Melanocortins and reproduction

doi:10.1016/S0165-0173(01)00159-X

Brain Research Reviews

Volume 38, Issue 3, February 2002, Pages 340-350

https://doi.org/10.1016/S0165-0173(01)00159-X Get rights and content

Abstract

Obesity, anorexia and general body weight fluctuations cause a variety of effects on the reproductive system. Our understanding of the neuro–biological mechanisms of the connections between body weight and the reproductive axis is not especially developed despite a number of interesting physiological observations. Several reports suggest that leptin could play a key role in connecting energy balance and reproduction. The melanocortin system, involving melanocyte stimulating hormone, adrenocorticotrophic hormone, agouti related peptide and the central melanocortin 3 and 4 receptors, plays a major role in the hypothalamic regulation of energy balance. The melanocortins have also been suggested to participate in possible downstream events of the adipose cell derived hormone, leptin. Leptin has importance for several aspects of reproduction including regulation of luteinizing hormone and prolactin release. This review discusses the interplay of hypothalamic regulation of food intake and the hormones involved in the hypothalamic–pituitary–gonadal axis with special emphasis on putative roles of the melanocortin system.

Introduction

There are obvious physiological connections between body weight homeostasis and the reproductive axis in both sexes. The rate of sexual maturation is much more closely associated with body growth than with chronological age. Inadequate nutrition retards growth and delays sexual maturation, while high intake of nutrition and rapid growth advance maturation. Alterations in nutrition during adulthood may similarly depress or enhance reproductive activity [52], [92]. Castration with removal of estrogen is followed by obesity in female animals and this can be prevented, as can many forms of obesity, by adrenalectomy [13]. Obesity in men is often accompanied with reduction in testosterone and obesity leads to earlier menarche in girls [13]. Changes in the hypothalamic–pituitary–gonadal (HPG) axis also induce changes in food intake, body weight and fat distribution. Hormonal fluctuations associated with the menstrual cycle influence appetite control and eating behaviour. Food intake varies during the menstrual cycle in humans and animals. Several studies show carbohydrate cravings in the pre-menstrual phase, particularly in women with pre-menstrual syndrome [22]. The cyclical nature of food cravings is also often associated with depression. The pre-menstrual phase is thus thought of as a time when women are especially vulnerable to over-consumption, food craving and even depression [22], [91]

These physiological observations of putative connections between body weight homeostasis and the reproductive axis are well documented, but our understanding of the underlying neuro–biological mechanisms are not very developed. Several reports suggest that leptin could play a key role in the connection between regulation of body weight and reproduction. The melanocortin system, involving MSH (melanocyte stimulating hormone), ACTH (adrenocorticotrophic hormone), agouti related peptide (Agrp) and the central melanocortin (MC) 3 and 4 receptors plays a major role in the hypothalamic regulation of energy balance. The melanocortins have also been suggested to participate in possible downstream events related to leptin. Gonadotropins are very much affected by nutritional levels and also by leptin, and are of obvious importance for several aspects of the reproduction.

The aim of this review is to discuss the interplay between hypothalamic regulation of food intake and the hormones involved in the HPG axis with a special emphasis on putative roles of the melanocortin system.

Section snippets

Melanocortin peptides and receptors

The melanocortic peptides, ACTH, α-MSH, β-MSH and γ-MSH are all pro-opiomelanocortin (POMC) cleavage products and represent the endogeneous agonist ligands in the system. α-MSH is phylogenetically a remarkable well conserved molecule and was one of the first peptide hormones to be discovered [56]. The principal source of the melanocortins is the pituitary but the POMC gene is also expressed in a variety of other brain regions and also in a number of peripheral tissues, in particular in the

Interaction of leptin with melanocortins

Leptin is a 16-kDa protein secreted from adipose tissue. It passes the blood–brain barrier and inhibits food intake, increases energy expenditure and lowers body weight. The inhibition of food intake is mediated by leptin receptor, a cytokine receptor that uses JAK-STAT pathway for signal transduction. The leptin receptor is primarily expressed in the hypothalamus, with particularly high levels in the arcuate, paraventricular, and dorsomedial nuclei and the lateral hypothalamic area. The leptin

Luteinizing hormone and prolactin

Lutenizing hormone (LH) is a gonadotropin released by either the anterior pituitary or the placenta. LH and follicle stimulating hormone (FSH) act together to stimulate maturation and function of the testis and ovary and regulate both gametogenesis and steroidogenesis. LH acts on the Leydig cells in the testis to maintain general metabolic processes, steroidogenic enzymes, and regulation of production and secretion of androgens. LH acts also on the ovaries to promote maturation of follicular

Interaction of leptin with luteinizing hormone and prolactin

Treatment of the ob/ob mice with leptin leads to increases in ovarian and uterine weight and also elevates serum LH levels [68]. Moreover, treatment of female rats with anti-leptin serum decreases the pulsatility of LH, indicating relationship between leptin levels and LH surges in female rats [14]. Starvation or treatment with anti-leptin serum abolishes LH surges in ovariectomized rats primed with estradiol and progesterone [53]. Moreover, leptin injections to starved female rats,

Interaction of melanocortins with luteinizing hormone and prolactin

It has been speculated for a while that α-MSH may be involved in PRL release [70], [111]. α-MSH is released after suckling stimulus and immuno-neutralization of α-MSH leads a to clear decrease in suckling induced PRL release [38]. Pituitary cells obtained from female rats release Ca²⁺ in response to γ3-MSH. This effect was partially blocked by the MC receptor antagonist SHU9119. Some of the cells expressed the MC3 receptor [75]. It is also interesting that i.c.v. [26] administration and

Overall integration of hypothalamic regulation of food intake with the HPG axis

In this section we discuss briefly how the overall mechanism of hypothalamic regulation of food intake is integrated with the HPG axis with special emphases on the role of the melanocortins, leptin and their receptors. We have drawn a schematic drawing of the putative interaction in Fig. 3. This figure shows that leptin is mainly produced in peripheral adipocytes and has receptors in the arcuate nucleus (ARC). Leptin transmits signals to NPY/Agrp releasing, POMC releasing neurons and GnRH

Concluding remarks

It is likely that drugs affecting the hypothalamic regulation of food intake will be developed within the next 5 years considering the enormous amount of resources and effort that all the major pharmaceutical companies are investing in obesity research and metabolic programmes. MSH. Agrp, leptin, NPY and their receptors, represent some of the most interesting elements in this drug discovery. These neuropeptides and their receptors are all to a larger or lesser extent involved in reproductive

Acknowledgements

Dr. Schiöth was supported by the Swedish Medical Research council (MRC), the Swedish Society for Medical Research (SSMF), Åke Wibergs Stiftelse and Melacure Therapeutics AB, Uppsala, Sweden. Dr. Watanobe was supported in part by a grant-in-aid from the Japan Society for the Promotion of Science (No. 12671072). We thank Dr. Earl T. Larsson, Uppsala University for general advice.

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ReviewMelanocortins and reproduction

Abstract

Introduction

Section snippets

Melanocortin peptides and receptors

Interaction of leptin with melanocortins

Luteinizing hormone and prolactin

Interaction of leptin with luteinizing hormone and prolactin

Interaction of melanocortins with luteinizing hormone and prolactin

Overall integration of hypothalamic regulation of food intake with the HPG axis

Concluding remarks

Acknowledgements

Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neurosci. Biobehav.

Brain Res.

Cell

Trends Endocrinol. Metab.

Neuropeptides

Brain Res.

J. Biol. Chem.

J. Biol. Chem.

Regul. Pept.

Biochem. Biophys. Res. Commun.

Cell

Biochem. Biophys. Res. Com.

Eur. J. Pharmacol.

Biochem. Biophys. Res. Commun.

Eur. J. Pharmacol.

Neurosci. Lett.

Am. J. Clin. Nutr.

Biochem. Biophys. Res. Commun.

Brain Res.

Neuron

Regul. Pept.

Neurosci. Lett.

Life Sci.

Vitam. Horm.

Eur. J. Pharmacol.

Peptides

Peptides

Peptides

Neurosci. Biobehav. Rev.

Biochem. Biophys. Res. Commun.

Brain Res.

Brain Res.

Brain Res. Bull.

Neuropeptides

Biochem. Biophys. Res. Commun.

Eur. J. Pharmacol.

Anatomy of an endogenous antagonist: relationship between Agouti-related protein and proopiomelanocortin in brain

J. Neurosci.

A novel selective melanocortin-4 receptor agonist reduces food intake in rats and mice without producing aversive consequences

J Neurosci.

Cross-species comparison of the ACTH-induced behavioral syndrome

Ann. NY Acad. Sci.

l-arginine/nitric oxide amplifies the magnitude and duration of the luteinizing hormone surge induced by estrogen: involvement of neuropeptide Y

Endocrinology

Evidence that nitric oxide may mediate the ovarian steroid-induced luteinizing hormone surge: involvement of excitatory amino acids

Endocrinology

Independent and additive effects of central POMC and leptin pathways on murine obesity

Science

A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse

Endocrinology

Obesity and reproduction

Hum. Reprod.

Influence of endogenous leptin tone on the estrous cycle and luteinizing hormone pulsatility in female rats

Neuroendocrinology

Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass

Nat. Genet.

Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus

Endocrinology

Review
Melanocortins and reproduction