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Leptin's Actions on the Reproductive Axis: Perspectives and Mechanisms

^a Graduate Program in Neurobiology&Behavior, ^b Department of Obstetrics&Gynecology, and ^c Department of Physiology & Biophysics, University of Washington, Seattle, Washington 98195-7290

	ABSTRACT

TOP ABSTRACT INTRODUCTION LEPTIN AS A REPRODUCTIVE... LEPTIN AND THE ONSET... MECHANISMS OF LEPTIN'S ACTIONS... SUMMARY REFERENCES

 
Energy availability influences reproductive fitness. The activity of the reproductive axis is sensitive to the adequacy of nutrition and the stores of metabolic reserves. The adipocyte-derived hormone leptin is postulated to reflect the state of nutrition and energy reserves and serve as a metabolic gate to the reproductive system. Genetically obese ob/ob mice (lacking endogenous leptin) are infertile, and treatment of these animals with exogenous leptin stimulates the activity of the reproductive endocrine system and induces fertility in both sexes. Severely food-restricted animals have reduced circulating levels of leptin, which are associated with markedly reduced secretion of the gonadotropins, LH, and FSH. Treatment of food-restricted mice, rats, sheep, and monkeys with exogenous leptin reverses the diet-induced inhibition of gonadotropin secretion. Leptin has also been suggested to have a role in timing the onset of puberty in several species, although evidence that leptin is the primary metabolic signal for initiating the onset of puberty in any species is controversial. Notwithstanding this debate, it is undisputed for all species studied to date that adequate levels of leptin in the circulation are essential (but not sufficient) for pubertal progression and that leptin treatment can reverse the delay in sexual maturation caused by food restriction. Double-label in situ hybridization studies in the brain of the mouse, rat, and monkey have revealed that hypothalamic neurons expressing proopiomelanocortin and neuropeptide Y coexpress the leptin receptor, whereas no evidence has been adduced that GnRH neurons express this receptor. Together, these observations suggest that leptin is a metabolic signal to the neuroendocrine reproductive system and that under conditions of inadequate energy reserves, low leptin levels act as a metabolic "gate" to inhibit the activity of the neuroendocrine reproductive axis in both sexes.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION LEPTIN AS A REPRODUCTIVE... LEPTIN AND THE ONSET... MECHANISMS OF LEPTIN'S ACTIONS... SUMMARY REFERENCES

 
The reproductive system of the mammal is exquisitely sensitive to the availability of energy (food) in the external environment. Acute changes in an animal's energetic status can result in modulation of the hypothalamic-pituitary-gonadal (HPG) axis. Suppression of pulsatile LH secretion has been documented after fasting or food restriction in myriad species, including rats [1, 2], mice [3], hamsters [4], sheep [5, 6], monkeys [7], and humans [8, 9]. In addition to its effects on reproductive hormonal profiles in adulthood, food restriction can delay the timing of pubertal onset [5, 10] and directly affect reproductive behavior [11, 12]. The caloric challenge resulting from intense exercise has also been shown to inhibit reproductive function in rats and humans [13, 14], as do pharmacological manipulations that block either glucose mobilization (with insulin) or utilization (with 2-deoxyglucose) [15–19]. Pulsatile LH secretion in fasted animals can be normalized in hours to minutes with refeeding [7, 20]. Fasting-induced LH suppression is believed, ultimately, to be a consequence of reduced release of GnRH from the ventral forebrain, as fasted animals show LH pulses similar in quantity and magnitude to fed animals when given exogenous GnRH [7, 21–25].

The causal link between nutritive resources and fertility is well established (reviewed in [26, 27]), and considering (in the female) the enormous metabolic requirements of pregnancy and lactation, it seems to be part of an effective strategy to ensure that energy resources are not wasted on reproductive efforts that are unlikely to succeed. However, while the HPG axis can be rapidly modulated by glucoprivation, this may not be the only metabolic signal to which the reproductive axis responds. Indeed, it is also well established that an animal's reserves of adipose tissue can influence reproductive capability in two ways: 1) the timing of the onset of puberty (specifically the time of first ovulation in females) and 2) the ability to maintain reproductive function during adulthood. Schneider and Wade [28] have demonstrated that fasting-induced anestrus occurs more rapidly in lean hamsters than in fat hamsters. Rats maintained on a high-fat diet come into first estrus earlier than do animals fed on a low-fat diet [29], yet body composition is similar among animals upon reaching first estrus [30]. Similarly, adolescent girls often differ in height and weight at menarche, but tend to have a similar percentage of body fat [31]. The observation that women with a low percentage of body fat are often amenorrheic [31] led Frisch and McArthur [32] to propose that minimal body fat levels are required for both the onset and maintenance of menstrual cycles in women. One of the criticisms of the "critical body fat" hypothesis has been the limited number of viable candidates for a molecule whose function is to convey body fat levels to the brain, in which it could in turn affect hypothalamic output.

	LEPTIN AS A REPRODUCTIVE SIGNAL

TOP ABSTRACT INTRODUCTION LEPTIN AS A REPRODUCTIVE... LEPTIN AND THE ONSET... MECHANISMS OF LEPTIN'S ACTIONS... SUMMARY REFERENCES

 
In 1994, the gene for the protein leptin was cloned and sequenced from both the mouse and human [33]. Leptin is a 167-amino acid protein made and secreted by adipocytes. The finding that leptin circulates in the plasma in proportion with body adiposity [34] led to the theory that leptin acts as an "adipostat," a humoral signal carrying information regarding energy reserves. Both peripheral and central injections of leptin to wild-type mice cause weight loss and reduced food intake [35–37]. The possibility of a link between leptin and reproduction became apparent when it was determined that a homozygous mutation in the leptin (ob) gene was responsible for the obesity syndrome in the obese (ob/ob) mouse [33]. Several papers testified to the reproductive shortcomings of ob/ob mice after the first published work on this mutant [38]. These mice are infertile [38], a condition believed to be due to reduced circulating gonadal steroids [39] and insufficient hypothalamic-pituitary drive [40]. Experiments from this laboratory and others [41–43] have demonstrated that correction of leptin deficiency in ob/ob mice by peripheral injections of recombinant leptin activates the reproductive axis and restores fertility in both sexes. Fourteen days of leptin treatment to ob/ob mice increases uterine and ovarian weights in females, while leptin increases seminal vesicle and testes weights in males compared to saline-treated, pair-fed ob/ob controls, despite considerable body weight loss in all groups [41]. The stimulatory effect on the reproductive organs appears to have functional significance, as leptin-treated male and female ob/ob mice are able to mate successfully with their wild-type counterparts [42, 43]. These studies (among others) show that the weight loss experienced by pair-fed ob/ob animals does not restore fertility, implying that obesity alone is not the cause of infertility to ob/ob mice and strengthening the case that leptin is directly responsible for these changes in reproductive capacity.

Circulating leptin levels decrease with fasting in rodents and humans [34, 44–47], indicating that leptin levels can also reflect acute changes in metabolic status. Could this decrease in leptin levels be responsible for the attenuation of gonadotropin secretion during fasting? In an experiment designed to mimic the fall of leptin levels during fasting, leptin antiserum was administered into the lateral ventricle of rats, which caused a decrease in LH pulsatility and a cessation of estrous cyclicity [48]. We attempted to answer this question more directly in the rhesus macaque [49]. Peripubertal male macaques were fasted for two days while being given i.v. infusions of either leptin or vehicle. During the second day of fasting, 3 out of 4 leptin-treated monkeys had LH pulses, whereas 0 out of 4 saline-treated monkeys had LH pulses (Fig. 1). Leptin-treated animals had higher mean plasma LH and FSH levels than controls, demonstrating the ability of leptin to counteract the effects of fasting on gonadotropin secretion. Similar results on LH secretion have been found by others in mice [44] and rats [47, 50]. After 48 h of fasting in adult female rats, reduced LH pulse frequency is restored to the level of fed animals by i.p. injections of leptin [47]. However, reinstatement of gonadotropin secretion during periods of fasting does not mean an animal is competent to reproduce. Wade et al. [51] found that leptin facilitates lordosis in fed hamsters, but apparently leptin cannot overcome the suppression of sexual behavior in food-deprived female hamsters.

View larger version (27K): [in this window] [in a new window]   FIG. 1. Plasma LH levels during fasting in two male monkeys. Animals were fasted for two days during which time they received either leptin or saline i.v. infusions. Each animal received both treatments (leptin and saline) on separate occasions. During the evening of the second day of fasting, saline-treated monkeys showed suppression of LH pulses, whereas leptin-treated animals showed clear evidence of LH pulsatility.

	LEPTIN AND THE ONSET OF PUBERTY

TOP ABSTRACT INTRODUCTION LEPTIN AS A REPRODUCTIVE... LEPTIN AND THE ONSET... MECHANISMS OF LEPTIN'S ACTIONS... SUMMARY REFERENCES

 
Concordant with its proposed role in relaying information about nutritional status, leptin has also been implicated in triggering the onset of puberty. Food restriction delays pubertal onset, and refeeding reverses this delay [5, 10]. We studied time of vaginal opening (VO) and first estrus in rats that were either 1) saline-treated and ad lib-fed, 2) leptin-treated and ad lib-fed, or 3) saline-treated and pair-fed to the leptin-treated group [52]. We found that leptin treatment (6.3 µg/g BW i.p. twice daily, starting on postnatal Day 23) caused animals to consume 80% of the amount of food eaten by ad lib-fed controls. Despite retarded growth due to food restriction, leptin-treated animals showed no differences in either the age of VO or first estrus compared to ad lib-fed animals, whereas at postnatal Day 38, none of the pair-fed animals had achieved either of these milestones. Ovarian and uterine weights corroborated these results, with pair-fed animals having underdeveloped ovaries and uteri compared to both ad lib-fed and leptin-treated rats. Interestingly, leptin treatment did not completely reverse the impact of a more severe food restriction (70% of ad lib-feeding) on the timing of pubertal onset in the same study [52]. At 43 days of age, only 5 of 8 leptin-treated animals had shown VO, and 4 of 8 showed first estrus, whereas all ad lib-fed animals and no pair-fed animals had experienced these events. Thus, artificially elevated leptin levels may be insufficient to reverse the delay of pubertal onset that comes with food deprivation—arguing that leptin by itself cannot trigger the changes in GnRH secretion required to initiate puberty.

The ability of leptin to reverse the effects of reduced food intake on sexual maturation appears to reflect an action on the brain. In a severe food restriction paradigm, Gruaz et al. [53] fed female rats at 36% of ad lib levels starting at postnatal Day 25, delaying the normal timing of VO. On Day 53, the animals received infusions of either saline or leptin (10 µg/day) into the lateral ventricle. By Day 63, 8 of 9 animals receiving leptin had experienced VO, whereas all of the saline-treated animals remained in an arrested state. The authors also performed an experiment similar in design to that of Cheung et al. [52], giving ventricular infusions of leptin (which reduced food intake to 63% of ad lib levels) starting at Day 29 and monitoring VO. As was the case with peripheral leptin injections [52], central delivery of leptin (at the dose used) was only partially able to rescue pubertal development, as by Day 38, 4 of 9 leptin-treated rats had showed VO compared with only 1 of 8 pair-fed animals [53].

Circulating leptin levels have been measured over development in several species. In female mice, a peak in plasma levels of leptin during the second week of postnatal life has been reported, which occurs independently of changes in body weight and before the developmental increase in estradiol [54]. Gruaz et al. [53] examined plasma leptin levels in female rats between postnatal Days 24 and 59 (average age of VO approximately Day 40) and observed a steady rise in leptin levels in proportion to body weight over the sampling period, although one cannot discount the possibility of a peak occurring before Day 24. Studies in male rhesus macaques show little change in leptin levels over the peripubertal period, when LH, FSH, and testosterone levels begin to climb to adult levels [55, 56]. In the human, as in the mouse, there is an absolute requirement of leptin to initiate human pubertal development, as evidenced by the fact that individuals with mutations in the leptin gene are hypogonadal and infertile [57]. Leptin levels in girls tend to increase steadily over the period of sexual development [58, 59], while in boys there is a peak in leptin levels around Tanner stage 2 accompanied by a gradual decline throughout the remainder of puberty [58–60].

Is leptin the primary signal to awaken the reproductive system at puberty? The ability of exogenous leptin to initiate puberty prematurely would seem to strengthen support for the "critical body fat" hypothesis of sexual development. Two studies [61, 62] demonstrate an advancement of pubertal onset in female mice by leptin treatment. Chehab et al. [62] treated mice beginning on postnatal Day 21 with daily i.p. injections of leptin (2 µg/g BW) or PBS. Leptin-treated animals showed 1–4 days advancement of VO, increased reproductive organ (uteri, ovaries, oviducts) weights, and decreased latency to first mating compared to PBS-treated animals. However, a footnote to this study [62] states that the authors had difficulty replicating their observation of a leptin-induced advancement of VO. In a similar study by Ahima et al. [61], mice given the same dose of leptin showed early onset of VO, vaginal estrus, and vaginal cycling compared to vehicle-treated mice, without undergoing significant weight loss. It should be noted that leptin treatment does not seem to advance pubertal onset in female rats [52], and experiments performed in this laboratory have been unable to confirm the results of Chehab et al. [62] and Ahima et al. [61] in female mice (unpublished observations). Given the conflicting reports in the literature and our own studies of this question, we believe it is more likely that leptin is a factor permissive to the onset of puberty, and that, although some minimal threshold level of leptin is necessary to pubertal development, leptin by itself is not sufficient to initiate puberty.

	MECHANISMS OF LEPTIN'S ACTIONS ON REPRODUCTION

TOP ABSTRACT INTRODUCTION LEPTIN AS A REPRODUCTIVE... LEPTIN AND THE ONSET... MECHANISMS OF LEPTIN'S ACTIONS... SUMMARY REFERENCES

 
Leptin would appear to play a role in relaying metabolic information to the reproductive axis, but the mechanism(s) by which this is accomplished remains unknown. The search for sites of leptin's action began with the cloning of its receptor (Ob-R) in mice and humans [63]. The Ob-R is a single-pass membrane receptor of the class I cytokine receptor family (reviewed in [64]). Multiple splice variants have been found [63, 65], which have identical extracellular domains and either a long (~300 amino acids) or short (~30 amino acids) intracellular domain. Stimulation of the long form activates signal transducer and activator of transcription (STAT) proteins both in vivo and in vitro, whereas the short form is apparently incapable of signaling via this pathway [66–68]. Classical parabiosis experiments (reviewed in [69]) predicted that other spontaneously obese animals, such as the diabetic mouse (db/db; [70]) and fatty rat (fa/fa; [71]), would be unable to respond to a circulating satiety factor (now known to be leptin). This prediction was verified when it was discovered that db/db mice and fa/fa rats, which are also infertile [72, 73], both have mutations in the long form of the Ob-R that render it ineffective [65, 74–76]. A mutation causing premature truncation of the Ob-R in humans has also been linked to obesity and hypogonadism [77].

Distribution of Ob-R and its mRNA has been examined in several species, including the mouse [63, 65, 78–81], rat [82–87], monkey [49], and human [88–90]. The Ob-R has been found at all points along the HPG axis. Several groups have documented evidence of Ob-R mRNA in the gonads of mice, rats, and humans [81, 84, 89]. Leptin has been shown to regulate expression of mRNAs for side chain cleavage enzyme and 17-hydroxylase [84] and to modulate LH-stimulated estradiol production [89] in the ovary, providing evidence of functional Ob-R in these tissues. The anterior pituitary is also a source of Ob-R mRNA [49, 84, 91] although currently, the phenotype(s) of pituitary cells expressing Ob-R mRNA has not been identified. Yu et al. [92] demonstrated that leptin stimulates gonadotropin release from rat pituitaries in vitro, indicating the ability of leptin to have a direct effect on pituitary tissue. Although evidence for leptin's ability to modulate HPG activity at either the gonads or pituitary exists and should not be discounted, the remainder of the discussion on this topic will concentrate on possible mechanisms of leptin action within the central nervous system, focusing on the hypothalamus.

Although distribution of Ob-R in the brain varies among those species studied thus far (for discussion see [49]), all species to date express Ob-R mRNA in the arcuate (Arc) and ventromedial nuclei (VMN) of the hypothalamus (Fig. 2A)—two areas acknowledged to influence both feeding and reproductive behaviors. To elucidate the neuronal pathways by which leptin influences reproductive function, we and others have begun to identify the phenotypes of neurons that are responsive to leptin (i.e., express Ob-R) through double-labeling experiments, using both in situ hybridization and immunohistochemistry. Since leptin has been shown to stimulate GnRH secretion from the basal hypothalamus [92, 93], it has been proposed that leptin may signal GnRH-containing neurons directly. However, experiments performed in both the rat [94] and the monkey [49] show little coexpression of Ob-R and GnRH at either the protein or mRNA level. Although this lack of evidence does not rule out the possibility of leptin's direct stimulation of GnRH release, it seems more likely that leptin exerts its actions on GnRH secretion by acting transsynaptically.

View larger version (102K): [in this window] [in a new window]   FIG. 2. A) Distribution of leptin receptor (Ob-R) mRNA in the female monkey hypothalamus. Areas in the hypothalamus expressing Ob-R mRNA (seen as clusters of white dots) include the VMN, Arc, median eminence (ME), and lateral hypothalamus (not shown). 3V, Third ventricle. Bar = 500 µm. B) Ob-R mRNA expression in POMC mRNA-expressing neurons in the Arc of the monkey. POMC mRNA-expressing neurons are filled with purple-black precipitate (arrows), and Ob-R mRNA is seen as clusters of white dots. Almost half of all POMC mRNA-containing neurons in the Arc also express Ob-R mRNA. Bar = 30 µm.

Other substances may be intermediaries in the signal transduction pathway between leptin and GnRH release. Neurons containing products of the proopiomelanocortin (POMC) gene (e.g., ß-endorphin, adrenocorticotropic hormone) make direct synaptic contacts with GnRH-containing neurons [95–97], and are found in the Arc, a region of high expression of Ob-R mRNA. Using double-label in situ hybridization, we have demonstrated a high coincidence of expression of both POMC and Ob-R mRNAs in the Arc of both rats [98] and monkeys [49] (Fig. 2B), while Håkansson et al. [94] have shown colocalization of Ob-R and adrenocorticotropic hormone immunoreactivity in the Arc of the rat. Does this coexpression reflect an actual ability of leptin to modify POMC signaling in the brain? We tested this hypothesis by comparing levels of POMC mRNA in wild-type and ob/ob mice. POMC gene expression in untreated ob/ob mice was approximately 50–70% of that found in wild-type animals throughout the Arc and retrochiasmatic area, whereas leptin-treated ob/ob mice showed POMC mRNA expression restored to levels of wild-type mice [99]. Regulation of POMC gene expression by leptin in ob/ob mice has been confirmed by others, who have also documented a reduction of POMC mRNA in fasted rats and mice, which are presumably hypoleptinemic [100, 101]. Thus the potential exists for leptin to influence reproductive function during fasting through altering the availability of POMC gene products. Indeed, the endogenous opioid ß-endorphin as well as -melanocyte-stimulating hormone (-MSH) have been implicated in modulating both feeding and reproduction [102–106]. If leptin-induced changes in ß-endorphin transmission influence GnRH secretion, it may be through indirect means, as GnRH neurons are believed to lack the classical opioid receptor subtypes (µ, , and ) [107, 108]. Leptin's inhibitory actions on food intake are thought to be due, in part, to signaling through hypothalamic melanocortin type 4 (MC4) receptors [109], for which -MSH (among other POMC gene products) is an endogenous ligand [110]. However, experiments demonstrating the involvement of MC4 receptors in transducing leptin's stimulatory effects on reproductive parameters using specific MC4 agonists/antagonists have not yet been published.

The orexigenic peptide neuropeptide Y (NPY) is another substance found in the Arc that plays a dual role in feeding and reproduction [105]. NPY has been shown to stimulate GnRH release, an action that may be mediated in vivo by synaptic contacts between NPY- and GnRH-containing neurons [105]. NPY mRNA levels in the Arc are elevated in both fasted and leptin-deficient animals [111, 112]; this increase is believed to be the cause, in part, of the hyperphagia and subsequent obesity in ob/ob mice [113–115]. NPY mRNA-containing neurons in the Arc also express Ob-R mRNA [49, 116, 117], suggesting the possibility that NPY mRNA levels are directly responsive to circulating leptin. Although evidence exists for stimulatory effects of NPY on GnRH/LH secretion when given acutely, NPY appears to act in an inhibitory fashion when delivered chronically or to animals with low estrogen levels [118–120]. However, overexpression of NPY alone cannot account for the reproductive failure of the ob/ob mouse, since mice that carry both the ob/ob genotype and a homozygous null mutation for NPY have only a partial restoration of fertility [114].

	SUMMARY

TOP ABSTRACT INTRODUCTION LEPTIN AS A REPRODUCTIVE... LEPTIN AND THE ONSET... MECHANISMS OF LEPTIN'S ACTIONS... SUMMARY REFERENCES

 
The facts presently available support the hypothesis that leptin plays an important role in relaying energetic status to the reproductive axis; however, the mechanisms subserving leptin's effects in this context remain elusive. While the presence of Ob-R in the ventral forebrain is tantalizing, there is as yet no conclusive evidence that leptin directly influences the activity of GnRH-containing neurons. If one proposes that leptin acts indirectly to affect GnRH secretion, several possible modes of action are conceivable. Leptin may positively or negatively influence the synthesis and/or secretion of other hypothalamic peptides (e.g., POMC gene products, NPY, corticotropin-releasing hormone, galanin), which then in turn modulate GnRH release (Fig. 3). This hypothesis has yet to be verified by pharmacological experiments that are designed to identify the signaling pathways purported to be involved. Promising new insights have come from experiments that have examined the possible interaction between leptin and glucose availability [121]. Syrian hamsters show disruption of sex behavior, estrous cyclicity, and ovulation with fasting [27]. Leptin treatment restores estrous cyclicity in fasted animals, but not in animals that have also received injections of 2-deoxyglucose [122]. This implies that leptin's effects on reproduction may be due to its influence on metabolic fuel availability, and that leptin acts to provide signals to glucose-sensitive regions of the brain, which then influence GnRH secretion.

View larger version (24K): [in this window] [in a new window]   FIG. 3. Proposed model of leptin's actions on the neuroendocrine reproductive axis. Leptin acts on hypothalamic neurons expressing its receptor (Ob-R). GnRH mRNA-containing neurons are not thought to be direct targets for leptin's actions, as they do not express easily detectable amounts of Ob-R mRNA. Neurons containing POMC and NPY mRNA also express Ob-R mRNA, and both POMC and NPY mRNA are regulated by leptin. Changes in the synthesis and/or release of these or other hypothalamic peptides could then act at GnRH neurons to affect GnRH release.

Does the discovery of leptin revise the way that we think about the "critical body fat" hypothesis of fertility? Should we now refer to a "critical leptin level" hypothesis? A majority of the data supporting the "critical body fat" hypothesis are correlative and do not prove causality (see [123] for review). Leptin has the potential to act as a metabolic signal to the reproductive system to reflect energy reserves; unfortunately, leptin's multi-faceted influence on metabolism makes it difficult to discern between primary and secondary actions of this hormone. Since reproductive failure can still be observed in fasted animals despite their having adequate leptin levels [52, 53, 122], there may not be a "leptin sensor" per se that acts as a switch to activate the HPG axis. Leptin may only be a signal insofar as it is able to influence the availability of metabolic fuels, such as glucose or fatty acids. Future experiments will undoubtedly clarify leptin's role as a regulator of the reproductive system.

	ACKNOWLEDGMENTS

 
The authors would like to thank the following people for their contributions to these endeavors: Tom Teal, Megan Corning, Laura Johnson, Shafeena Nurani, and Diana Rickard. We also thank Dr. Doug Foster for helpful discussions, and Clement Cheung, John Hohmann, Tom Knight, and Dr. Patricia Finn for their critical comments on this manuscript.

	FOOTNOTES

 
¹ Correspondence: Robert A. Steiner, Department of Physiology&Biophysics, University of Washington, Box 357290, Seattle, WA 98195-7290. FAX: 206 685 0619; steiner{at}u.washington.edu

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TOP ABSTRACT INTRODUCTION LEPTIN AS A REPRODUCTIVE... LEPTIN AND THE ONSET... MECHANISMS OF LEPTIN'S ACTIONS... SUMMARY REFERENCES

 

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