When Did Leptin Become a Reproductive Hormone?
Almost 50 years ago the obese mouse model was identified, and parabiosis studies were able to demonstrate that some humoral factor was involved in adiposity, so that the genetics and endocrine nature of this process have been apparent for many years. With the discovery of leptin just a few years ago, early studies validated the role of this protein product of the obese gene. Early studies in the obese mouse model (ob/ob mouse) demonstrated that the genetic basis was truly a deficiency in leptin. Coincidentally, the relationship to fertility was also associated with leptin. These early studies were also able to demonstrate a relationship to puberty and the time of pubertal development. Very quickly, the recognition that the placenta was a source of leptin and that leptin levels were elevated in pregnancy in a number of species also broadened our appreciation of the relationship to reproductive functions. These many rapidly elucidated relationships to leptin were reported soon after the identification and availability of leptin as a research reagent and have firmly put leptin into the area of reproductive physiology in addition to establishing roles in metabolism, satiety, and energy metabolism. Subsequent studies have expanded all of these situations. Species beyond the rodent model, including the human, have now introduced these physiologic studies into the clinical arena and the role of leptin in fertility, puberty, pregnancy, and genetics. In this issue, all of these topics are reviewed to bring the reader up to date with leptin and its role in reproductive function, many of which overlap with the control of obesity.
Obesity and the regulation of appetite have always been of interest, although the recent epidemic of obesity in Western countries and especially the United States has provoked a higher level of research activity. Not surprisingly, the discovery of leptin and associated molecules has made a significant impact in this area. In the 1950s the genetically obese mouse model (ob/ob mouse) was identified so that a genetic relationship to adiposity was appreciated many years ago. Early studies with this animal model and with hypothalamic-lesioned obese animals were able to demonstrate that a humoral factor may be responsible for the regulation of adiposity. If a normal lean animal was parabiosed to an ob/ob mouse, the ob/ob mouse would lose body weight, indicating that the normal animal produced some humoral substance that would suppress appetite in the obese model. This lipostat theory prevailed for many years but it required the elucidation and availability of leptin1 as the prime candidate to validate this experimental conclusion. It is now presumed that leptin represents the signal molecule from body stores to the brain, responding with receptors in the hypothalamus that regulate appetite. The first study to be done with available leptin was to demonstrate that the ob/ob mouse model could be restored to normal weight by the administration of leptin. This has given rise to the hope, perhaps prematurely, that leptin administration to the obese human subject might result in significant weight loss and serve as a tool in the medical management of obesity. In the first studies that have been extensively reported, the promise is not as great as had been hoped. There are indeed situations and individuals that may respond to leptin but not as effectively as hoped for, and some individuals do not respond at all. Clearly, other studies are needed to determine why leptin administration might be effective in some individuals but not others, and to determine a possible relation to serum levels or free leptin concentrations. Certainly, many modifications and analogs will be developed in the next decade before any clinical utility of leptin is appreciated. The development of leptin has also given rise to a variety of other molecules beyond the scope of this monograph, which may also be pharmaceutical candidates for the management of obesity. This article will introduce several reproductive actions in which leptin was demonstrated to be involved in the first studies performed when leptin became available as a research tool.
When the ob protein (leptin) became available, studies to demonstrate its physiologic role were rapidly initiated. The genetic obese mouse model (ob/ob mouse) was a prime candidate for these studies as it was reliably presumed to be deficient in some humoral factor, presumably the protein product of the obese gene, leptin. Administration of leptin to the ob/ob mouse not only restored normal body weight but also reversed the infertility in this genetic model. Studies with food restriction were able to restore body weight to normal but could not restore fertility. This association of leptin with a reproductive function may have been our first indication of a relationship with the broader area of reproductive physiology. With the finding of the leptin receptor, the localization of this receptor was demonstrated in many sites but the first and most well studied was the long form of the leptin receptor in the hypothalamus. The role in the hypothalamus was thought to be exclusively for the regulation of neuropeptide Y (NPY), as one of the primary regulators of appetite. We have learned that there are other associations within the hypothalamus and that leptin may be the body's signal to the hypothalamus that metabolically it is efficacious to have leutinizing hormone (LH) surges. The leptin and the leptin receptor system are important to mediate the release of LH. Leptin has been found in ovarian follicular fluid and is generally comparable to serum levels. Follicles have been reported to have leptin receptors, and several reports have indicated the ability to synthesize leptin, although the most convincing is the recent report that demonstrates expression of leptin mRNA, yet another tissue that is able to produce leptin. In infertility patients, there are several reports to demonstrate that serum leptin levels increase in concert with estradiol following gonadotropic stimulation. More importantly, Brannian et al. have recently shown that the increasing the ratio of leptin to body mass index (BMI) predicts a decreasing probability for reproductive success in in vitro fertilization patients. The relationship to leptin and ovarian function, including aspects of infertility, are covered in this issue by Brannian and Hansen.
When recombinant leptin became available as a research tool, other early studies were able to demonstrate that leptin administration to immature mouse would accelerate the time of puberty. This observation was the first in a series of studies to investigate the role(s) of leptin on pubertal development, not only in the mouse but in other species, including the human. Studies in several species now suggest some role for leptin in this process but the exact nature of this involvement remains controversial. Studies in humans reported increases in leptin, which preceded gonadal endocrinologic development. Levels of leptin continued to increase in females but declined in males when testosterone levels increased. Studies in the rhesus monkey, a classic nonhuman primate model for human development, has not confirmed such a role for leptin. The role for leptin in pubertal development may be more permissive than required. This controversy is covered in greater detail by Mann and Plant, and the genetics of leptin in both the rodent and human with regard to puberty are reviewed by Farooqi in this issue.
Production of leptin by adipose tissue was confirmed soon after the elucidation of leptin structure and the ability to quantify its presence, but very soon other tissues came to be identified as sources of leptin. One of the first was the placenta, which has been reported to express the leptin message in a variety of species. Interestingly, in both the human and the baboon, the placenta expresses leptin mRNA at high levels in early pregnancy but the levels decline over the course of gestation, although the mass of the placenta is increased. It was reported soon after this that leptin levels are increased in pregnancy in several species including the mouse, the rat, and the human, and in our own studies we have emphasized the use of the baboon, a nonhuman primate model used extensively as a reproductive surrogate for human reproductive physiology. Serum leptin levels can increase dramatically in some species more so than in others, and the contribution of placental leptin to these elevated maternal levels remains controversial. Leptin receptors are found in the placenta, and preliminary results indicate a paracrine role. The question of whether placental leptin is responsible for the increases in the maternal circulation is not clear, although in vitro studies suggest that within the placenta leptin may serve paracrine actions related to angiogenesis, hematopoesis, and endocrine activities and is less likely to make a significant contribution to peripheral serum increases in leptin. Interestingly, the normal physiology of leptin in pregnancy has now progressed to high-risk pregnancies where observations in preeclampsia, gestational diabetes, and fetal-maternal differences have been presented. Indeed, leptin in the fetal system has been reported to be important for growth and function in many tissues. In the present issue, we have reviewed the role of leptin in pregnancy. Poston has reviewed the relationship of leptin to preeclamptic pregnancies and Christou et al have discussed leptin and its relationship to fetal growth and development.
A distinct gender difference was observed in the early studies. In those first studies in humans it was clear that levels were generally higher in females than in males and when plotted against some index of adiposity (BMI, percent body fat, etc.), there was always a linear relationship with increasing adiposity associated with increasing serum leptin levels. This linear expression was always higher in females than in males. There are several possible explanations for the difference. One is that females have more adipose tissue than males but a growing literature indicates that estrogen, especially at higher levels, will stimulate the production of leptin, whereas androgens will suppress the levels of leptin. This may play an important role in establishing the gender difference. In vitro studies have shown that adipose tissue from men and women are different and that there is a greater leptin release from female adipose tissue. A full understanding of gender differences remains to be established. The role of leptin in the male is covered in this issue by Lado-Abeal and Norman.
Since the discovery of leptin, just a few short years ago, there are now thousands of papers that have involved all of these areas of reproductive physiology. The question of leptin's role in fertility certainly will be investigated vigorously in the next few years but clearly some role in ovarian and/or pituitary function seems to be indicated. Studies of pubertal development remain controversial, but the interesting isolated cases in human genetics clearly make the point that there is a genetic component to leptin regulation and that the physiological sequelae of the absence of leptin or leptin receptors clearly impacts on pubertal development. The controversial nature of the clinical significance of leptin and the initiation of pubertal development still has to be elucidated. The role of leptin in pregnancy, in light of several high-risk pregnancy conditions associated with leptin alterations, may represent important consideration in future studies. What is the role of leptin in pregnancy? How is it regulated and can this be, if not a treatment tool, at least a diagnostic test to evaluate these situations? These areas are being actively researched as indicated by the explosion in the leptin literature, and this issue, hopefully, will serve to introduce this topic from a physiological standpoint and to aid in understanding clinical situations that are rapidly evolving.
Almost 50 years ago the obese mouse model was identified, and parabiosis studies were able to demonstrate that some humoral factor was involved in adiposity, so that the genetics and endocrine nature of this process have been apparent for many years. With the discovery of leptin just a few years ago, early studies validated the role of this protein product of the obese gene. Early studies in the obese mouse model (ob/ob mouse) demonstrated that the genetic basis was truly a deficiency in leptin. Coincidentally, the relationship to fertility was also associated with leptin. These early studies were also able to demonstrate a relationship to puberty and the time of pubertal development. Very quickly, the recognition that the placenta was a source of leptin and that leptin levels were elevated in pregnancy in a number of species also broadened our appreciation of the relationship to reproductive functions. These many rapidly elucidated relationships to leptin were reported soon after the identification and availability of leptin as a research reagent and have firmly put leptin into the area of reproductive physiology in addition to establishing roles in metabolism, satiety, and energy metabolism. Subsequent studies have expanded all of these situations. Species beyond the rodent model, including the human, have now introduced these physiologic studies into the clinical arena and the role of leptin in fertility, puberty, pregnancy, and genetics. In this issue, all of these topics are reviewed to bring the reader up to date with leptin and its role in reproductive function, many of which overlap with the control of obesity.
Obesity and the regulation of appetite have always been of interest, although the recent epidemic of obesity in Western countries and especially the United States has provoked a higher level of research activity. Not surprisingly, the discovery of leptin and associated molecules has made a significant impact in this area. In the 1950s the genetically obese mouse model (ob/ob mouse) was identified so that a genetic relationship to adiposity was appreciated many years ago. Early studies with this animal model and with hypothalamic-lesioned obese animals were able to demonstrate that a humoral factor may be responsible for the regulation of adiposity. If a normal lean animal was parabiosed to an ob/ob mouse, the ob/ob mouse would lose body weight, indicating that the normal animal produced some humoral substance that would suppress appetite in the obese model. This lipostat theory prevailed for many years but it required the elucidation and availability of leptin1 as the prime candidate to validate this experimental conclusion. It is now presumed that leptin represents the signal molecule from body stores to the brain, responding with receptors in the hypothalamus that regulate appetite. The first study to be done with available leptin was to demonstrate that the ob/ob mouse model could be restored to normal weight by the administration of leptin. This has given rise to the hope, perhaps prematurely, that leptin administration to the obese human subject might result in significant weight loss and serve as a tool in the medical management of obesity. In the first studies that have been extensively reported, the promise is not as great as had been hoped. There are indeed situations and individuals that may respond to leptin but not as effectively as hoped for, and some individuals do not respond at all. Clearly, other studies are needed to determine why leptin administration might be effective in some individuals but not others, and to determine a possible relation to serum levels or free leptin concentrations. Certainly, many modifications and analogs will be developed in the next decade before any clinical utility of leptin is appreciated. The development of leptin has also given rise to a variety of other molecules beyond the scope of this monograph, which may also be pharmaceutical candidates for the management of obesity. This article will introduce several reproductive actions in which leptin was demonstrated to be involved in the first studies performed when leptin became available as a research tool.
When the ob protein (leptin) became available, studies to demonstrate its physiologic role were rapidly initiated. The genetic obese mouse model (ob/ob mouse) was a prime candidate for these studies as it was reliably presumed to be deficient in some humoral factor, presumably the protein product of the obese gene, leptin. Administration of leptin to the ob/ob mouse not only restored normal body weight but also reversed the infertility in this genetic model. Studies with food restriction were able to restore body weight to normal but could not restore fertility. This association of leptin with a reproductive function may have been our first indication of a relationship with the broader area of reproductive physiology. With the finding of the leptin receptor, the localization of this receptor was demonstrated in many sites but the first and most well studied was the long form of the leptin receptor in the hypothalamus. The role in the hypothalamus was thought to be exclusively for the regulation of neuropeptide Y (NPY), as one of the primary regulators of appetite. We have learned that there are other associations within the hypothalamus and that leptin may be the body's signal to the hypothalamus that metabolically it is efficacious to have leutinizing hormone (LH) surges. The leptin and the leptin receptor system are important to mediate the release of LH. Leptin has been found in ovarian follicular fluid and is generally comparable to serum levels. Follicles have been reported to have leptin receptors, and several reports have indicated the ability to synthesize leptin, although the most convincing is the recent report that demonstrates expression of leptin mRNA, yet another tissue that is able to produce leptin. In infertility patients, there are several reports to demonstrate that serum leptin levels increase in concert with estradiol following gonadotropic stimulation. More importantly, Brannian et al. have recently shown that the increasing the ratio of leptin to body mass index (BMI) predicts a decreasing probability for reproductive success in in vitro fertilization patients. The relationship to leptin and ovarian function, including aspects of infertility, are covered in this issue by Brannian and Hansen.
When recombinant leptin became available as a research tool, other early studies were able to demonstrate that leptin administration to immature mouse would accelerate the time of puberty. This observation was the first in a series of studies to investigate the role(s) of leptin on pubertal development, not only in the mouse but in other species, including the human. Studies in several species now suggest some role for leptin in this process but the exact nature of this involvement remains controversial. Studies in humans reported increases in leptin, which preceded gonadal endocrinologic development. Levels of leptin continued to increase in females but declined in males when testosterone levels increased. Studies in the rhesus monkey, a classic nonhuman primate model for human development, has not confirmed such a role for leptin. The role for leptin in pubertal development may be more permissive than required. This controversy is covered in greater detail by Mann and Plant, and the genetics of leptin in both the rodent and human with regard to puberty are reviewed by Farooqi in this issue.
Production of leptin by adipose tissue was confirmed soon after the elucidation of leptin structure and the ability to quantify its presence, but very soon other tissues came to be identified as sources of leptin. One of the first was the placenta, which has been reported to express the leptin message in a variety of species. Interestingly, in both the human and the baboon, the placenta expresses leptin mRNA at high levels in early pregnancy but the levels decline over the course of gestation, although the mass of the placenta is increased. It was reported soon after this that leptin levels are increased in pregnancy in several species including the mouse, the rat, and the human, and in our own studies we have emphasized the use of the baboon, a nonhuman primate model used extensively as a reproductive surrogate for human reproductive physiology. Serum leptin levels can increase dramatically in some species more so than in others, and the contribution of placental leptin to these elevated maternal levels remains controversial. Leptin receptors are found in the placenta, and preliminary results indicate a paracrine role. The question of whether placental leptin is responsible for the increases in the maternal circulation is not clear, although in vitro studies suggest that within the placenta leptin may serve paracrine actions related to angiogenesis, hematopoesis, and endocrine activities and is less likely to make a significant contribution to peripheral serum increases in leptin. Interestingly, the normal physiology of leptin in pregnancy has now progressed to high-risk pregnancies where observations in preeclampsia, gestational diabetes, and fetal-maternal differences have been presented. Indeed, leptin in the fetal system has been reported to be important for growth and function in many tissues. In the present issue, we have reviewed the role of leptin in pregnancy. Poston has reviewed the relationship of leptin to preeclamptic pregnancies and Christou et al have discussed leptin and its relationship to fetal growth and development.
A distinct gender difference was observed in the early studies. In those first studies in humans it was clear that levels were generally higher in females than in males and when plotted against some index of adiposity (BMI, percent body fat, etc.), there was always a linear relationship with increasing adiposity associated with increasing serum leptin levels. This linear expression was always higher in females than in males. There are several possible explanations for the difference. One is that females have more adipose tissue than males but a growing literature indicates that estrogen, especially at higher levels, will stimulate the production of leptin, whereas androgens will suppress the levels of leptin. This may play an important role in establishing the gender difference. In vitro studies have shown that adipose tissue from men and women are different and that there is a greater leptin release from female adipose tissue. A full understanding of gender differences remains to be established. The role of leptin in the male is covered in this issue by Lado-Abeal and Norman.
Since the discovery of leptin, just a few short years ago, there are now thousands of papers that have involved all of these areas of reproductive physiology. The question of leptin's role in fertility certainly will be investigated vigorously in the next few years but clearly some role in ovarian and/or pituitary function seems to be indicated. Studies of pubertal development remain controversial, but the interesting isolated cases in human genetics clearly make the point that there is a genetic component to leptin regulation and that the physiological sequelae of the absence of leptin or leptin receptors clearly impacts on pubertal development. The controversial nature of the clinical significance of leptin and the initiation of pubertal development still has to be elucidated. The role of leptin in pregnancy, in light of several high-risk pregnancy conditions associated with leptin alterations, may represent important consideration in future studies. What is the role of leptin in pregnancy? How is it regulated and can this be, if not a treatment tool, at least a diagnostic test to evaluate these situations? These areas are being actively researched as indicated by the explosion in the leptin literature, and this issue, hopefully, will serve to introduce this topic from a physiological standpoint and to aid in understanding clinical situations that are rapidly evolving.