were mostly performed in prenatally underfed rats; in postnatally underfed rats, one study reported a normal thyroid function Using the Vickers' model of prenatal maternal undernutrition, female rats that have a low body weight and high fat mass were found to have reduced activity levels in adulthood , Other studies using prenatal undernutrition have reported normal levels of activity and normal body temperature and resting energy expenditure These data are suggestive of normal total energy expenditure, which together with an unaltered food intake points to a normal energy balance for these rats that are prenatally exposed to maternal undernutrition.

In juvenile pups born after maternal overfeeding, food intake may be normal , , , although dramatic overfeeding has also been reported In adulthood, these animals are usually hyperphagic , , , , , Moreover, rats born to cafeteria-diet-fed mothers showed a stronger preference to fatty and sugary foods themselves In offspring of high-energy diet-fed dams, reduced activity levels and slightly increased diet-induced thermogenesis have been reported , This will probably lead to lower total energy expenditure, with the reduction in locomotor activity only enhancing the obesogenic effects of the elevated food intake.

An elevated food intake was also reported in rats born after gestational diabetes Food intake was not widely studied after uterine artery ligation; one study reported decreased food intake , whereas another found an unaltered intake per kilogram body weight In both studies, the experimental animals had similar body weight as controls which nullifies the interpretational problems of the per kilogram representation.

In both juvenile and adult rats, cellular metabolism was reduced , , , whereas locomotor activity has been reported to be normal , Taken together, a reduced or normal food intake, lower basal metabolic rate, and probably normal activity-related energy expenditure suggest that energy balance may be either approximately normal intake and expenditure both reduced or more positive than in control animals normal intake with reduced expenditure , respectively.

In virtually all small-litter rats that were heavier than controls, food intake was reported to be elevated throughout life , , — , , , , , although this was not always the case In rats that would later lose their overweight, unchanged food intake was found in juvenile life , Fewer studies have reported on the expenditure side of the balance.

Rats raised in small litters were found to have a higher body temperature and resting expenditure , and in young animals, elevated total energy expenditure was reported The latter study found that the elevation in energy expenditure was appropriate for the larger body size of the small-litter rats.

Because both energy intake and expenditure are increased in these animals, the overall effect on energy balance depends on the relative sizes of the effects on intake and expenditure.

These are difficult to compare between studies. On the other hand, large-litter rats were generally reported to have lower energy intake and expenditure than controls , , , , Again, the fact that these measurements were taken in separate studies complicates interpretations about the overall effect on energy balance in these animals.

The foregoing paragraphs have shown that different models of perinatal malnutrition can have different effects on adult energy balance.

They have also shown that, although there is a lot of information about the effects of these manipulations on components of the energy balance, the exact information needed to assess a directional change in energy balance is not always available.

Furthermore, in the interpretation of these studies, it is vital to distinguish absolute measurements from adjusted data. Comparisons should only be made between data that are expressed in the same dimensions.

A related parameter that marks the transition to the subject of the next paragraph is the anorexigenic effect of leptin. Peripheral leptin administration acutely reduces food intake in control animals, but not in adult rats that were previously subjected to prenatal or postnatal maternal food restriction or a postnatal maternal low-protein diet , , In young adult small-litter rats, central injections of leptin are effective, in contrast to peripheral injections This suggests that this leptin resistance may be due to impaired leptin transport, rather than an altered hypothalamic response It has been known for quite some time that perinatal malnutrition can have profound effects on brain development Nevertheless, studies investigating programming effects on the hypothalamic peptides that regulate energy balance are relatively scarce compared with the other two categories of measurements discussed above.

Most of these have studied relatively short-term effects. Weanling rats subjected to a maternal low-protein diet during gestation and lactation were shown to have a reduced number of NPY immunoreactive cells in the ARC This was combined with an increase of the concentration of NPY protein in the PVN and LHA and a tendency for an increased concentration in the ARC, whereas the NPY content of other hypothalamic nuclei was unaltered This is suggestive of an increased orexigenic drive in these animals, provided that the PVN and LHA are fully responsive to NPY.

In view of the slightly hypophagic phenotype of these animals see Section IV. a , the responsiveness of these areas or other regions further downstream is probably reduced. Rats that were only exposed to a low-protein diet prenatally did not show changes in ARC gene expression of Ob-Rb, NPY, AgRP, POMC, and CART at weaning In contrast, weanling pups that were subjected to the diet postnatally had increased expression of Ob-Rb, NPY, and AgRP and decreased expression of the anorexigenic POMC and CART , again suggesting an increased orexigenic drive.

After fasting, NPY and AgRP mRNA were increased relative to control levels in weanling rats that were exposed either prenatally only or both pre- and postnatally, although the effects were stronger in the latter group In adulthood, CART mRNA was found to be increased in animals that were exposed prenatally but not in those exposed both pre- and postnatally , with no changes in expression of NPY, AgRP, and POMC Prenatal maternal food restriction has been shown to drastically increase hypothalamic mRNA levels of Ob-Rb at birth , an effect that was reversed by weaning to levels below normal , In adulthood, hypothalamic Ob-Rb expression had normalized , but Ob-Ra expression was lower than in control animals , which points to a reduction in leptin transport.

The latter is supported by a normal reaction to central injections of leptin, with a reduced reaction to peripheral leptin In weanling rats, reductions in leptin, ghrelin, NPY, and α-MSH peptide levels, as well as NPY and POMC mRNA levels have been reported Adult hypothalamic expression of the ARC peptide AgRP was reduced, whereas that of NPY and POMC was normal Despite this, the PVN in these adult animals did receive a larger number of NPY and CART terminals This was not reflected in a change in PVN CRH expression , although the PVN in juvenile rats did show increased neuronal activity and CRH mRNA levels , When the maternal diet was continued postnatally, juvenile pups showed very low serum levels of leptin This was accompanied by reduced POMC expression and axons, but surprisingly, hypothalamic NPY expression and its protein levels in the PVN were normal There does not seem to be a predominant direction in which energy balance regulation is shifted, which is in line with the variation in the general phenotype described above for these animals.

After perinatal maternal overfeeding, changes have also been found in energy balance regulation. In two studies that found normal birth weight after maternal high-fat diet, serum leptin levels and hypothalamic gene expression for Ob-R, NPY, and POMC were either up-regulated or down-regulated at birth , In the former case, hypothalamic Ob-R peptide and AgRP and MC4 receptor mRNA were also elevated After a maternal cafeteria diet, a much more pronounced neonatal leptin surge was reported By the time of weaning when these animals were heavier than controls , serum leptin levels were increased , , , In the hypothalamus, this resulted in down-regulated Ob-Rb mRNA , with normal to reduced NPY and AgRP and increased POMC expression , But although the ARC response to elevated leptin signaling seemed roughly normal, the VMN showed reduced responsiveness Fasting revealed more changes that were not seen under basal conditions: pups born to high-fat diet-fed dams showed increased elevations in mRNA levels of NPY, AgRP, and the Y 1 receptor but lacked the decrease in MC4 receptor expression that is found in control animals upon fasting From weaning on, leptin levels in these animals were found to be normal to elevated , , , , , where the larger increases in leptin were usually in more overweight animals.

Shortly after weaning, at a point that the rats born to overfed mothers had normal body weights, the number of projections from the ARC to the PVN containing AgRP was reduced, whereas projections containing α-MSH were normal In addition, gene expression for the MC4 receptor was up-regulated in the VMN, and that for the leptin receptor Ob-R was down-regulated in the ARC , accompanied by a reduction in leptin sensitivity that remained at least until the age of 3 months In adulthood, offspring of high-energy-fed dams showed enlargement of the VMN and DMN nuclei In addition, hypothalamic gene expression was either reported to be normal for Ob-R and NPY and reduced for AgRP and POMC , or was up-regulated for NPY with normal expression of AgRP and POMC Because in the former study, the reduction of POMC expression seemed stronger than that of AgRP, despite the conflicting details, both profiles could be expected to lead to more orexigenic signaling.

Hypothalamic alterations have also been found in pups born to or cross-fostered to dams with gestational diabetes due to streptozotocin injections. At weaning, despite normal serum leptin levels, postnatal-only exposure increased the size of the PVN , whereas combined pre- and postnatal exposure led to a reduction in PVN and VMN size At the same time, ARC peptide levels of NPY and AgRP were elevated, and those of POMC and α-MSH were reduced , , suggestive of increased orexigenic signaling.

The up-regulation of NPY levels was also found in middle-aged animals In rats that were prenatally growth restricted by uterine artery ligation, NPY mRNA and protein were both increased at weaning, whereas CRH levels were unaffected In young adulthood, the number of ARC cells expressing NPY mRNA was normal, but the levels of expression were reduced This suggests an increased orexigenic drive in the juvenile animals, which is in accordance with the complete catch-up growth reported for these animals see Section IV.

Lower NPY expression in the adult rats is concurrent with the incomplete catch-up growth that these animals display see Section IV. Weanling small-litter rats were shown to have reduced Ob-Rb expression , which is in agreement with the high serum leptin levels found in these rats.

ARC NPY, AgRP, and CART mRNA levels were all increased, but this predominantly orexigenic signal did not seem to reach the PVN and LHA because expression of TRH, MCH, and ORX was unaltered This was also suggested by the fact that NPY peptide levels in both the ARC and the PVN were normal In young adulthood, expression of the ARC peptides NPY, AgRP, and CART is normal, as well as CRH and TRH expression in the PVN and MCH and ORX expression in the LHA , At this age, leptin transport across the blood-brain barrier appears to be impaired , which indicates a state of leptin resistance.

This leptin resistance seems to develop only after weaning because weanling small-litter rats are still responsive to peripheral injections of leptin Taken together, these studies suggest that the obese phenotype of adult small-litter rats see Section IV.

b may be at least partly attributable to central leptin resistance caused by high neonatal leptin levels and the resulting hyperproductivity of the ARC.

Additionally, studies by Davidowa and colleagues reviewed in Refs. Interestingly, juvenile large-litter rats also show more orexigenic signaling.

In the ARC, the balance between orexigenic and anorexigenic gene expression was shifted , or AgRP and NPY expression and NPY peptide levels were increased with unchanged CART expression , This resulted in elevated PVN NPY peptide levels , but did not affect its expression of CRH or TRH, nor LHA ORX expression , LHA MCH gene expression was shown to be transiently increased, with elevated levels at d 10, but not at 25 d of age Unlike small-litter rats, juvenile rats raised in large litters had normal hypothalamic Ob-Rb expression Instead, some of the short forms of Ob-R were expressed at increased levels One study suggested that ARC NPY mRNA was no longer elevated in young adulthood , although there still seemed to be a small tendency toward higher expression levels.

These results generally appear to be in agreement with the phenotype described above. The acute effects of juvenile food restriction seem to be mostly orexigenic, although apparently not enough to achieve full catch-up growth.

Information on the long-term effects of this model is still largely missing. Although the studies described here have all used nutritional manipulations, perinatal nonnutritional manipulations have also been shown to program hypothalamic an orexigenic signaling.

One example is neonatal stress, which has been shown to have long-term effects on levels of POMC, CRH, ORX, and ORX receptors , As has been mentioned in Section III.

Instead, it seems to play a more developmental role. It is responsible for the proper development of intrahypothalamic connections , that occurs during the early postnatal period Even general brain development seems to depend on leptin because the brains of leptin-deficient mice show a variety of abnormalities that can be rescued by juvenile leptin treatment In recent years, several researchers have hypothesized that altered neonatal leptin levels may play a key role in developmental programming 12 , 15 , — This hypothesis is supported by several recent studies that manipulated perinatal leptin levels.

Interestingly, the direction of the reported effects differed between these studies. Some researchers have found a beneficial effect of perinatal leptin administration on adult body adiposity , Moreover, one study reported the absence of an anorexigenic reaction to peripheral leptin in adulthood when leptin action was blocked neonatally Similarly, different effects of perinatal leptin on susceptibility to diet-induced obesity were reported.

Some studies found perinatal leptin to be protective against diet-induced obesity , , whereas others reported increased weight gain on a high-fat diet after neonatal leptin injections , Based on some of the positive effects mentioned above, several groups have investigated whether perinatal leptin administration might rescue the obesity-prone phenotype of rats that were programmed by perinatal nutritional manipulations.

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Correspondence to Uberto Pagotto. Icahn School of Medicine at Mt. Sinai, New York, New York, USA. Reprints and permissions. Preiato, V. The Endocrine Regulation of Energy and Body Weight. In: Belfiore, A. eds Principles of Endocrinology and Hormone Action.

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Keywords Hormone Hypothalamus Food intake Mesolimbic system Brainstem Gut Adipose tissue Endocrine pancreas. References Abbott CR, Monteiro M, Small CJ, et al.

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Furthermore, the fluctuations and decline of ovarian hormones that occur during menopause are associated with an increased risk of obesity and other metabolic disorders 6 , 7. While the relationship between ovarian steroid hormones and satiety metabolic peptides like leptin has been examined previously 5 , 8 , 9 , most studies on the role othe orexigenic hormone ghrelin in energy balance comes from research conducted on male rodents.

Here we review studies investigating the interaction between ovarian hormones and ghrelin in the regulation of feeding and energy balance in female mammals. Ghrelin, a amino acid peptide secreted from the stomach, binds to the growth hormone secretagogue receptor GHSR 10 , Given previous work demonstrating the orexigenic and adpogenic effects of growth hormone secretagogues 12 , it was not surprising to find that ghrelin was a potent stimulator of caloric intake and promoted carbohydrate metabolism and fat accumulation 11 , 13 , Ghrelin is secreted from the stomach during states of negative energy balance and in anticipation of regularly scheduled meals.

As food is consumed, ghrelin secretion declines to baseline levels 15 — Two forms of ghrelin are present in circulation, des-acyl and acyl-ghrelin.

Des-acyl ghrelin was often referred to as the inactive form of the peptide, because it does not activate the GHSR There is work, however, that suggests this peptide has other biological actions Acyl-ghrelin, hereafter referred to as ghrelin unless specified, is produced following octanolyation of desacyl-ghrelin via the enzyme ghrelin o-acyltransferase GOAT Once acylated, ghrelin can effectively induce its biological effects via activation of the GHSR.

Ghrelin promotes food intake and metabolic changes in part through GHSR activation within the arcuate nucleus ARC of the hypothalamus 13 , 14 See Figure 1.

Within the ARC, Neuropeptide Y NPY and agouti-related peptide AgRP neurons promote increases in food intake and decreases in energy expenditure, whereas neurons producing pro-opiomelanocortin POMC and cocaine and amphetamine-regulated transcript CART promote satiety and increase metabolic rate 4 , Upon release, NPY directly stimulates feeding and decreases energy expenditure via activation of NPY 1 and 5 receptor subtypes expressed throughout a number of hypothalamic and extrahypothalamic regions 4.

The routes through which ghrelin accesses the ARC and other brain regions have been the subject of much debate [reviewed in 25 ]. However, the ARC is strategically situated bilaterally at the bottom of the third ventricle and above the median eminence, a region with direct access to circulating peripheral metabolic signals, including ghrelin and leptin 4.

Evidence suggests that the fenestrated capillaries of the median eminence allow for passive movement of ghrelin into the ARC and perhaps to other hypothalamic and extrahypothalamic regions 26 — Figure 1 Effects of ghelin A , and estradiol B on the activity of the melanocortin system. In addition to the ARC, peripheral ghrelin binds to GHSR expressing cells in brain stem regions that regulate feeding in response to rapid changes in metabolic signals like glucose and fatty acids in blood, and that integrate hormonal and neural signals coming from the gut via the ascending branch of the vagus nerve Ghrelin receptors are located in the nodose ganglia which transmit sensory information from the alimentary tract 30 , and their target the nucleus of the solitary tract NTS In addition to GHSR, the NTS expresses receptors for most metabolic signals including estrogen, leptin, and cholecystokinin CCK.

Noradrenergic cells in the NTS integrate ascending vagal stimulation and project to other brain stem regions such as the parabrachial nucleus PB , which when stimulated, are important for a reduction in appetite through hypothalamic corticolimbic projections including projections to the ARC 31 — Indeed, peripheral ghrelin decreases afferent vagal discharge in the NTS whereas CCK increases discharge, suggesting that vagal stimulation of NTS targets represents an integration of orexigenic and anorexigenic signals 35 , Increases in peripheral ghrelin leads to activation of NTS noradrenergic neurons that project to the ARC and disrupting this pathway prevents peripheral ghrelin-induced feeding Ghrelin targets other brain regions to modulate food preference and food motivation.

These effects are believed to be mediated via GHSR expression throughout brain regions important in reward regulation [For review see 37 ]. This system comprises dopaminergic neurons originating in the ventral tegmental area VTA that project to the nucleus accumbens, amygdala, hippocampus, and prefrontal cortex VTA dopaminergic neurons express the GHSR 29 , 39 , 40 , and intra-VTA ghrelin administration in rodents results in increased DA release into NAcc as well as increasing food intake and food motivation as measured by increased lever presses for food, or in response to contextual or specific cues such as the presence of a light associated with food availability 39 , 41 — 44 see Figure 2.

In human functional MRI studies, intravenous ghrelin administration coupled with the presentation of images of palatable food increased neural activity within the VTA along with self reports of cravings Figure 2 Effects of ghrelin A , and estradiol B on the mesolimbic dopaminergic system.

Ghrelin stimulates the activity of dopamine neurons and the release of dopamine at target regions to promote food seeking behaviors in male mice A. While studies ghave not done similar work on females, estradiol appears to increase the activity of dopamine cells, but appears to decrease food seeking behaviors B.

Of the studies carried out in females, most have focused on the effects of ghrelin on the somatotrophic and reproductive axes along with the effects of reproductive hormones on ghrelin synthesis See Table 1.

For example, GHSR are localised in the pituitary where ghrelin stimulates growth hormone secretion 10 , The GHSR is also expressed in multiple sites along the hypothalamo-pituitary ovarian axis including the medial preoptic area MPOA , kisspeptin neurons in the ARC, gonadotrophs in the pituitary, and the ovaries 29 , 52 , Ghrelin acting on GHSR in the MPOA of estradiol-primed rats decreases luteinizing hormone LH release 55 — 57 and can also decrease progesterone secretion directly by acting on GHSR within corpus luteum cells 58 , These effects have led to the suggestion that ghrelin, acting as a signal of food shortage, suppresses the reproductive axis Table 1 List of publications looking at the effects of ghrelin on homeostatic feeding, and the interaction of these effects with estrogen.

Conversely, there is also evidence that ovarian hormones modulate ghrelin secretion. Estrogen receptor alpha ERα is expressed in ghrelin producing cells in the stomach of rats, and locally produced estrogen acts directly on these ghrelin producing cells to stimulate ghrelin expression and secretion 61 , Notably, ghrelin expression or secretion were altered three weeks after gonadectomy in either male or female rats suggesting that this effect is independent of cirulating levels of estrogen 62 , although others have reported a transient increase in circulating ghrelin, after ovariectomy 48 , Nevetheless, it is unclear if these studies measured total, des-acyl or ghrelin, and this distinction is important for assessing the functional consequences of such changes, because an increase in total ghrelin does not necessarily entail an increase in ghrelin and hence greater orexigenic drive.

Böchers et al. recently confirmed that female rats have higher circulating ghrelin levels than males, and that ovariectomy resulted in reduced acyl-ghrelin concentrations using a well characterized acyl-ghrelin assay.

These authors also and also showed that females have lower plasma concentrations of the liver anitimicrobial peptide-2 LEAP-2 , an endogenous antagonist to the GHSR 63 , In women, chronic oral estrogen treatment increases plasma ghrelin concentrations but this effect is not seen after acute or short term transdermal administration of estrogen 65 , A number of studies have reported higher circulating levels of ghrelin in females than in males 67 , As with rodent work, most of these studies either measured total ghrelin 67 or did not define whether total ghrelin or ghrelin were measured For example Kaur et al, found that in mice total ghrelin was higher in late pregnant mice than in nonpregnant controls but that ghrelin levels were unchanged whereas in mid pregnancy ghrelin levels were lower while total ghrelin levels were unchanged Ghrelin secretion can be enhanced directly by estradiol treatment, but the interaction between these two hormones is complex.

Indeed, while estrogen increases the secretion of ghrelin, it also has metabolic effects that are opposite to those of ghrelin Food intake varies across the reproductive cycle in many mammals and is lowest in the periovulatory phase when estradiol levels peak.

Studies of the effects of estradiol replacement in ovariectomized rats suggests that the tonic moderate levels of estradiol seen in the follicular phase of the cycle are sufficient to decrease food intake and these are further reduced by the peak levels of E seen in the periovulatory phase The estradiol-induced reduction in food intake is related to a decrease in meal size, but not frequency, suggesting that part of the anorectic effect of estradiol are associated with greater sensitivity to satiety signals during the periovulatory period 46 , Consistent with this, estradiol facilitates the satiating effects of oxytocin, leptin, CCK, and GLP-1 32 , 47 , The effects of estrogen on energy balance are not limited to food intake, as estrogen also stimulates energy expenditure In addition, Giles et al.

reported that the respiratory exchange ratio RER declines during proestrus and estrus, supporting a role for estrogen in fuel utilization 74 and consistent with the hypothesis that estradiol promotes the utilization of fats as a source of energy.

In sum, this evidence suggests that the effects of estrogen on metabolism are opposite to those of ghrelin so that high circulating levels of estrogen are associated with decreased food intake, increased energy expenditure and utilization of fat rather than carbohydrate.

In the brain, estradiol influences food intake and energy expenditure in regions that overlap with those targeted by ghrelin and these include the NTS, ARC and other hypothalamic nuclei with rich expression of estrogen receptors ERs and GHSR 75 , Stimulation of estrogen receptor α ERα in the NTS potentiates CCK induced Fos-ir ICV treatment with estradiol, or with a selective ERα agonist increases the activity of POMC neurons in the ARC and decreases food intake in intact male and female mice 8 , and deletion of ERα from POMC neurons decreases food intake but has no effect on either energy expenditure Of these, the VMH is a particularly critical region for convergence of estrogen and ghrelin signalling.

Ghrelin can directly stimulate food intake when delivered into the VMH, and may do this through activation of nutrient sensing mechanisms that include activation of AMPK and mTOR In contrast, estradiol inhibits AMPK activity in the VMH Silencing ERα in the VMH of mice and rats resulted in a transient increase in food intake, but a dramatic decrease in energy expenditure 82 , an effect that was recapitulated when ERα was deleted specifically from SF-1 expressing neurons in the VMH This effect of ERα activation is likely mediated by modulation of activity of a pathway projecting from the VMH to serotonergic neurons in the dorsal raphe nucleus a pathway important for the regulation of brown fat thermogenesis BAT and locomotor activity It is therefore likely that, as in the ARC, ghrelin and estrogen have opposite effects on VMH cells and that there are sex differences in these effects, but this requires further examination.

Indirect evidence for this was first observed in some of the first studes conducted on transgenic mice lacking ghrelin or GHSR. While females were also studied, the authors simply stated that females, regardless of the genotype, were resistant to weight gain when fed the same high fat diet.

These data suggested a greater contribution of ghrelin to food intake in female than in male mice. Nevertheless, Clegg et al. reported soon after that female rats required higher doses of peripheral ghrelin than males to stimulate food intake This sex difference was eliminated after ovariectomy, with females showing feeding responses to similar doses as those that were effective in males.

When exogenos estradiol was given to ovariectomized rats, these again required higher doses of ghrelin to stimulate a significant increase in feeding. Clegg et al. also demonstrated that the orexigenic effects of both peripheral and icv ghrelin administration fluctuated across the estrous cycle in rats with ghrelin treatment being more effective in stimulating feeding during diestrus, when plasma estradiol concentrations are low, but ineffective with the same dose during proestrus and estrus when estradiol concentrations are higher 48 , Finally, this study showed that the typical increase in food intake and body weight that accompanies ovariectomy in many species was not seen in ovariectomized GHSR-null mice Overall this paper suggests that ghrelin does make an important contribution to energy balance in female rats but only in the absence of estrogen.

One way in which estradiol could alter the effectiveness of ghrelin would be to regulate the expression of GHSR in hypothalamic and extrahypothalamic brain regions, and hence decrease ghrelin sensitivity. Few studies, however, have examined this possibility. Moreover, studies thoroughly examining sex differences in central GHSR expression have not been conducted.

Using quantitative polymerase chain reaction qPCR , a recent study compared GHSR mRNA expression in the ARC and amygdala of male and female ad lib fed mice and mice that were fasted overnight.

Female mice showed higher overall GHSR expression in both of these regions, especially in the amygdala In another study, the issue of ghrelin sensitivity was examined indirectly by measuring Fos immunoreactivity Fos-ir in response to icv ghrelin infusions in female rats at different phases of the cycle.

More Fos-ir was induced in the ARC following icv administration of ghrelin in female rats in the diestrous phase than in the proestrus phase of the cycle but, no changes in GHSR1a expression in the ARC as a function of phase of the cycle were observed in this study In contrast to NPY neurons, GHSR is only expressed in few POMC neurons within the ARC, suggesting that ghrelin primarily enhances orexgenic drive.

Importantly, POMC neurons express receptors for, and respond to estradiol, suggesting that estradiol may oppose ghrelin levels directly by inhibiting NPY neurons and indirectly by stimulating POMC neurons 8 , Increases in GHSR expression have also been observed in cells of the ARC that colocalize with ERα when ovariectomized rodents are treated with estradiol 52 , 53 , These cells were later identified as kisspeptin neurons, a subgroup of cells that have been linked to the control of luteinizing hormone pulsatility, but also recently implicated in the regulation of energy balance Clearly there is a need for further investigation into the effect of changes in circulating estrogen on GHSR expression in the brain to ascertain in which cell groups effects occur and whether the alterations in estrogen levels seen across the cycle are sufficient to induce these changes.

Like ghrelin, estrogen influences the rewarding properties of food. Clinical data show that food cravings for high-fat, palatable foods, as well as binge-eating episodes,increase in the luteal phase of the menstrual cycle when estrogen levels are low and similar results have been seen in rodents see 93 for review.

Moreover, eating disorders like binge-eating, anorexia and bulimia nervosa are primarily diagnosed in females, and have been associated with dysregulation of reward circuitry Importantly, sex differences have been reported in the soma size, number and proportion of dopamine cells in the VTA with females having more and larger dopamine cells in the VTA than do male rodents see 95 for review.

In rodents, the effects of estrogen on food motivation have largely been examined using two behavioral paradigms — the food hoarding paradigm and the progressive ratio operant responding paradigm see Table 2. Food hoarding refers to the behavior of collecting food without eating it and occurs in rats and hamsters Hoarding behaviors in female hamsters and rats decrease during the estrous phase of the cycle increase in ovariectomized females and are reduced by estrogen or estrogen and progesterone replacement — Using the progressive-ratio operant task, a task where the number of responses required to obtain a reward usually bar presses increases across the testing session, Richard et al.

Similarly, ovariectomy increases motivation to obtain a sucrose reward , whereas estradiol treatment in gonad-intact or ovariectomized rats reduces the motivation to obtain a chocolate flavored sucrose reward Interestingly, the anorectic peptide GLP-1 was more effective in reducing the amount of bar presses to obtain food pellets when ovariectomized rats were also treated with estradiol Together these data suggest that, opposite to ghrelin, estradiol decreases food seeking in female rats see Figure 3.

Table 2 List of publications looking at the effects of ghrelin on hedonic feeding and stress, and the interaction of these effects with estrogen.

Figure 3 Panels A, B depict some of the brain regions affected by ghrelin A and estrogen B to regulate food intake and energy balance.

As shown in Panel A , ghrelin targets hypothalamic and extrahypothalamic regions to increase homeostatic and hedonic feeding. In addition ghrelin stimulates cells located in the NTS and VTA to increase food intake through the stimulation of ascendind catecholaminergic cells that also influence the activity of the hypothalamus and limbic system.

Of these, ghrelin stimulates dopamine cells in the VTA to increase food seeking behaviors and food reward. In contrast and as shown in panel B , estradiol acts in the hypothalamus to produce effects that are opposite to those of ghrelin with an overall anorectic effects and an increase in energy expenditure.

In the brain stem estrogen also decreases food intake directly and it enhances the anorectic effects of leptin and CCK. Paradoxically, estrogen, like ghrelin, stimulates the activity of dopamine cells and their release of dopamine into the nucleus accumbens [NAc; See Panel B ].

As noted above food reward seeking has been linked to activity in the mesocorticolimbic dopaminergic system, and given the data discussed above, one would suspect that estradiol decreased the activity of the dopaminergic system to reduce food seeking and food reward.

Nevertheless, data suggest that estradiol, like ghrelin, can act directly on dopaminergic neurons to stimulate dopamine neurotransmission. For instance, the activity of DA neurons in the VTA is higher in estrous females than it is in either males or females in diestrus and estradiol administration results in increased dopamine release in the nucleus accumbens and other targets 95 , These effects of estrogen are thought to be mediated by intracellular and membrane bound receptors including ERα, ERβ, GPER-1 localized in VTA dopamine neurons and at their pre-and post synaptic targets In one behavioral study intra-VTA ghrelin administration in female rats increased sucrose intake and extracellular dopamine in the nucleus accumbens, confirming that ghrelin stimulates the reward system in a way similar to males The dose used in this study was, however, at least double the dose needed to produce similar effects in males, but it is not clear if lower doses were used unsuccessfully in females.

Also in female rats, infusions of the GHSR antagonist JMV into the VTA did not affect food intake but did decrease alcohol consumption following exposure to the intermittent alcohol access paradigm, suggesting that full GHSR signalling in the VTA is required for the reinforcing effects of alcohol but not food Whether further disruption of GHSR signalling is required to affect food is required and whether the effects described above vary across all stages of the estrous cycle has yet to be investigated.

It is also unclear whether intra-VTA ghrelin or GHSR antagonist treatment leads to different levels of dopamine release at different phases of the estrous cycle. For instance, intra nucleus accumbens NAc ghrelin administration increases feeding in male rats Ghrelin administration into the LHA increases food intake and increased food-seeking behaviors in male and female rats.

Importantly, in the current context inhibition of LH GHSR activity using the GHSR antagonist YIL, decreased the amount of sucrose rewards earned by female but not male rats Similarly, estradiol acts directly on the NAc to increase dopamine release In all ghrelin, and estrogen seem to prodce the same effects on the mesolimbic dopaminergic system all the while having opposite food reward feeding responses.

Recent work using a behavioral model that increases binging in mice shows that ghrelin and its receptor are implicated in the processes associated with overconsumption of a palatable hypercaloric diet that is available only during a restricted time.

The relationship between stress and feeding is complex, with some stressors decreasing feeding while others increasing feeding. Overall, it appears that although acute exposure to a mild stressor, such as tail pinch in rodents, generates a transient feeding response, similar exposure to stronger stressors have an anorectic effect , Chronic exposure to unpredictable stressors also induces a decrease in food intake whereas chronic stress paradigms in which stress exposure is predictable increases food intake, and in some cases is associated with weight gain and increased adiposity , That the ability to anticipate a stressor leads to increases in food intake suggests that stress-induced feeding is a method of coping with stress, and there is considerable evidence suggesting that ghrelin may play a role in this effect , , but very little data on whether these responses are sexually differentiated.

Chronic social defeat stress CSDS is one example of a chronic stressor that induces increases in food intake. These effects are associated with an increase in circulating ghrelin , and specifically with ghrelin actions in the ARC.

Exposure to CSDS also increases the incentive value of palatable food, an effect dependent on ghrelin actions on GHSR in catecholamine producing cells including dopamine cells in the VTA Similar effects have not been confirmed in female rodents.

This might be because social defeat paradigms are more difficult to implement in females, but other social stress paradigms do point to social stressors as promoting weight gain and adiposity in females.

For instance, social crowding increases adiposity in female mice despite causing decreases in food intake There are a number of new models of female social defeat but these have not directly evaluated metabolic alterations, and studies are needed to address that gap.

The exception is a recent paper, using a modified version of the chronic social defeat paradigm in which female experimental mice were laced with urine from males and introduced into the cage of an aggressive CD-1 mouse resident every day for 21 days.

This protocol resulted in increases in body weight in stressed females compared to controls Social isolation stress has been linked to decreases in caloric intake and weight gain and the effects of 6-hours of isolation have been shown to decrease food intake in intact female mice to a greater extent than in males Two hours of isolation in intact females is sufficient to increase circulating ghrelin, but this is associated with a reduction in food intake, compared to that of non-stressed controls.

The anorectic effect of isolation was not eliminated by ovariectomy although ovariectomized females continued to eat more than controls. Overall, this suggests that estradiol continues to inhibit feeding during stress, regardless of increased ghrelin.

Further, given that intact non stressed female mice in this study showed a robust response to ghrelin, these data also suggest that some other factor s may be suppressing the orexigenic response to ghrelin at this time In contrast to the effects of acute social isolation, two weeks of social isolation stress induce significant increases in caloric intake in both male and female young but not old mice.

Body weight was not altered by isolation in the younger groups but a decrease was observed in the older cohort.

In addition to these age effects, some sex differences were observed in the response to isolation stress in the younger cohort: 1 week of isolation and an overnight fast were sufficient to increase circulating ghrelin levels in young males and increases in AgRP and NPY mRNA expression but these effects were not seen in young females.

Two month old females did, however, show an increase in locomotor activity that was absent in males. Together, these data suggest that isolation stress induces an array of behavioral and metabolic responses some of which differ between males and females.

Chronic restraint stress has also been linked to changes in caloric intake, diet preference and metabolism together with obesity and insulin resistance Zareian et al.

In another study, 3 weeks of 20 mins daily restraint induced elevated ghrelin concentrations accompanied by increased caloric intake and weight gain in both male and female rats and were still seen if females were ovariectomized.

These data suggest thatstress induced increases in ghrelin do not depend on the presence of ovarian hormones although as only des-acyl ghrelin was measured whether these might influence ghrelin levels remains to be examined In primates, social stressors have also been associated with increased weight gain, changes in food preference, and bingeing , Female rhesus monkeys that are subordinates in a colony tend to gain more weight than those that are higher ranking and that receive fewer social threats.

It is not known, however whether ghrelin concentrations are elevated in these individuals and how this might contribute to these effects. In humans, women report that stress increases their food consumption and the consumption of highly palatable foods Interestingly, female subjects exposed to the Trier stress paradigm, an experimental model to study social stress in humans, show rapid increases in plasma levels of ghrelin and these are associated with scores in a questionnaire measuring emotional eating Using the same task, Raspopow et al.

also found that ghrelin and cortisol levels were elevated also in anticipation of the social stressor Because these studies were conducted only in females, it is unclear if similar changes occur in males, but these results support the notion that social stressors may increase ghrelin concentrations which could lead to eating as a coping mechanism to deal with the stressor.

The discovery of ghrelin in was followed by an explotion of research to determine the biological role of this peptide and its potential for the treatment of metabolic disorders as well as disorders associated with altered emotional, cognitive and motivational states like depression, anxiety and addiction.

Despite this enthusiasm, studies conducted on females were few, leaving a significant gap in knowledge on ghrelin biology. The studies discussed above suggest that, as in males, ghrelin increases feeding, promotes adiposity, and facilitates the oxidation of carbohydrates over fat.

These effects, however, interact with those of the hormone estrogen, which opposes the metabolic effects of ghrelin see Figure 3. In addition, it also seems that estradiol directly modulates the synthesis, secretion, or degradation of ghrelin, and the expression of the GHSR, perhaps as a feed-forward mechanism that allows for increased feeding after ovulation.

Although there is some data showing estrogen-induced changes in GHSR expression within a particular subset of cells in the ARC, there is obviously a need for a broader examination of sex differences in GHSR expression in this and other GHSR expressing brain regions that are sexually differentiated, and on whether GHSR expression changes in these subsets of cells across the estrus cycle.

Indirectly, estradiol may offset the orexigenic effects of ghrelin simply through its ability to potentiate the satiety-inducing pathways in the hypothalamus and brain stem and this may occur in a manner that independent from direct effects upon ghrelin secreting or ghrelin sensitice cells.

A recent paper seems to substantiate this by showing that male mice show a more robust feeding and growth hormone response to exogenous ghrelin treatment than females, but females show a more robust response to leptin than males Ghrelin and estrogen not only have opposing effects on food intake but also on substrate utilization.

reported that RER declines during proestrus and estrus, supporting a role for estrogen in fuel utilization 74 and consistent with the hypothesis that estradiol promotes the utilization of fats as a source of energy. Conversely, ghrelin promotes the utilization of carbohydrates over fat Clearly, more studies are required to determine the role of estrogen in regulating substrate metabolism in females, and how this interacts with the ghrelin system under different conditions that include acute and chronic stress.

Perhaps one of the most neglected areas of research is the interaction between estradiol and ghrelin in the modulation of reward circuitry and food seeking. In studies where effort based motivation has been examined, ghrelin increases while estradiol decreases food seeking.

Paradoxically, the responses of dopamine cells in the VTA to the direct effects of these hormones are very similar and these may be the underlying substrate for how these hormones influence preference for palatable reinforcers and enhance the effects of psychostimulants like cocaine Antagonism of GHSR in this region produces greater effects on working for palatable food rewards in female rodents than in males and there is evidence that estrogen potentiates rewarding brain stimulation in this area The specific neural phenotypes through which these effects are produced are currently unknown, as is whether GHSR and ER colocalize in this region.

Furthermore, a more detailed examination of sex differences in different components of motivated behavioral in response to ghrelin and estrogen alone and in combination is required.

Finally, while emphasis has been placed on the interaction between estrogen and ghrelin, estrogen is not the only ovarian hormone that modulates food intake. Progesterone and its metabolite allopregnenalone stimulates food intake in male rodents A recent study showed that allopregnanolone increased food intake when co-administered with ghrelin in male rats and significantly increased the orexigenic capabilities of ghrelin in a subset of rats in the study possibly via its action as a positive modulator of the GABA A receptor The interaction between ghrelin and progesterone in females remains to be determined.

Overall, the research reviewed here supports clear sex differences in the regulation of homeostatic and hedonic feeding by ghrelin. To improve our understanding of the physiological effects of ghrelin, more research that includes females in experimental design is needed to close the gap in knowledge that exists in the study of ghrelin biology in females.

These studies need to include close monitoring of the estrus cycle if we are to understand the complex relationship. AS generated the first draft of the document.

AA and BW complemented and edited the manuscript by adding their expertise in the subject of feeding and reproductive neuroendocrinology. All authors contributed to the article and approved the submitted version. This work was supported by funding from the Canadian Institutes for Health Research CIHR awarded to AA Grant No.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Manna P, Jain SK. Obesity, Oxidative Stress, Adipose Tissue Dysfunction, and the Associated Health Risks: Causes and Therapeutic Strategies.

Metab Syndr Relat Disord 13 10 — doi: PubMed Abstract CrossRef Full Text Google Scholar. Bremner JD, Moazzami K, Wittbrodt MT, Nye JA, Lima BB, Gillespie CF, et al. Diet, Stress and Mental Health.

Nutrients 12 8 CrossRef Full Text Google Scholar. Rao WW, Zong QQ, Zhang JW, An FR, Jackson T, Ungvari GS, et al. Obesity Increases the Risk of Depression in Children and Adolescents: Results From a Systematic Review and Meta-Analysis.

J Affect Disord — Abizaid A, Horvath TL. Brain Circuits Regulating Energy Homeostasis. Regul Pept :3— Gao Q, Horvath TL. Cross-Talk Between Estrogen and Leptin Signaling in the Hypothalamus. However, no significant correlation seems to exist between plasma ghrelin concentrations and circulating levels of GH or IGF-I unpublished data, Tschöp et al.

even though both ghrelin and GH increase during fasting 34 , Very recent data indicate that most of the ghrelin-induced GH secretion is not only directly opposed by somatostatin action, but also involves mediation through GHRH 33 , 36 , However, ghrelin also releases GH in vitro from primary rat pituitary cells 8 , 12 , and GHRP-2, a potent ghrelin receptor agonist, releases GH in vivo in patients with GHRH receptor mutations This indicates the existence of GHRH-independent effects of ghrelin on GH secretion mediated by hypophyseal GHS-Rs, which were originally cloned from the pituitary Alternatively, ghrelin may stimulate an unidentified hypothalamic agent U-factor that, in turn, stimulates GH release The first published evidence for the involvement of ghrelin in the regulation of appetite was provided by Ghigo and co-workers This hunger-inducing effect of ghrelin has now been confirmed in two more studies, where, again, 3 out of 7 33 and 9 out of 11 individuals report hunger as the only sensation after ghrelin injection A large number of animal studies added strength to the argument that ghrelin is involved in the regulation of energy balance.

For example, exogenous ghrelin induces adiposity in rodents by stimulating an acute increase in food intake, as well as a reduction in fat utilization 12 , 41 — Adipogenic as well as orexigenic effects of ghrelin are independent from its ability to stimulate GH secretion 12 , 46 and are most likely mediated by a specific central network of neurons that is also modulated by leptin 2 — 7 , 9 , 12 , 41 — Regulation of ghrelin secretion, as well as its biological effects, appear to be opposite those of leptin.

However, from a teleological point of view, ghrelin and leptin might really be complementary players of one regulatory system that has developed to inform the central nervous system about the current status of acute and chronic energy balance 12 , 38 — In addition, a specific role for ghrelin might be to ensure the provision of calories that GH requires for growth and repair In humans, circulating ghrelin levels are decreased in chronic obesity 48 and acute caloric intake 26 , 34 , 47 states of positive energy balance, whereas plasma levels of ghrelin are increased by fasting 12 , 34 and in cachectic patients with anorexia nervosa Of course, it has yet to be proven that the rather modest changes in circulating ghrelin, in the fmol range, have physiological relevance for hypothalamic receptor sites.

One plausible explanation is that if ghrelin is indeed a hormone signaling the need to conserve energy 12 , ghrelin secretion is triggered to counter further deficit of energy storage and to prevent starvation or cachexia. A very recent study shows a pre-meal rise of human plasma ghrelin, suggesting a possible role of ghrelin as a hunger signal triggering meal initiation In rodents, fasting and hypoglycemia increase ghrelin levels, whereas intake of food, especially carbohydrates dextrose , decreases ghrelin secretion 12 , 41 , We speculate that this obvious connection between glucose levels, ghrelin secretion and GH secretion is likely to be involved in the physiological mechanism of diagnostic procedures such as oral glucose tolerance testing for acromegaly and insulin tolerance testing for GH deficiency.

Differential effects of ghrelin might be mediated by separate ghrelin GHS-R subtypes as recently suggested by Thorner and co-workers Based on a series of elaborate studies using GHS-R antagonists [ d -Lys 3 ]GHRP-6 and BMS, also an NPY-antagonist and an NPY-Y1-R antagonist [ d -Trp32]NPY , they showed that the orexigenic effect of ghrelin can be dissociated from its GH releasing effects, suggesting distinct GHS-R-subtypes.

Based on the observation of differential orexigenic effects of hexarelin and its analogs and GH secretagogue actions at the pituitary gland 52 , 53 , the existence of additional subtypes of the GHS-R 16 — 18 had previously been hypothesized.

The putative adipogenic effects of ghrelin in humans remains to be shown because it is possible that ghrelin has different effects on energy balance in humans and rodents. In addition, ghrelin-induced adiposity could be only a transient effect and the therapeutic potential of ghrelin in cachectic humans might therefore turn out to be as disappointing as the efficacy of leptin for the therapy of human obesity 5 , Carefully conducted clinical studies focusing on body composition as well as long-term studies on ghrelin treatment in rodents are necessary to further address this question.

Our current understanding of the involvement of different hypothalamic systems in metabolic regulation arises from early degeneration studies in rats. Destruction of distinct hypothalamic regions, particularly the ventromedial nucleus but also the areas of the paraventricular and dorsomedial nuclei, induced hyperphagia 55 — In contrast, discrete lesions placed in the lateral hypothalamus 61 , 62 reduced food intake.

During the last two decades, a substantial amount of research demonstrated that NPY, administered into the cerebral ventricles 63 or other specific hypothalamic sites 64 , induced food intake.

However, in addition to NPY, several other hypothalamic peptides were found to affect appetite and feeding behavior for details see Refs. Appetite-suppressing neuropeptides include the POMC derivate, α-MSH 6 , 7 , 72 that is produced in arcuate nucleus perikarya An important milestone to link the central regulation of metabolism with peripheral levels of energy storage was the discovery of the adipose hormone, leptin.

Similar examples of obesity in humans have been found and are associated with a mutation of leptin or the leptin-receptor 78 — Leptin is released by adipose tissue and has been suggested to be the key-signal reflecting adipose stores.

Leptin receptors are found in the hypothalamus, particularly in the arcuate nucleus where leptin is thought to exert its primary feedback signaling 81 — Recent experiments in rodents and primates have been attempting to tie together the diverse hypothalamic peptidergic systems with hormone receptors, including leptin receptors, to decipher the hypothalamic signaling modality underlying the regulation of daily energy homeostasis 81 — A schematic illustration of some of these interactions and the way ghrelin signaling may be integrated into these circuits is shown on Fig.

Schematic representation of the interaction between key hypothalamic peptidergic systems in the central regulation of daily energy homeostasis and their relationship to peripheral and putative hypothalamic ghrelin.

Ghrelin, a hunger signal, is released from the stomach into the circulation and may be produced? in a subset of hypothalamic neurons red. Leptin, a satiety signal, is released from white adipose tissue WAT into the circulatory system. Ghrelin red arrows and leptin orange arrows directly target the hypothalamus and brain stem areas.

While brain stem areas on this drawing are illustrated as efferent targets of hypothalamic circuits, critical pathways exists from the brain stem to the hypothalamus, as well, that can mediate ascending ghrelin and leptin signaling. AGRP is produced in NPY cells yellow and acts to block the inhibitory action of the POMC derivate, α-MSH green , on feeding.

The NPY neurons that receive lateral hypothalamic input, including HCRT brown and melanin concentrating hormone MCH blue innervation, project to a number of regions of the brain, particularly those implicated in feeding mechanisms, including the paraventricular nucleus PVN , lateral hypothalamus, LH, ventromedial nucleus VMH , perifornical region PF , and dorsomedial nucleus DMH.

The same regions also receive direct lateral hypothalamic input as well as innervation fromα -MSH cells. These regions, in turn, project large black arrow widely throughout the brain to loci including the medial thalamic nuclei MT , central gray cg , dorsal motor nucleus of the vagus DMV , cortex, nucleus of the solitary tract NTS , locus coeruleus LC , spinal cord, and amygdala.

It is yet to be determined what role central vs. peripheral ghrelin plays in the regulation of this circuitry and at what sites and subcellular levels ghrelin signaling is interacting with that of leptin.

Peripheral ghrelin is mainly produced in the gastrointestinal tract 8 , 10 , 22 — It reaches ghrelin-receptors in the anterior pituitary and potentially in the mediobasal and mediolateral hypothalamus through the general circulation to stimulate GH release and to regulate energy homeostasis It remains to be determined whether circulating ghrelin can reach brain areas outside of the blood brain barrier only, such as the ventromedial arcuate nucleus 93 , or it has the ability to target areas protected by the blood brain barrier.

Areas protected by the blood brain barrier include most hypothalamic nuclei and the rest of the brain Ghrelin-containing cells are also present in the mediobasal hypothalamus, where GHRH cells and the neuronal network that regulates energy balance are located 8 , Detailed phenotypes and macroscopic connectivity of different hypothalamic networks regulating metabolism have been described by numerous recent outstanding reviews 2 — 7.

Among hypothalamic peptidergic circuits, particular significance is attributed to the arcuate nucleus opiate neurons that produce α-MSH, a main anorexigen and energy expenditure enhancer 72 , and to its interrelationship with another group of arcuate nucleus neurons that produce both NPY and an endogenous antagonist of α-MSH, AGRP The interaction between these two distinct populations of cells is currently considered as a primum movens in the regulation of energy homeostasis.

In light of the aforementioned excellent reviews 2 — 7 , we will avoid an in-depth description of these peptidergic systems here but will attempt to emphasize a better appreciation of the neuronal doctrine for the integration of emerging experimental data on ghrelin.

In the brain, receptors for ghrelin were detected in multiple hypothalamic nuclei as well as in the hippocampus, substantia nigra, ventral tegmental area, and dorsal and median raphe nuclei 8 , 94 — In a series of experiments, Dickson and co-workers, first using synthetic GHS-R agonist, and then ghrelin, provided evidence that this novel metabolic hormone, in fact, interacts with the aforementioned hypothalamic peptidergic systems in the central regulation of metabolism 99 — The effect of ghrelin on metabolism seems to be the exact opposite to that of leptin 2 — 7 , 9 , 10 , In obesity, when plasma leptin levels are elevated, ghrelin plasma levels are decreased indicating physiological adaptations to the positive energy balance rather than an involvement in the etiology of obesity 48 , Of course, it is important to note that, while ghrelin is regulated acutely like a satiety factor, leptin levels are not regulated by meals, but rather by actual increase in adipose stores.

Figure 1 depicts a highly complex interaction between a variety of hypothalamic peptidergic systems, including the putative ghrelin network, in the central regulation of energy balance.

In addition, receptors for the different neuropeptides as well as for peripheral hormones that affect metabolism, including insulin, thyroid hormones, gonadal steroids and glucocorticoids, are also present in these regions. For that, a multidisciplinary approach is mandatory.

The hypothalamus is composed of a complicated set of regulatory neurons that in most cases cannot be identified by traditional means of cell segregation, i. location, soma size, or dendritic arbor. Therefore, to identify specific types of neurons, cytochemistry must be used.

In addition, as in all other brain areas, the primary mode of communication between hypothalamic peptidergic circuits is via synapses. The only reliable way for assessing synapses is by the use of conventional electron microscopy and electrophysiology because proximity of different cells assessed by light microscopy is not a convincing indicator of neuronal interaction.

Thus, determination of the qualitative and quantitative synaptological relationship between GHS-Rs, ghrelin-producing neurons, and other key hypothalamic peptidergic systems and their receptors will be an important step for gaining insight into the hypothalamic signaling modality of ghrelin.

Of course, the anatomical experiments alone will not be sufficient to determine the actual involvement of the presynaptic ghrelin system in the regulation of the postsynaptic circuit, but provides an invaluable map that is necessary for the correct interpretation of data gathered with other tools.

In fact, anatomical studies need to be complemented by parallel electrophysiological analyses. That approach not only eliminated the pitfalls of the individual experimental techniques but immediately provided a more comprehensive view on a given hypothalamic neuronal system The significance in determining the spatial relationship between different afferents using anatomical and electrophysiological tools may further be appreciated when one considers that a synapse is more potently able to affect postsynaptic cells when located proximally either on the cell body or postsynaptic dendrite than when it is located more distally.

The impact of ghrelin on arcuate and parvicellular paraventricular nucleus neurons will be readily dependent on their synaptic organization on the postsynaptic cells and their interaction with other systems presynaptically.

Electrophysiological and anatomical observations pointed to both the arcuate and paraventricular nuclei as primary sites for the interplay between AGRP and α-MSH systems , It may be that peripheral and central ghrelin contribute equally to the regulation of both of these hypothalamic areas, but it is also conceivable that stomach-derived ghrelin affects the arcuate nucleus where the blood-brain barrier is less effective, whereas hypothalamic ghrelin is more involved in the modulation of hypothalamic sites within the blood-brain barrier, such as the paraventricular nucleus.

An alternative and equally feasible pathway for ghrelin signaling from the stomach is via an ascending neural network through the vagus nerve and brain stem nuclei that ultimately reaches the hypothalamus When electrophysiological and anatomical techniques are combined with conventional physiological and molecular biological approaches, as well as with the very recently developed revolutionary tracing technique of DeFalco et al.

We are thankful to Michael Statnick, Paul Burn, Jose Caro, and Marya Shanabrough for critical review. Mokdad AH , Serdula MK , Dietz WH , Bowman BA , Marks JS , Koplan JP The continuing epidemic of obesity in the United States.

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