leptin and Infertility

In obesity, an elevated accumulation and dysregulation of adipose tissue, due to an imbalance between energy intake and energy expenditure, usually coexists with the loss of responsiveness to leptin in central nervous system, and subsequently with hyperleptinemia. Leptin, a peptide hormone mainly produced by white adipose tissue, regulates energy homeostasis by stimulating energy expenditure and inhibiting food intake. Human obesity is characterized by increased plasma leptin levels, which have been related with different obesity-associated complications, such as chronic inflammatory state (risk factor for diabetes, cardiovascular and autoimmune diseases), as well as infertility and different types of cancer. Besides, leptin is also produced by placenta, and high leptin levels during pregnancy may be related with some pathological conditions such as gestational diabetes. This review focuses on the current insights and emerging concepts on potentially valuable nutrients and food components that may modulate leptin metabolism. Notably, several dietary food components, such as phenols, peptides, and vitamins, are able to decrease inflammation and improve leptin sensitivity by up- or down-regulation of leptin signaling molecules. On the other hand, some food components, such as saturated fatty acids may worsen chronic inflammation increasing the risk for pathological complications. Future research into nutritional mechanisms that restore leptin metabolism and signals of energy homeostasis may inspire new treatment options for obesity-related disorders.

Topics: Adipose Tissue; Adipose Tissue, White; Animals; Autoimmune Diseases; Diabetes Mellitus; Energy Intake; Energy Metabolism; Fatty Acids; Female; Humans; Infertility; Inflammation; Leptin; Male; Neoplasms; Nutritional Physiological Phenomena; Obesity

Optimal fertility in humans and animals relies on the availability of sufficient metabolic fuels, information about which is communicated to the brain via levels of the hormones leptin and insulin. The circadian clock system is also critical; this input is especially evident in the precise timing of the female-specific surge of GnRH and LH secretion that triggers ovulation the next day. Chronodisruption and metabolic imbalance can both impair reproductive activity, and these two disruptions exacerbate each other, such that they often occur simultaneously. Kisspeptin neurons located in the anteroventral periventricular nucleus of the hypothalamus are able to integrate both circadian and metabolic afferent inputs and use this information to modulate the timing and magnitude of the preovulatory GnRH/LH surge. In an environment in which exposure to high caloric diets and chronodisruptors such as artificial night lighting, shift work, and transmeridian travel have become the norm, the implications of these factors for couples struggling to conceive deserve closer attention and more public education.

Topics: Animals; Circadian Rhythm; Fertility; Gonadotropin-Releasing Hormone; Humans; Hypothalamus, Anterior; Infertility; Insulin; Kisspeptins; Leptin; Lighting; Luteinizing Hormone; Neurons; Ovulation; Reproduction; Shift Work Schedule; Travel

Hypothalamic obesity represents a rare diagnosis applicable to only a small subset of obese patients. It is important to identify, diagnose, and treat these patients. This article reviews the physiology of the hypothalamus, focusing on its role in regulation of hunger, feeding, and metabolism. The causes of hypothalamic obesity are discussed including genetic, anatomic, and iatrogenic etiologies. The complex hormonal environment leading to obesity is explored for each etiology and treatment strategies are discussed. Reproductive consequences are also reviewed.

Topics: Appetite; Appetite Depressants; Bariatric Surgery; Craniopharyngioma; Energy Metabolism; Feeding Behavior; Humans; Hyperphagia; Hypogonadism; Hypothalamic Diseases; Hypothalamic Hormones; Hypothalamus; Iatrogenic Disease; Infertility; Leptin; Nerve Tissue Proteins; Obesity; Pituitary Neoplasms; Postoperative Complications; Pro-Opiomelanocortin; Puberty, Delayed; Receptors, Leptin; Receptors, Melanocortin; Sedentary Behavior

PLeptin is an adipocyte-derived hormone with pleiotropic effects on energy homeostasis, endocrine and reproductive functions, and immune responses. The multiple actions of leptin have led to the design and development of several leptin-based approaches to modulate the metabolic and endocrine status, to reduce inflammation, and to improve immune responses. Here, we review the current patents on leptin in different clinic applications.

Topics: Animals; Biomimetics; Genetic Therapy; Humans; Immune System Diseases; Immunization; Infertility; Leptin; Metabolic Diseases; Neoplasms; Patents as Topic

Obesity, characterized by enhanced food intake (hyperphagia) and reduced energy expenditure that results in the accumulation of body fat, is a major risk factor for various diseases, including diabetes, cardiovascular disease, and cancer. In the United States, more than half of adults are overweight, and this number continues to increase. The adipocyte-secreted hormone leptin and its downstream signaling mediators play crucial roles in the regulation of energy balance. Leptin decreases feeding while increasing energy expenditure and permitting energy-intensive neuroendocrine processes, such as reproduction. Thus, leptin also modulates the neuroendocrine reproductive axis. The gonadal steroid hormone estrogen plays a central role in the regulation of reproduction and also contributes to the regulation of energy balance. Estrogen deficiency promotes feeding and weight gain, and estrogen facilitates, and to some extent mimics, some actions of leptin. In this review, we examine the functions of estrogen and leptin in the brain, with a focus on mechanisms by which leptin and estrogen cooperate in the regulation of energy homeostasis.

Topics: Animals; Energy Metabolism; Estrogens; Humans; Hypothalamus; Infertility; Leptin; Melanocortins; Obesity; Receptor Cross-Talk; Receptors, Estrogen; Signal Transduction; STAT3 Transcription Factor

Leptin, a key hormone in energy homeostasis and neuroendocrine function, has a permissive role in initiating puberty and is crucial in the pathogenesis of reproductive dysfunction in several disease states of energy imbalance. KiSS1 neurons have recently been suggested to mediate leptin's effect on the reproductive system. New insights from recent animal studies and clinical trials are discussed.. Alterations in the expression profile of the KiSS1 gene and the kisspeptin receptor have been linked to reproductive dysfunction in leptin-deficient states. Neuroendocrine, including reproductive, dysfunction can be restored in humans and animals by leptin-replacement therapy. These insights have significantly advanced our understanding of hormonal systems needed to maintain normal reproduction. These data, if confirmed, also suggest a role for leptin as a novel therapeutic approach in several disease states.. Recent proof-of-concept studies involving leptin administration to humans underline the critical role of leptin not only in regulating energy homeostasis, but also in maintaining normal reproductive function. Leptin-replacement therapy is currently under intensive investigation as a potential novel therapeutic option for several conditions associated with reproductive dysfunction due to hypoleptinemia.

Topics: Amenorrhea; Animals; Anorexia Nervosa; Energy Metabolism; Female; Gonads; Humans; Hypothalamo-Hypophyseal System; Infertility; Kisspeptins; Leptin; Male; Menarche; Obesity; Polycystic Ovary Syndrome; Puberty; Reproduction; Sex Characteristics; Tumor Suppressor Proteins

Leptin, a 16-KD protein secreted primarily by adipose tissue, was first discovered in the search for a satiety signal. When administered into the brain, leptin depresses appetite. Interestingly, hyperphagic, obese, transgenic mice with leptin deficiency were noted to be reproductively incompetent, and administration of leptin restored their fertility. These pivotal observations led to numerous studies on the site of action of leptin within the hypothalamo-hypophyseal-gonadal axis, and a variety of models have been used ranging from the prepubertal condition to fasting suppression of reproductive hormones. The preponderance of studies thus far has focused on how leptin serves as a metabolic signal of energy balance within the neuroendocrine system, particularly as a regulator of GnRH/LH secretion. Less research has been conducted with other components of the reproductive system, but local effects of leptin have been demonstrated in the gonads where hyperleptinemia suppresses steroidogenesis and potentially affects gamete maturation. This presentation will review the major concepts for the role of leptin in the modulation of fertility and will consider the potential use of leptin in assisted reproductive technology and embryo transfer.

Topics: Animals; Female; Fertility; Gonadotropin-Releasing Hormone; Infertility; Leptin; Reproduction; Signal Transduction

Topics: Adipose Tissue; Adolescent; Adult; Androgens; Child; Feeding and Eating Disorders; Female; Humans; Infertility; Leptin; Male; Obesity; Proteins; Reference Values

Insulin resistance and disrupted secretion of adipokines are the major contributors to the pathogenesis of polycystic ovary syndrome (PCOS). Previous research has indicated that adiponectin/leptin (A/L) and HOMA/adiponectin (H/A) ratios have a strong association with insulin resistance and metabolic syndrome. The current study aimed to assess the predictability of the A/L and H/A ratios for PCOS women infertility and recurrent pregnancy loss (RPL). In this study, we investigated the association of A/L and H/A ratios with PCOS, as well as infertility and RPL in Iranian women with PCOS.. This case-control study included 150 PCOS (60 infertile and 90 PCOS-RPL) and 50 non-PCOS women. Clinical, biochemical, and hormonal features were evaluated, and the A/L and H/A ratios were calculated.. The A/L and H/A ratios were significantly decreased and increased in women with PCOS, respectively. A significant association was observed between the A/L and H/A ratios with PCOS, as well as PCOS-infertile and PCOS-RPL, even after adjusting for potential confounders. Although there was no significant difference between PCOS-infertile and PCOS-RPL subgroups, ROC curve analysis showed that A/L and H/A ratios could strongly predict PCOS with the area under the curve (AUC) of 0.867 and 0.861, respectively.. The ratios of A/L and H/A may serve as biomarkers to distinguish women with PCOS from non-PCOS in the Iranian population. However, it seems that they are not discriminatory markers for PCOS-associated RPL and infertility.

Topics: Adiponectin; Body Mass Index; Case-Control Studies; Female; Humans; Infertility; Insulin; Insulin Resistance; Iran; Leptin; Polycystic Ovary Syndrome; Pregnancy

Reproduction is an energetically costly event across vertebrates and tightly linked to nutritional status and energy reserves. In mammals, the hormone leptin is considered as a link between energy homeostasis and reproduction. However, its role in fish reproduction is still unclear. In this study, we investigated the possible role of leptin in the regulation of reproduction in zebrafish, using a loss of function leptin receptor (lepr) strain. Impaired leptin signaling resulted in severe reproductive deficiencies in female zebrafish. lepr mutant females laid significantly fewer eggs, with low fertilization rates compared to wild-type females. Folliculogenesis was not affected, but oocyte maturation and ovulation were disrupted in lepr mutants. Interestingly, the expression of luteinizing hormone beta (lhb) in the pituitary was significantly lower in mutant females. Analysis of candidate genes in the ovaries and isolated fully grown follicles revealed differential expression of genes involved in steroidogenesis, oocyte maturation and ovulation in the mutants, which are known to be regulated by LH signaling. Moreover, subfertility in lepr mutants could be partially restored by administration of human chorionic gonadotropin. In conclusion, our results show that leptin deficiency does not affect early stages of follicular development, but leptin might be essential in later steps, such as in oocyte maturation and ovulation. To our knowledge, this is the first time that leptin is associated to reproductive deficiencies in zebrafish.

Topics: Animals; Female; Infertility; Leptin; Mammals; Ovulation; Receptors, Leptin; Zebrafish; Zebrafish Proteins

Topics: Case-Control Studies; Female; Fertility; Humans; Infertility; Leptin; Pregnancy; Sensitivity and Specificity

Classical Galactosaemia (CG) (OMIM #230400) is a rare inborn error of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). Long-term complications persist in treated patients despite dietary galactose restriction with significant variations in outcomes suggesting epigenetic glycosylation influences. Primary Ovarian Insufficiency (POI) is a very significant complication affecting females with follicular depletion noted in early life. We studied specific glycan synthesis, leptin system and inflammatory gene expression in white blood cells as potential biomarkers of infertility in 54 adults with CG adults (27 females and 27 males) (age range 17-51 yr) on a galactose-restricted diet in a multi-site Irish and Dutch study. Gene expression profiles were tested for correlation with a serum Ultra-high Performance Liquid Chromatography (UPLC)-Immunoglobulin (IgG)-N-glycan galactose incorporation assay and endocrine measurements.. Twenty five CG females (93%) had clinical and biochemical evidence of POI. As expected, the CG female patients, influenced by hormone replacement therapy, and the healthy controls of both genders showed a positive correlation between log leptin and BMI but this correlation was not apparent in CG males. The strongest correlations between serum leptin levels, hormones, G-ratio (galactose incorporation assay) and gene expression data were observed between leptin, its gene and G-Ratios data (r. These results validate our previous findings and provide novel experimental evidence for dysregulation of genes LEP, LEPR, ANXA1, ICAM1 and SEPT4 for CG patients and combined with our findings of abnormalities of IgG glycosylation, hormonal and leptin analyses elaborate on the systemic glycosylation and cell signalling abnormalities evident in CG which likely influence the pathophysiology of POI.

Topics: Adolescent; Adult; Female; Fucosyltransferases; Galactose; Galactosemias; Humans; Infertility; Intercellular Adhesion Molecule-1; Leptin; Middle Aged; N-Acetylglucosaminyltransferases; Primary Ovarian Insufficiency; Receptors, Leptin; Septins; Young Adult

The cellular processes that cause high caloric diet (HCD)-induced infertility are poorly understood but may involve upregulation of suppressor of cytokine signaling (SOCS-3) proteins that are associated with hypothalamic leptin resistance. Deletion of SOCS-3 from brain cells is known to protect mice from diet-induced obesity, but the effects on HCD-induced infertility are unknown. We used neuron-specific SOCS3 knock-out mice to elucidate this and the effects on regional hypothalamic leptin resistance. As expected, male and female neuron-specific SOCS3 knock-out mice were protected from HCD-induced obesity. While female wild-type mice became infertile after 4 months of HCD feeding, infertility onset in knock-out females was delayed by 4 weeks. Similarly, knock-out mice had delayed leptin resistance development in the medial preoptic area and anteroventral periventricular nucleus, regions important for generation of the surge of GnRH and LH that induces ovulation. We therefore tested whether the suppressive effects of HCD on the estradiol-induced GnRH/LH surge were overcome by neuron-specific SOCS3 knock-out. Although only 20% of control HCD-mice experienced a preovulatory-like LH surge, LH surges could be induced in almost all neuron-specific SOCS3 knock-out mice on this diet. In contrast to females, HCD-fed male mice did not exhibit any fertility decline compared with low caloric diet-fed males despite their resistance to the satiety effects of leptin. These data show that deletion of SOCS3 delays the onset of leptin resistance and infertility in HCD-fed female mice, but given continued HCD feeding this state does eventually occur, presumably in response to other mechanisms inhibiting leptin signal transduction.. Obesity is commonly associated with infertility in humans and other animals. Treatments for human infertility show a decreased success rate with increasing body mass index. A hallmark of obesity is an increase in circulating leptin levels; despite this, the brain responds as if there were low levels of leptin, leading to increased appetite and suppressed fertility. Here we show that leptin resistant infertility is caused in part by the leptin signaling molecule SOCS3. Deletion of SOCS3 from brain neurons delays the onset of diet-induced infertility.

Topics: Age Factors; Animals; Body Weight; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Diet, High-Fat; Disease Models, Animal; Estrous Cycle; Female; Gene Expression Regulation; Hypothalamus; Infertility; Leptin; Luteinizing Hormone; Male; Mice; Mice, Inbred DBA; Mice, Transgenic; Neurons; Obesity; Prosencephalon; Suppressor of Cytokine Signaling 3 Protein

Leptin is a cytokine produced by white fat cells, skeletal muscle, the placenta, and the pituitary gland among other tissues. Best known for its role in regulating appetite and energy expenditure, leptin is produced largely by and in proportion to white fat cells. Leptin is also important to the maintenance and function of the GH cells of the pituitary. This was shown when the deletion of leptin receptors on somatotropes caused decreased numbers of GH cells, decreased circulating GH, and adult-onset obesity. To determine the source of leptin most vital to GH cells and other pituitary cell types, we compared two different leptin knockout models with Cre-lox technology. The global Lep-null model is like the ob/ob mouse, whereby only the entire exon 3 is deleted. The selective adipocyte-Lep-null model lacks adipocyte leptin but retains pituitary leptin, allowing us to investigate the pituitary as a potential source of circulating leptin. Male and female mice lacking adipocyte leptin (Adipocyte-lep-null) did not produce any detectable circulating leptin and were infertile, suggesting that the pituitary does not contribute to serum levels. In the presence of only pituitary leptin, however, these same mutants were able to maintain somatotrope numbers and GH mRNA levels. Serum GH trended low, but values were not significant. However, hypothalamic GHRH mRNA was significantly reduced in these animals. Other serum hormone and pituitary mRNA differences were observed, some of which varied from previous results reported in ob/ob animals. Whereas pituitary leptin is capable of maintaining somatotrope numbers and GH mRNA production, the decreased hypothalamic GHRH mRNA and low (but not significant) serum GH levels indicate an important role for adipocyte leptin in the regulation of GH secretion in the mouse. Thus, normal GH secretion may require the coordinated actions of both adipocyte and pituitary leptin.

Topics: Adipocytes; Animals; Cell Differentiation; Female; Gene Expression Regulation; Infertility; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Pituitary Gland; Pituitary Hormones; Somatotrophs

Female fertility depends on adequate nutrition and energy reserves, suggesting a correlation between the metabolic reserve and reproductive capacity. Leptin regulates body weight and energy homeostasis. The aim of this study was to investigate whether estradiol or FSH alone has a direct effect on the production of leptin.. A total of 64 patients submitted to controlled ovarian hyperstimulation with recombinant FSH for assisted reproduction and 20 patients using estradiol valerate for endometrial preparation for oocyte donation treatment were included in the study. All patients used GnRH analogues before starting treatment to achieve pituitary suppression. Blood samples for hormonal measurements were collected before starting and after completing the respective treatments. Data were analyzed statistically by the chi-square test, Student's t-test and Pearson's correlation test.. We observed an elevation of serum leptin levels secondary to the increase in estradiol, in the absence of influence of any other ovarian or pituitary hormone. The rising rate of leptin levels was higher in women treated with recombinant FSH, which also had higher levels of estradiol, than in those treated with estradiol valerate.. This study demonstrates a correlation between serum levels of estradiol and leptin, suggesting that estradiol is an important regulator of leptin production and that its effects can be amplified by its association with FSH.

Topics: Adult; Estradiol; Female; Fertilization in Vitro; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Goserelin; Humans; Infertility; Leptin; Pituitary Gland; Prospective Studies; Recombinant Proteins; Superovulation

To evaluate whether serum leptin levels are predictive of in vitrofertilization (IVF) outcome.. A nested, case-control study was performed on patients undergo-formed on patients undergoing IVF. Ovarian stimulation was performed with a set protocol. At the conclusion of the stimulation, patients were divided into 2 groups, poor stimulator (PS) and high stimulator (HS), based on the number of follicles seen on ultrasound. The PS group contained patients with < 12 follicles > 13 mm in diameter; the HS group contained patients with > or = 12 follicles > 13 mm. Blood from the start of the cycle in which human chorionic gonadotropin (hCG) was administered was assayed for leptin and estradiol. The number of follicles obtained, number of oocytes retrieved, quality of the oocytes and quality of the embryos were calculated. Mean leptin and estradiol levels were compared using Student's t test. Pearson correlation coefficients were calculated to assess the relationship between leptin and the other outcome variables.. Mean leptin levels (+/- SEM) at the start of the cycle (21.5 +/- 2.9 ng/dL for PS and 34.6 +/- 14.0 ng/dL for HS) and on the day of hCG (53.2 +/- 5.37 ng/dL for PS and 50.4 +/- 9.1 ng/dL for HS) were not significantly different.. Leptin levels obtained at the start of stimulation or on the day of hCG administration are not predictive of IVF outcome.

Topics: Adult; Biomarkers; Case-Control Studies; Female; Fertilization in Vitro; Humans; Infertility; Leptin; Ovulation Induction; Predictive Value of Tests; Pregnancy; Pregnancy Outcome; Risk Factors; Treatment Outcome

Secretion of leptin from adipocytes communicates body energy status to the brain by activating the leptin receptor long form (LRb). LRb regulates energy homeostasis and neuroendocrine function; the absence of LRb in db/db mice results in obesity, impaired growth, infertility and diabetes. Tyr 1138 of LRb mediates activation of the transcription factor STAT3 during leptin action. To investigate the contribution of STAT3 signalling to leptin action in vivo, we replaced the gene encoding the leptin receptor (lepr) in mice with an allele coding for a replacement of Tyr 1138 in LRb with a serine residue (lepr(S1138)) that specifically disrupts the LRb-STAT3 signal. Here we show that, like db/db mice, lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short and diabetic, s/s mice are fertile, long and less hyperglycaemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY) is elevated in db/db mice but not s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. LRb-STAT3 signalling thus mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth and glucose homeostasis.

Topics: Alleles; alpha-MSH; Animals; Blood Glucose; Body Weight; Cell Line; Diabetes Mellitus; DNA-Binding Proteins; Energy Metabolism; Estrous Cycle; Female; Homeostasis; Humans; Infertility; Leptin; Male; Mice; Neuropeptide Y; Obesity; Phenotype; Receptors, Cell Surface; Receptors, Leptin; Reproduction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Trans-Activators

Severe dietary restriction, catabolic states and even short-term caloric deprivation impair fertility in mammals. Likewise, obesity is associated with infertile conditions such as polycystic ovary syndrome. The reproductive status of lower organisms such as Caenorhabditis elegans is also modulated by availability of nutrients. Thus, fertility requires the integration of reproductive and metabolic signals. Here we show that deletion of insulin receptor substrate-2 (IRS-2), a component of the insulin/insulin-like growth factor-1 signalling cascade, causes female infertility. Mice lacking IRS-2 have small, anovulatory ovaries with reduced numbers of follicles. Plasma concentrations of luteinizing hormone, prolactin and sex steroids are low in these animals. Pituitaries are decreased in size and contain reduced numbers of gonadotrophs. Females lacking IRS-2 have increased food intake and obesity, despite elevated levels of leptin. Our findings indicate that insulin, together with leptin and other neuropeptides, may modulate hypothalamic control of appetite and reproductive endocrinology. Coupled with findings on the role of insulin-signalling pathways in the regulation of fertility, metabolism and longevity in C. elegans and Drosophila, we have identified an evolutionarily conserved mechanism in mammals that regulates both reproduction and energy homeostasis.

Topics: Animals; Energy Intake; Energy Metabolism; Estrus; Female; Fertility; Gonadal Steroid Hormones; Homeostasis; Infertility; Insulin; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Leptin; Luteinizing Hormone; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovary; Phosphoproteins; Pituitary Gland; Receptor, Insulin; Reproduction; Signal Transduction; Steroids

Topics: Animals; Body Weight; Embryonic and Fetal Development; Female; Humans; Hypertension; Infertility; Leptin; Pregnancy; Pregnancy Complications, Cardiovascular

Obesity is often associated with an impairment of the hypothalamic-pituitary-gonadal axis. The leptin-deficient ob/ob mouse model is characterized by a morbid obesity with a sterility in males and females that is corrected by continuous leptin treatment. Since ob/ob mice are maintained on the C57BL/6J inbred genetic background, we sought to determine whether their infertility can be corrected without leptin treatment but via the effect of modifier genes brought into the obese-sterile phenotype by a different genetic background. Thus, we generated via an F2 intercross ob/ob mice on a mixed C57BL/6J-BALB/cJ genetic background and assayed them for fertility by mating with wild-type C57BL/6J mice. Whereas genetically heterogeneous F2 obese females remained sterile like male and female C57BL/6J ob/ob mice, 41% of F2 C57BL/6J-BALB/cJ obese males were capable of reproducing despite a morbidly obese state. Therefore, the sterility of the original C57BL/6J ob/ob mouse model was genetically corrected independently of its obese state via the effects of modifier genes. Unlike testosterone levels, triglyceride levels, and testes weight-to-body weight ratios, which were all higher in fertile vs. sterile mice, glucose levels were similar in both groups, indicating that the underlying hyperglycemia of ob/ob mice was not an impediment to the onset of fertility. A genome-wide scan in F2 ob/ob males resulted in the localization of four modifier loci on chromosomes 1, 3, 5, and 14 with respective quantitative traits consisting of number of pregnancies, testes weights normalized to body weights, body weight at 8 weeks of age, and circulating testosterone. We conclude that the inheritance of modifier genes at the identified loci acts to promote fertility of otherwise sterile leptin-deficient obese male mice.

Topics: Animals; Body Weight; Chromosome Mapping; Female; Infertility; Leptin; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Obesity, Morbid; Pregnancy; Proteins; Reproduction

Leptin, a hormone secreted from white adipose tissue, has been shown to normalize the body weight of ob/ob but not db/db mice as postulated by Coleman in his classical parabiosis experiments. The major effect of leptin is therefore to decrease food intake, thus resulting in a breakdown of fat stores. Recently, we have suggested that leptin plays a role in reproductive physiology based on the observation that leptin treatment but not food restriction rescues the sterility of ob/ob females. In the present communication, we treated sterile ob/ob males with leptin and asked whether fertility could be induced, thus selecting their reproductive ability as the endpoint of the experiment. Our results show that all food-restricted ob/ob males are unable to impregnate normal C57BL/6J females. However, all leptin-treated ob/ob males fertilized normal females mice that carried out normal pregnancies and deliveries, demonstrating that the reproductive capacity of ob/ob males was corrected only with leptin treatment. Furthermore, reproductive indices such as testicular weight and histology are normalized in leptin-treated animals. Therefore, as in ob/ob females, leptin plays a significant role in the male mouse reproductive pathways.

Topics: Animals; Body Weight; Eating; Female; Fertility; Infertility; Leptin; Male; Mice; Obesity; Organ Size; Proteins; Testis

The expression of leptin and its receptors was examined by reverse transcriptase-polymerase chain reaction and immunofluorescence in granulosa and cumulus cells of pre-ovulatory follicles and in meiotically mature oocytes obtained from women undergoing in-vitro fertilization. Leptin concentrations were measured in newly aspirated follicular fluids and in maternal serum before and after the administration of an ovulatory dose of human chorionic gonadotrophin. The findings demonstrate leptin expression at the mRNA and protein levels by granulosa and cumulus cells, and the presence of leptin in mature human oocytes. While an association between follicular leptin concentration and embryo development was not observed, a post-ovulatory increase in serum leptin concentration was associated with implantation potential. The results are discussed with respect to possible roles of leptin in early human development.

Topics: Adult; Base Sequence; Carrier Proteins; DNA Primers; Embryo Transfer; Female; Fertilization in Vitro; Follicular Fluid; Follicular Phase; Gene Expression; Granulosa Cells; Humans; In Vitro Techniques; Infertility; Leptin; Oocytes; Ovarian Follicle; Polymerase Chain Reaction; Pregnancy; Proteins; Receptors, Cell Surface; Receptors, Leptin