| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
REVIEW |
Research Centre for Reproductive Health, Department of Obstetrics and Gynaecology, The University of Adelaide, Australia, 5011
Correspondence should be addressed to R J Norman; Email: di.sutton{at}adelaide.edu.au
| Abstract |
|---|
|
|
|---|
| Introduction |
|---|
|
|
|---|
Metabolic disorders such as the development of insulin resistance result from the increasing incidence of obesity, and have serious ramifications on the progression of lifetime health problems such as type II diabetes, cardiovascular disease, dyslipidemia and hypertension. A significant proportion of the infertile or sub-fertile population are obese or overweight (Hamilton-Fairley et al. 1992, Zaadstra et al. 1993, Pettigrew & Hamilton-Fairley 1997, Norman & Clark 1998, Crosignani et al. 2002), with a plethora of reproductive complications including menstrual dysfunction and anovulation (Hartz et al. 1979, Lake et al. 1997) and miscarriage (Wang et al. 2002). The development of obesity and insulin resistance commonly go hand-in-hand with the development of fertility problems, but it is the link between this metabolic state and infertility that remains to be defined.
Adipose tissue functions as a highly specialised, endocrine and paracrine organ producing an array of adipokines, as well as eliciting cell mediated effects via pro-inflammatory and anti-inflammatory cells, producing various cytokines and chemokines. Such factors have local and systemic biological effects, influence insulin sensitivity and the development of diseases such as atherosclerosis. This review will focus on these adipokines and female fertility, regarding their complex interactions with energy metabolism at the level of the hypothalamus, the pituitary, and peripheral tissues including the gonads, skeletal muscle and adipose tissue. In the last decade the study of one of these adipokines, leptin, has highlighted the interaction with female reproduction. Here, the links between excessive adiposity with obesity and associated metabolic states such as insulin resistance, and interactions with aspects of female fertility will be explored in the context of leptin and two new adipokines, adiponectin and resistin.
| Insulin resistance, adipokines and fertility in the obese |
|---|
|
|
|---|
(TNF-
), and nuclear receptors including peroxisome proliferator- activated receptor-
(PPAR-
) have been implicated in the aetiology of insulin resistance associated with obesity. Furthermore the role of adipokines including leptin, resistin and adiponectin with obesity and insulin resistance is emerging (Kadowaki et al. 2003, Greenfield & Campbell 2004, Eckel et al. 2005) Evidence supporting an interrelationship between insulin and fertility exists (Gong 2002, Hunter et al. 2004) but the mechanistic actions of dysregulated insulin functioning at a physiological and cellular level as associated with obesity, remain obscure. The adipokines resistin and adiponectin have been touted as this link, because they modulate glucose homeostasis, fat homeostasis, influence insulin action, and thus may potentially mechanistically link obesity, insulin resistance and fertility.
Increased production and secretion of the satiety hormone leptin correlates with the amount of fat tissue in animals (Maffei et al. 1995, Considine et al. 1996). Ordinarily leptin functions to reduce food intake and maintain energy homeostasis, but in obesity the development of a state of leptin resistance results in a dysfunctional energetic state (Sahu 2004). Obese rodents have elevated serum resistin levels (Steppan et al. 2001, Steppan & Lazar 2002, Lee et al. 2005) but adipose mRNA resistin levels are generally lower or unchanged in these models (Juan et al. 2001, Le Lay et al. 2001, Masuzaki et al. 2001, Way et al. 2001, Milan et al. 2002, Lee et al. 2005), which may be explained by altered translational or post-translational modifications of resistin protein, or altered metabolic clearance of resistin. In humans obese individuals, or those with a higher body mass index (BMI), have higher serum and adipose expression levels of resistin (Savage et al. 2001, Azuma et al. 2003, Degawa-Yamauchi et al. 2003b, Yannakoulia et al. 2003), although not all studies confer (Lee et al. 2003) and in obese pigs, elevated adipose mRNA and protein levels have been reported (Chen et al. 2004). In contrast, serum and adipose expression levels of adiponectin are reduced in obese humans (Arita et al. 1999, Cnop et al. 2003, Diamond et al. 2004, Bullo et al. 2005), pigs (Jacobi et al. 2004) and rodents (Hu et al. 1996, Yamauchi et al. 2001). Studies investigating the interaction between levels of these adipokines with increased adiposity in obesity, and with nutrition and energy supply in humans and animal models are summarised in Table 1
.
|
| Biological functions of adipokines |
|---|
|
|
|---|
|
In peripheral tissues, leptin generally has a fat metabolising role with limited direct effect on glucose metabolism. However, leptin antagonises insulin action and decreases its production by pancreatic ß-cells (Seufert 2004), it indirectly affects glucose metabolism, for example glucose transport in skeletal muscle via the hypothalamus and central nervous system (Kamohara et al. 1997, Minokoshi et al. 1999). Evidence suggests that leptin increases lipolysis in adipose tissue and cells, and in skeletal muscle, but it appears less critical to liver function (Cohen et al. 2001). Leptin receptor signalling in peripheral tissues is not well understood but involves various transcription factors, such as activation of signal transducer and activator of transcription 1 (STAT1) and STAT3 in adipose tissue (Bendinelli et al. 2000) and of STAT3 and Akt in skeletal muscle (Maroni et al. 2003). Furthermore the increase in fatty acid oxidation by leptin in skeletal muscle has been attributed to the activation of the cellular nutrient-sensing AMP-activated protein kinase (AMPK) signalling pathway (Minokoshi et al. 2002, Steinberg et al. 2003).
Adiponectin
Adiponectin (previously termed by initial investigators: ACRP30; Scherer et al. 1995, AdipoQ; Hu et al. 1996, APM1; Maeda et al. 1996 and gbp28; Nakano et al. 1996), was first described in cultured murine adipocytes 3T3-L1 a decade ago (Scherer et al. 1995) and is abundantly produced by adipose tissue. The adiponectin gene is located on chromosome 3q27 (Saito et al. 1999), in a region recently mapped as a susceptibility locus for type II diabetes and adiposity (Kissebah et al. 2000, Vionnet et al. 2000), and is thought to potentially link obesity to insulin resistance. Receptors for adiponectin, AdipoR1 and AdipoR2, were discovered recently in mice (Yamauchi et al. 2003) and a third receptor, t-cadherin, has also been identified, although the tissue distribution and functional significance of the latter remain to be elucidated (Hug et al. 2004).
Adiponectin functions as an insulin sensitising agent by reducing hepatic glucose production and enhancing insulin action in the liver (Berg et al. 2001, Combs et al. 2001). Furthermore, adiponectin reduces the activity of gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phophatase (G6Pase), and reduces fatty acid oxidation in the liver (Combs et al. 2001, Yamauchi et al. 2002). A direct effect on insulin production is yet to be determined, however AdipoR1 are expressed in islets cells of the pancreas (Kharroubi et al. 2003) and adiponectin treatment of in vitro cultured islet cells from normal and high-fat fed rats, showed a differential response in insulin production suggesting an alternative role in insulin resistant states (Winzell et al. 2004). Adiponectin increases fatty acid oxidation in the liver, via a reduction in CD36 expression, reducing fatty-acid influx and liver triglycerides (Yamauchi et al. 2001). In skeletal muscle a reduction of triglyceride accumulation involves increased expression of proteins that transport lipids (CD36), fuel oxidation (acyl-CoA oxidase) and energy dissipation (uncoupling protein 2; UCP2) (Fruebis et al. 2001, Yamauchi et al. 2001). Although not completely defined, post-receptor signalling involving AMPK and downstream acetyl-CoA carboxylase (ACC), p38 mitogen-activated protein kinase (MAPK) and PPAR-
is described in skeletal muscle, liver and adipocytes (Tomas et al. 2002, Yamauchi et al. 2002, Wu et al. 2003, Yamauchi et al. 2003) and are thought to regulate glucose and lipid metabolism.
A transgenic mouse model generating a 23 fold elevation of circulating adiponectin levels improved hepatic insulin sensitivity (Combs et al. 2004), although studies using adiponectin knock-out models are yet to demonstrate a clear relationship with glucose homeostasis, under various control and dietary treatments (Kubota et al. 2002, Ma et al. 2002, Maeda et al. 2002).
Resistin
The discovery of resistin (also known as FIZZ3 and adipocyte specific secretory factor; ADSF) was concurrent in three separate groups, focusing on aspects of lung inflammation (Holcomb et al. 2000), adipocyte differentiation (Kim et al. 2001) and screening targets of the insulin sensitising drug thiazolidinedione (Steppan et al. 2001). Despite the initial promise of resistin as the link between obesity and diabetes (Steppan et al. 2001), the discovery of low inter-species sequence homology (Gerstmayer et al. 2003), different chromosomal location of the gene between species (pig; Cepica et al. 2002, rat; Lin et al. 2003, bovine; Komatsu et al. 2003, Otieno et al. 2005) and differing sites of synthesis between species (Kim et al. 2001, Nagaev & Smith 2001, Savage et al. 2001, Steppan et al. 2001, McTernan et al. 2002, Fain et al. 2003, Patel et al. 2003), have resulted in some confusion in relation to resistins role in the development of obesity and insulin resistance. The majority of studies investigating a wider metabolic role of resistin is limited to rodents and humans, but data should be interpreted with caution when comparing these models and when extrapolating to other species.
In rodents resistin is abundantly expressed in adipose tissue and has been linked to reduced insulin tolerance, via increased hepatic glucose production through increased hepatic gluconeogenic enzymes PEPCK and G6Pase, and decreased AMPK activity (Rajala et al. 2003, Banerjee et al. 2004, Muse et al. 2004). Furthermore, resistin decreases glucose uptake by adipocytes (Steppan et al. 2001) and skeletal muscle (Moon et al. 2003, Pravenec et al. 2003) indicating that muscle, adipose tissue and liver contribute to impaired glucose sensitivity in rodents. In contrast, resistin mRNA expression in human adipocytes is comparably low (Nagaev & Smith 2001, Savage et al. 2001, McTernan et al. 2002). Although resistin altered proliferation of cultured human adipocytes (Ort et al. 2005), it did not affect glucose uptake or Akt phosphorylation (Ort et al. 2005), which raises the possibility that in humans resistin is not directly involved in glucose homeostasis in adipocytes. Resistin is however highly expressed in macrophages and monocytes (Savage et al. 2001, Patel et al. 2003) suggesting it may influence insulin resistance via effects on inflammation. Therefore, in rodents the direct role of resistin in obesity and glucose utilisation is more apparent than in humans, where it may be related to the functioning of adipose tissue rather than insulin resistance per se.
| Adipokines and fertility |
|---|
|
|
|---|
|
|
Adipokine role in maturation and action of the hypothalamus and pituitary
Serum levels of leptin at puberty are generally increased in mice (Chehab et al. 1997), pigs (Qian et al. 1999) and cattle (Garcia et al. 2002), and are positively correlated to age of first period in women (Matkovic et al. 1997). Although there are some exceptions (Bronson 2001, Cheung et al. 2001) it is generally hypothesised that an elevation in leptin to a threshold level permits the activation of the hypothalamicpituitary axis and the onset of puberty. Similar to serum levels of leptin, the expression of resistin in adipose tissue and the pituitary increased peripubertally in rodents (Morash et al. 2002, Nogueiras et al. 2003a). Plasma adiponectin levels in mice increase at puberty (Combs et al. 2003) in contrast to declining serum levels in boys and girls throughout puberty (Bottner et al. 2004). The mechanism responsible for the increase in mice appears to be common for both sexes, as the removal of the gonads prior to puberty did not affect its timing (Combs et al. 2003). Therefore a role for adipokines at the central level of the hypothalamus and pituitary in the regulation of pubertal development and subsequent cyclic female fertility is likely, and is explored herein.
Leptins central role in fertility influences GnRH secretion by the hypothalamus and the pituitary secretion of gonadotrophins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (Nagatani et al. 1998). The availability of nutrients influences this central effect, with fasting causing a decrease in leptin and LH levels in numerous species and the restoration of LH pulsatility following leptin administration (Ahima et al. 1996, Amstalden et al. 2000, Henry et al. 2001, Whisnant & Harrell 2002). In the well-fed ruminant (Henry et al. 2001, Amstalden et al. 2002) and pig (Barb et al. 2004), leptin administration failed to alter LH secretion, in contrast to data in well-fed rodents. Experiments conducted in vitro using tissue from well-fed rodents and pigs, showed that leptin stimulated the release of gonadotrophin-releasing hormone (GnRH) from hypothalamic explants and cells (Yu et al. 1997, Barb 1999, Woller et al. 2001) and stimulated LH and FSH release from adenohypophyseal explants and cells (Yu et al. 1997, Barb 1999, De Biasi et al. 2001, Ogura et al. 2001), suggesting both the hypothalamus and the pituitary as central sites of leptin action. However, similar experiments using cells and explants from well-fed cattle showed no change in GnRH or gonadotrophin secretion in response to the administration of leptin (Amstalden et al. 2005). Thus, the central role of leptin and the interactions between species and nutritional status remain to be explored further but suggest the possible development of central leptin resistance in ruminants when energy balance is positive or neutral (Amstalden et al. 2005).
Any prediction of a central role for adiponectin or resistin, interacting with GnRH and gonadotrophin production, or regulating energy metabolism is premature at this stage. However, a small number of studies have investigated expression and activity of these adipokines in cells from the hypothalamus and the pituitary. Studies using cultured rat hypothalamic neurons, failed to show a stimulatory effect of adiponectin on the production of various neuro-transmitters involved in central energy metabolism, and this was in contrast to the enhanced production in response to resistin (Brunetti et al. 2004). Resistin mRNA expression has been localised to the pituitary and the hypothalamus, but expression of adiponectin by these tissues has not yet been reported. Resistin expression levels were low in mouse pituitary at birth, increasing to peak levels at puberty, in contrast to the consistent expression by cells of the hypothalamus throughout development (Morash et al. 2002). The changes in expression by the pituitary around the time of puberty require signals from the hypothalamus, as was demonstrated by an absence of resistin expression in peri-pubertal mice with ablated hypothalamic cells (Morash et al. 2002). Furthermore, the reduction in pituitary levels of resistin in obese mice compared with control mice (Morash et al. 2004) and the co-localisation of resistin protein in rodent hypothalamus with neurons involved in feeding behaviour (Wilkinson et al. 2005) give weight to a link between resistin and the central control of feeding and obesity. Although a report in male rodents suggests that expression of resistin in the testis is regulated by the pituitary hormones LH and FSH (Nogueiras et al. 2004), like studies in female reproductive tissue are yet to be documented. Further exploration of resistins role in central energy metabolism, and gonadotrophin production will undoubtedly provide insight into its function in puberty attainment and the regulation of female fertility.
The central expression of adiponectin and its receptors in the hypothalamus and pituitary are yet to be completely explored but studies in mice suggest unaltered feed intake by mice lacking (Kubota et al. 2002, Maeda et al. 2002) or mice over-expressing (Combs et al. 2004) adiponectin protein. In addition, both the central and peripheral administration of adiponectin protein failed to influence feed intake of obese mice (Masaki et al. 2003). This was in contrast to similar studies of leptin, whereby its central function via the hypothalamus resulted in reduced intake of food in well-fed ruminants (Henry et al. 1999, Morrison et al. 2001), pigs (Barb et al. 1998, Ramsay et al. 2004, Weber & Spurlock 2004) and rodents (Pelleymounter et al. 1995, Mistry et al. 1997). As discussed in the Adiponectin section above, one known pathway through which adiponectin functions in peripheral tissues is via the cellular nutrient- sensor AMPK. Leptin too operates via this pathway, and in the hypothalamus it inhibits AMPK activation causing a reduction in food intake (Andersson et al. 2004). In contrast to this central action, leptin stimulates AMPK activation in skeletal muscle, (Minokoshi et al. 2002), a stimulation mirrored by adiponectin in various peripheral tissues (Tomas et al. 2002, Yamauchi et al. 2002, Wu et al. 2003). Given that both adipokines function to stimulate AMPK in peripheral tissues, it is conceivable that adiponectin in fact influences energy utilisation centrally via the same AMPK mechanism as leptin in the hypothalamus.
The underlying cause of reduced fertility in models of diet-induced obesity are important because unlike the ob/ob and db/db monogenic mutations researched extensively to date, human and rodent obesity results from complex interactions between genetics and the environment. Such obesity is often characterised by high circulating levels of leptin and increased leptin resistance (Halaas et al. 1997, Van Heek et al. 1997, Heymsfield et al. 1999, Hukshorn et al. 2000). A report by Tortoriello and colleagues discussed the development of leptin resistance and acquired obesity in a diet-induced animal model of obesity, with a rare and specific focus on fertility (Tortoriello et al. 2004). Diet-induced obesity exerted a greater effect on fertility in female mice compared with males. This was linked more closely to hyperleptinemia than hyperinsulinemia, and was overcome with GnRH stimulation, suggesting causes other than ovarian or uterine dysfunction for the infertility observed in this model (Tortoriello et al. 2004). Despite previous studies of diet-induced obesity in rodents failing to agree with regards to altered hypothalamic leptin receptor expression (El-Haschimi et al. 2000, Martin et al. 2000), the cause of infertility in this study was related to decreased leptin receptor expression and increased neuropeptide-Y levels in the hypothalamus, that is, reduced central leptin sensitivity and decreased GnRH pulsatility.
Adipokine role in the ovary and reproductive tissue
In general, the effects of adipokines on the process of ovulation, ovarian steroidogenesis and the maintenance of pregnancy have received limited attention. Reduced ovulation rate in in vivo experiments in which leptin was administered to intact rats, and in vitro culture studies of whole ovaries perfused with leptin, indicate a direct role for leptin in the ovulation process, independent of any change in steroid production (Duggal et al. 2000). In addition a recent report in mice that were deficient in GnRH indicated an effect of leptin on ovulation independent of GnRH and LH that involved a local function in the ovary, such as induction of ADAMTS-1 (a disintegrin and metalloproteinase with a thrombospondin-like motif), although other undefined hypothalamic pathways could not be excluded (Barkan et al. 2005). As yet, there are no similar mechanistic studies of the function of resistin or adiponectin in the process of ovulation. Furthermore, data concerning serum and local levels of adipokines in the ovary, with regards to the anovulatory disorder in humans polycystic ovary syndrome (PCOS) are not always clear, as is summarised in Table 2
. Therefore, this remains as a significant area for future investigation.
The fat-soluble steroid hormones are produced by ovary cell steroidogenesis, and the adipocyte derived adipokines may have a localised function in this process. Expression of both leptin mRNA and protein in granulosa and theca cells, support this possibility (Cioffi et al. 1997, Karlsson et al. 1997). Leptin influences steroidogenesis in isolated ovarian cells by modulating the metabolic actions of insulin and IGF-I and the stimulatory actions of gonadotrophins in cattle (Spicer & Francisco 1997, 1998, Spicer et al. 2000), pig (Gregoraszczuk et al. 2003, 2004), rodent (Zachow & Magoffin 1997, Duggal et al. 2002) and human (Agarwal et al. 1999, Guo et al. 2001, Tsai et al. 2002). Furthermore in humans, blood leptin levels correlate closely with those of progesterone throughout the menstrual cycle, and with both oestradiol and human choriogonadotrophin (hCG) throughout pregnancy (Hardie et al. 1997).
A role for adiponectin in ovarian steroidogenesis is yet to be described but an interaction is likely given the negative effects of testosterone on circulating adiponectin in humans (Lanfranco et al. 2004, Page et al. 2005) and mice (Nishizawa et al. 2002). Such an interaction has been demonstrated by resistin, which has stimulatory effects on testosterone production by cultured human theca cells that synergise with insulin (Munir et al. 2005). Furthermore, resistin dose-dependently increased the production of testosterone by cultured rat testis (Nogueiras et al. 2004), and the adrenal androgen dehydroepiandrosterone (DHEA) reduced mRNA expression of resistin in adipose tissue taken from rats (Kochan & Karbowska 2004).
Studies of the expression and activity of adipokines in the oviduct and endometrium are limited to leptin. Leptin and its receptors (mRNA and protein) are expressed in the oviduct (Kawamura et al. 2002, Craig et al. 2005) and the endometrium (Gonzalez et al. 2000, Kawamura et al. 2002, Cerevo et al. 2005), suggesting possible involvement in endometrial receptivity for the developing embryo.
Adipokine role in oocyte quality and embryo development
The discovery of leptin expression in mature human oocytes, combined with a post-ovulatory surge in its circulating levels (Cioffi et al. 1997), indicate that leptin may also effect maturation of the oocyte and influence early embryo development. Studies in humans, rodents and pigs have shown mRNA and/or protein expression for the leptin receptors in oocytes and developing early embryos (Kawamura et al. 2002, Cerevo et al. 2005, Craig et al. 2005), and leptin expression itself in the rodent blastocyst (Cioffi et al. 1997, Ryan et al. 2002), with some variability related to species. Some conflict surrounds the nature of leptins direct role in oocyte maturation, in different rodent species and between cultured whole follicles and oocytes (Ryan et al. 2002, Duggal et al. 2002, Swain et al. 2004). There are also conflicting reports concerning whether leptin enhances (Kawamura et al. 2002) or impedes (Fedorcsak & Storeng 2003) development of the pre-implantation mouse embryo but in the pig, leptin improves oocyte nuclear maturation via the MAPK pathway and increases embryo development in vitro (Craig et al. 2004).
Adiponectin receptors R1 and R2 are weakly expressed in the pig ovary (Lord et al. 2005), and to date this is the only documentation of expression in ovarian tissue or oocytes. Given that AMPK activity has been described in oocytes, coincident with germinal vesicle breakdown and induction of meiosis in preparation for fertilisation (Downs et al. 2002), adiponectin may be involved in regulation of oocyte nutrient-sensing via the AMPK pathway. There have been no reports to date of resistin expression in the ovary, oocyte or embryo of any species. This highlights a basic gap in our knowledge of how adipokines may regulate nutrient use for the developing oocyte and embryo.
Adipokines in pregnancy
Pregnancy invokes a large shift in maternal metabolism, which enables the provision of appropriate nutrients to the developing fetus as well as providing for physiological maintenance of the mother and preparation for lactation. Investigation of adipokines such as leptin, adiponectin and resistin in this metabolic shift is not a focus of this review but is an important aspect of fertility reviewed most notably for the role of leptin (Sagawa et al. 2002). The developing placenta expresses both leptin and its receptor (Masuzaki et al. 1997, Senaris et al. 1997) and placental resistin production has been reported recently in humans (Yura et al. 2003). Resistin serum and placental levels increases as pregnancy progresses (Yura et al. 2003), which is in contrast to levels of leptin (Masuzaki et al. 1997). These levels correlate with the state of reduced insulin sensitivity often developed in the latter stages of pregnancy, thus contributing to successful development of the fetus (Yura et al. 2003). Adiponectin and its receptors (R1 and R2) have also recently been localised to the placenta of humans and rats (Caminos et al. 2005), and the uterus of pigs (Lord et al. 2005). In the rat, placental expression of adiponectin mRNA increased during pregnancy and decreased in response to feed restriction, whereas the AdipoR2 receptor expression decreased during pregnancy but remained unchanged during under-nutrition (Caminos et al. 2005), adding support for numerous roles of these adipokines in the maintenance of a normal pregnancy.
| Conclusion |
|---|
|
|
|---|
| Acknowledgements |
|---|
|
|
|---|
| Footnotes |
|---|
| References |
|---|
|
|
|---|
Agarwal SK, Vogel K, Weitsman SR & Magoffin DA 1999 Leptin antagonizes the insulin-like growth factor-I augmentation of steroidogenesis in granulosa and theca cells of the human ovary. Journal of Clinical Endocrinology and Metabolism 84 10721076.
Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E & Flier JS 1996 Role of leptin in the neuroendocrine response to fasting. Nature 382 250252.[CrossRef][Medline]
Amstalden M, Garcia MR, Williams SW, Stanko RL, Nizielski SE, Morrison CD, Keisler DH & Williams GL 2000 Leptin gene expression, circulating leptin, and luteinizing hormone pulsatility are acutely responsive to short-term fasting in prepubertal heifers: relationships to circulating insulin and insulin-like growth factor I(1). Biology of Reproduction 63 127133.
Amstalden M, Garcia MR, Stanko RL, Nizielski SE, Morrison CD, Keisler DH & Williams GL 2002 Central infusion of recombinant ovine leptin normalizes plasma insulin and stimulates a novel hypersecretion of luteinizing hormone after short-term fasting in mature beef cows. Biology of Reproduction 66 15551561.
Amstalden M, Harms PG, Welsh TH Jr, Randel RD & Williams GL 2005 Effects of leptin on gonadotropin-releasing hormone release from hypothalamic-infundibular explants and gonadotropin release from adenohypophyseal primary cell cultures: further evidence that fully nourished cattle are resistant to leptin. Animal Reproductive Science 85 4152.[CrossRef]
Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D & Small CJ 2004 AMP-activated protein kinase plays a role in the control of food intake. Journal of Biological Chemistry 279 1200512008.
Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T & Matsuzawa Y 1999 Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochemical and Biophysical Research Communications 257 7983.[CrossRef][ISI][Medline]
Armellini F, Zamboni M & Bosello O 2000 Hormones and body composition in humans: clinical studies. International Journal of Obesity and Related Metabolic Disorders 24 Suppl 2 S18S21.[CrossRef]
Azuma K, Katsukawa F, Oguchi S, Murata M, Yamazaki H, Shimada A & Saruta T 2003 Correlation between serum resistin level and adiposity in obese individuals. Obesity Research 11 9971001.[ISI][Medline]
Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y, Wang J, Rajala MW, Pocai A, Scherer PE, Steppan CM, Ahima RS, Obici S, Rossetti L & Lazar MA 2004 Regulation of fasted blood glucose by resistin. Science 303 11951198.
Barb CR, Yan X, Azain MJ, Kraeling RR, Rampacek GB & Ramsay TG 1998 Recombinant porcine leptin reduces feed intake and stimulates growth hormone secretion in swine. Domestic Animal Endocrinology 15 7786.[CrossRef][ISI][Medline]
Barb CR 1999 The brain-pituitary-adipocyte axis: role of leptin in modulating neuroendocrine function. Journal of Animal Science 77 12491257.
Barb CR, Barrett JB & Kraeling RR 2004 Role of leptin in modulating the hypothalamic-pituitary axis and luteinizing hormone secretion in the prepuberal gilt. Domestic Animal Endocrinology 26 201214.[CrossRef][ISI][Medline]
Barkan D, Hurgin V, Dekel N, Amsterdam A & Rubinstein M 2005 Leptin induces ovulation in GnRH-deficient mice. FASEB 19 133135.
Bendinelli P, Maroni P, Pecori Giraldi F & Piccoletti R 2000 Leptin activates Stat3, Stat1 and AP-1 in mouse adipose tissue. Molecular and Cellular Endocrinology 168 1120.[CrossRef][ISI][Medline]
Berg AH, Combs TP, Du X & Brownlee M 2001 Scherer PE, The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nature Medicine 7 947953.[CrossRef][ISI][Medline]
Bjorbaek C & Kahn BB 2004 Leptin signaling in the central nervous system and the periphery. Recent Progress in Hormone Research 59 305331.
Bottner A, Kratzsch J, Muller G, Kapellen TM, Bluher S, Keller E, Bluher M & Kiess W 2004 Gender differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels. Journal of Clinical Endocrinology and Metabolism 89 40534061.
Bronson FH 2001 Puberty in female mice is not associated with increases in either body fat or leptin. Endocrinology 142 47584761.
Brown R, Wiesner G, Ur E & Wilkinson M 2005 Pituitary Resistin Gene Expression Is Upregulated in vitro and in vivo by Dexamethasone but Is Unaffected by Rosiglitazone. Neuroendocrinology 81 4148.[CrossRef][ISI][Medline]
Brunetti L, Orlando G, Recinella L, Michelotto B, Ferrante C & Vacca M 2004 Resistin, but not adiponectin, inhibits dopamine and norepinephrine release in the hypothalamus. European Journal of Pharmacology 493 4144.[CrossRef][ISI][Medline]
Brzechffa PR, Jakimiuk AJ, Agarwal SK, Weitsman SR, Buyalos RP & Magoffin DA 1996 Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 81 41664169.
Bullo M, Salas-Salvado J & Garcia-Lorda P 2005 Adiponectin expression adipose tissue lipolytic activity in lean and obese women. Obesity Surgery 15 382386.[CrossRef][ISI][Medline]
Caminos JE, Nogueiras R, Gallego R, Bravo S, Tovar S, Garcia-Caballero T, Casanueva FF & Dieguez C 2005 Expression and Regulation of Adiponectin and Receptor in Human and Rat Placenta. Journal of Clinical Endocrinology and Metabolism 90 42764286.
Carmina E, Orio F, Palomba S, Cascella T, Longo RA, Colao AM, Lombardi G & Lobo RA 2005 Evidence for altered adipocyte function in polycystic ovary syndrome. European Journal of Endocrinology 152 389394.
Cepica S, Rohrer GA, Masopust M, Kubickova S, Musilova P & Rubes J 2002 Partial cloning, cytogenetic and linkage mapping of the porcine resistin (RSTN) gene. Animal Genetics 33 381383.[CrossRef][ISI][Medline]
Cervero A, Horcajadas JA, Dominguez F, Pellicer A & Simon C 2005 Leptin system in embryo development and implantation: a protein in search of a function. Reproductive Biomedicine Online 10 217223.[ISI][Medline]
Chapman IM, Wittert GA & Norman RJ 1997 Circulating leptin concentrations in polycystic ovary syndrome: relation to anthropometric and metabolic parameters. Clinical Endocrinology (Oxf) 46 175181.
Chehab FF, Lim ME & Lu R 1996 Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nature Genetics 12 318320.[CrossRef][ISI][Medline]
Chehab FF, Mounzih K, Lu R & Lim ME 1997 Early onset of reproductive function in normal female mice treated with leptin. Science 275 8890.
Chen XD, Lei T, Xia T, Gan L & Yang ZQ 2004 Increased expression of resistin and tumour necrosis factor-alpha in pig adipose tissue as well as effect of feeding treatment on resistin and cAMP pathway. Diabetes Obesity and Metabolism 6 271279.[CrossRef][ISI][Medline]
Cheung CC, Clifton DK & Steiner RA 1997 Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 138 44894492.
Cheung CC, Thornton JE, Nurani SD, Clifton DK & Steiner RA 2001 A reassessment of leptins role in triggering the onset of puberty in the rat and mouse. Neuroendocrinology 74 1221.[CrossRef][ISI][Medline]
Cioffi JA, Van Blerkom J, Antczak M, Shafer A, Wittmer S & Snodgrass HR 1997 The expression of leptin and its receptors in pre-ovulatory human follicles. Molecular Human Reproduction 3 467472.
Cnop M, Havel PJ, Utzschneider KM, Carr DB, Sinha MK, Boyko EJ, Retzlaff BM, Knopp RH, Brunzell JD & Kahn SE 2003 Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 46 459469.[ISI][Medline]
Cohen P, Zhao C, Cai X, Montez JM, Rohani SC, Feinstein P, Mombaerts P & Friedman JM 2001 Selective deletion of leptin receptor in neurons leads to obesity. Journal of Clinical Investigation 108 11131121.[CrossRef][ISI][Medline]
Combs TP, Berg AH, Obici S, Scherer PE & Rossetti L 2001 Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. Journal of Clinical Investigation 108 18751881.[CrossRef][ISI][Medline]
Combs TP, Berg AH, Rajala MW, Klebanov S, Iyengar P, Jimenez-Chillaron JC, Patti ME, Klein SL, Weinstein RS & Scherer PE 2003 Sexual differentiation, pregnancy, calorie restriction, and aging affect the adipocyte-specific secretory protein adiponectin. Diabetes 52 268276.
Combs TP, Pajvani UB, Berg AH, Lin Y, Jelicks LA, Laplante M, Nawrocki AR, Rajala MW, Parlow AF, Cheeseboro L, Ding YY, Russell RG, Lindemann D, Hartley A, Baker GR, Obici S, Deshaies Y, Ludgate M, Rossetti L & Scherer PE 2004 A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. Endocrinology 145 367383.
Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL & Caro JF 1996 Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New England Journal of Medicine 334 292295.
Craig J, Zhu H, Dyce PW, Petrik J & Li J 2004 Leptin enhances oocyte nuclear and cytoplasmic maturation via the mitogen-activated protein kinase pathway. Endocrinology 145 53555363.
Craig JA, Zhu H, Dyce PW, Wen L & Li J 2005 Leptin enhances porcine preimplantation embryo development in vitro. Molecular and Cellular Endocrinology 229 141147.[CrossRef][ISI][Medline]
Crosignani PG, Vegetti W, Colombo M & Ragni G 2002 Resumption of fertility with diet in overweight women. Reproductive Biomedicine Online 5 6064.[Medline]
De Biasi SN, Apfelbaum LI & Apfelbaum ME 2001 In vitro effect of leptin on LH release by anterior pituitary glands from female rats at the time of spontaneous and steroid-induced LH surge. European Journal of Endocrinology 145 659665.[Abstract]
Degawa-Yamauchi M, Dilts JR, Bovenkerk JE, Saha C, Pratt JH & Considine RV 2003a Lower serum adiponectin levels in African-American boys. Obesity Research 11 13841390.[ISI][Medline]
Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, Jones R, Zhu Q & Considine RV 2003b Serum resistin (FIZZ3) protein is increased in obese humans. Journal of Clinical Endocrinology and Metabolism 88 54525455.
Diamond FB Jr, Cuthbertson D, Hanna S & Eichler D 2004 Correlates of adiponectin and the leptin/adiponectin ratio in obese and non-obese children. Journal of Pediatric Endocrinology and Metabolism 17 10691075.
Downs SM, Hudson ER & Hardie DG 2002 A potential role for AMP-activated protein kinase in meiotic induction in mouse oocytes. Developmental Biology 245 200212.[CrossRef][ISI][Medline]
Duggal PS, Van Der Hoek KH, Milner CR, Ryan NK, Armstrong DT, Magoffin DA & Norman RJ 2000 The in vivo and in vitro effects of exogenous leptin on ovulation in the rat. Endocrinology 141 19711976.
Duggal PS, Ryan NK, Van der Hoek KH, Ritter LJ, Armstrong DT, Magoffin DA & Norman RJ 2002 Effects of leptin administration and feed restriction on thecal leucocytes in the pre-ovulatory rat ovary and the effects of leptin on meiotic maturation, granulosa cell proliferation, steroid hormone and PGE2 release in cultured rat ovarian follicles. Reproduction 123 891898.[Abstract]
Eckel RH, Grundy SM & Zimmet PZ 2005 The metabolic syndrome. Lancet 365 14151428.[CrossRef][ISI][Medline]
El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C & Flier JS 2000 Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. Journal of Clinical Investigation 105 18271832.[ISI][Medline]
Fain JN, Cheema PS, Bahouth SW & Lloyd Hiler M 2003 Resistin release by human adipose tissue explants in primary culture. Biochemical and Biophysical Research Communications 300 674678.[CrossRef][ISI][Medline]
Fedorcsak P & Storeng R 2003 Effects of leptin and leukemia inhibitory factor on preimplantation development and STAT3 signaling of mouse embryos in vitro. Biology of Reproduction 69 15311538.
Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE & Lodish HF 2001 Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. PNAS 98 20052010.
Garaulet M, Viguerie N, Porubsky S, Klimcakova E, Clement K, Langin D & Stich V 2004 Adiponectin gene expression and plasma values in obese women during very-low-calorie diet. Relationship with cardiovascular risk factors and insulin resistance. Journal of Clinical Endocrinology and Metabolism 89 756760.
Garcia MR, Amstalden M, Williams SW, Stanko RL, Morrison CD, Keisler DH, Nizielski SE & Williams GL 2002 Serum leptin and its adipose gene expression during pubertal development, the estrous cycle, and different seasons in cattle. Journal of Animal Science 80 21582167.
Gerstmayer B, Kusters D, Gebel S, Muller T, Van Miert E, Hofmann K & Bosio A 2003 Identification of RELMgamma, a novel resistin-like molecule with a distinct expression pattern. Genomics 81 588595.[CrossRef][ISI][Medline]
Gong JG 2002 Influence of metabolic hormones and nutrition on ovarian follicle development in cattle: practical implications. Domestic Animal Endocrinology 23 229241.[CrossRef][ISI][Medline]
Gonzalez RR, Caballero-Campo P, Jasper M, Mercader A, Devoto L, Pellicer A & Simon C 2000 Leptin and leptin receptor are expressed in the human endometrium and endometrial leptin secretion is regulated by the human blastocyst. Journal of Clinical Endocrinology and Metabolism 85 48834888.
Greenfield JR & Campbell LV 2004 Insulin resistance and obesity. Clinical Dermatology 22 289295.[CrossRef][ISI][Medline]
Gregoraszczuk EL, Wojtowicz AK, Ptak A & Nowak K 2003 In vitro effect of leptin on steroids secretion by FSH- and LH-treated porcine small, medium and large preovulatory follicles. Reproductive Biology 3 227239.[Medline]
Gregoraszczuk EL, Ptak A, Wojtowicz AK, Gorska T & Nowak KW 2004 Estrus cycle-dependent action of leptin on basal and GH or IGF-I stimulated steroid secretion by whole porcine follicles. Endocrine Regulation 38 1521.
Gui Y, Silha JV & Murphy LJ 2004 Sexual dimorphism and regulation of resistin, adiponectin, and leptin expression in the mouse. Obesity Research 12 14811491.[ISI][Medline]
Guo X, Chen S & Xing F 2001 [Effects of leptin on estradiol and progesterone production by human luteinized granulosa cells in vitro]. Zhonghua Fu Chan Ke Za Zhi 36 9597.[Medline]
Hakansson ML, Hulting AL & Meister B 1996 Expression of leptin receptor mRNA in the hypothalamic arcuate nucleus-relationship with NPY neurones. Neuroreport 7 30873092.[ISI][Medline]
Halaas JL, Boozer C, Blair-West J, Fidahusein N, Denton DA & Friedman JM 1997 Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. PNAS 94 88788883.
Hamilton-Fairley D, Kiddy D, Watson H, Paterson C & Franks S 1992 Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary syndrome treated with low dose gonadotrophin. British Journal of Obstetrics and Gynaecology 99 128131.[ISI][Medline]
Hardie L, Trayhurn P, Abramovich D & Fowler P 1997 Circulating leptin in women: a longitudinal study in the menstrual cycle and during pregnancy. Clinical Endocrinology (Oxf) 47 101106.
Hartz AJ, Barboriak PN, Wong A, Katayama KP & Rimm AA 1979 The association of obesity with infertility and related menstural abnormalities in women. International Journal of Obesity 3 5773.[ISI][Medline]
Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E & Smith SR 2004 Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects. Journal of Clinical Endocrinology and Metabolism 89 18441848.
Henry BA, Goding JW, Alexander WS, Tilbrook AJ, Canny BJ, Dunshea F, Rao A, Mansell A & Clarke IJ 1999 Central administration of leptin to ovariectomized ewes inhibits food intake without affecting the secretion of hormones from the pituitary gland: evidence for a dissociation of effects on appetite and neuroendocrine function. Endocrinology 140 11751182.
Henry BA, Goding JW, Tilbrook AJ, Dunshea FR & Clarke IJ 2001 Intracerebroventricular infusion of leptin elevates the secretion of luteinising hormone without affecting food intake in long-term food-restricted sheep, but increases growth hormone irrespective of bodyweight. Journal of Endocrinology 168 6777.[Abstract]
Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P & McCamish M 1999 Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282 15681575.
Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, Nelson C, Lowman HB, Wright BD, Skelton NJ, Frantz GD, Tumas DB, Peale FV Jr, Shelton DL & Hebert CC 2000 FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO Journal 19 40464055.[CrossRef][ISI][Medline]
Hu E, Liang P & Spiegelman BM 1996 AdipoQ is a novel adipose-specific gene dysregulated in obesity. Journal of Biological Chemistry 271 1069710703.
Huang KC, Lue BH, Yen RF, Shen CG, Ho SR, Tai TY & Yang WS 2004 Plasma adiponectin levels and metabolic factors in non-diabetic adolescents. Obesity Research 12 119124.[ISI][Medline]
Huang SW, Seow KM, Ho LT, Chein Y, Chung DY, Chang CL, Lai YH, Hwang JL & Juan CC 2005 Resistin mRNA levels are down regulated by estrogen in vivo and in vitro. FEBS Letters 579 449454.[CrossRef][ISI][Medline]
Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS & Lodish HF 2004 T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. PNAS 101 1030810313.
Hukshorn CJ, Saris WH, Westerterp-Plantenga MS, Farid AR, Smith FJ & Campfield LA 2000 Weekly subcutaneous pegylated recombinant native human leptin (PEG-OB) administration in obese men. Journal of Clinical Endocrinology and Metabolism 85 40034009.
Hunter MG, Robinson RS, Mann GE & Webb R 2004 Endocrine and paracrine control of follicular development and ovulation rate in farm species. Animal Reproductive Science 8283 461477.
Jacobi SK, Ajuwon KM, Weber TE, Kuske JL, Dyer CJ & Spurlock ME 2004 Cloning and expression of porcine adiponectin, and its relationship to adiposity, lipogenesis and the acute phase response. Journal of Endocrinology 182 133144.[Abstract]
Juan CC, Au LC, Fang VS, Kang SF, Ko YH, Kuo SF, Hsu YP, Kwok CF & Ho LT 2001 Suppressed gene expression of adipocyte resistin in an insulin-resistant rat model probably by elevated free fatty acids. Biochemical and Biophysical Research Communications 289 13281333.[CrossRef][ISI][Medline]
Kadowaki T, Hara K, Yamauchi T, Terauchi Y, Tobe K & Nagai R 2003 Molecular mechanism of insulin resistance and obesity. Exp Biol Med (Maywood) 228 11111117.
Kamohara S, Burcelin R, Halaas JL, Friedman JM & Charron MJ 1997 Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 389 374377.[CrossRef][Medline]
Karlsson C, Lindell K, Svensson E, Bergh C, Lind P, Billig H, Carlsson LM & Carlsson B 1997 Expression of functional leptin receptors in the human ovary. Journal of Clinical Endocrinology and Metabolism 82 41444148.
Kawamura K, Sato N, Fukuda J, Kodama H, Kumagai J, Tanikawa H, Nakamura A & Tanaka T 2002 Leptin promotes the development of mouse preimplantation embryos in vitro Endocrinology 143 19221931.
Kharroubi I, Rasschaert J, Eizirik DL & Cnop M 2003 Exp