Elsevier

Biochimie

Volume 94, Issue 10, October 2012, Pages 2075-2081
Biochimie

Review
Leptin and reproductive function

https://doi.org/10.1016/j.biochi.2012.02.022Get rights and content

Abstract

Adipose tissue plays a dynamic role in whole-body energy homeostasis by acting as an endocrine organ. Collective evidence indicates a strong link between neural influences and adipocyte expression and secretion of leptin. Developmental changes in these relationships are considered important for pubertal transition in reproductive function. Leptin augments secretion of gonadotropin hormones, which are essential for initiation and maintenance of normal reproductive function, by acting centrally at the hypothalamus to regulate gonadotropin-releasing hormone (GnRH) neuronal activity and secretion. The effects of leptin on GnRH are mediated through interneuronal pathways involving neuropeptide-Y, proopiomelanocortin and kisspeptin. Increased infertility associated with diet induced obesity or central leptin resistance are likely mediated through the kisspeptin-GnRH pathway. Furthermore, Leptin regulates reproductive function by altering the sensitivity of the pituitary gland to GnRH and acting at the ovary to regulate follicular and luteal steroidogenesis. Thus leptin serves as a putative signal that links metabolic status with the reproductive axis. The intent of this review is to examine the biological role of leptin with energy metabolism, and reproduction.

Highlights

► Leptin alters secretion of gonadotropin hormones essential for normal reproduction. ► Leptin regulates hypothalamic gonadotropin-releasing hormone neuronal activity. ► Leptin affects on GnRH are mediated by NPY, proopiomelanocortin and kisspeptin. ► Kisspeptin-GnRH pathway mediates infertility due to obesity or leptin resistance. ► Adipose tissue leptin may be involved in leptin's influence on reproduction.

Section snippets

Adipose tissue as an endocrine organ

Adipose tissue plays a dynamic role in physiological mechanisms and whole-body homeostasis. The role of adipose tissue includes responding to a variety of signals and subsequently secreting factors or “adipokines” that have important roles in physiology [1]. Current evidence indicates that many of the adipose tissue “adipokines, can be considered true endocrine factors [2]. Therefore, adiposity could impact physiological states, such as reproductive condition or status, through secretion of

Leptin: a metabolic signal and puberty

Metabolic signals are considered important in the initiation of puberty [24], [25], [26]. Identification of these signals has, however, remained elusive primarily due to the large number of substances originating peripherally that can act centrally to modify gonadotropin-releasing hormone (GnRH) neuronal activity. The discovery of leptin has improved our understanding of the relationship between adipose tissue, energy homeostasis and puberty [27]. Leptin treatment advanced sexual maturation in

Leptin secretion and reproductive state

Changes in body weight or nutritional status are characterized by alterations in serum levels of many hormones and growth factors that regulate adipocyte function and development, such as insulin, glucocorticoids, growth hormone (GH) and IGF-I [3], [41], [45]. In vivo studies demonstrated that increased leptin gene expression followed administration of glucocorticoids or insulin, suggesting that hormonal factors may mediate nutritionally induced changes in secretion of leptin [46], [47].

Central effect of leptin on the hypothalamic-pituitary axis

Acute intracerebroventricular (ICV) administration of leptin increased LH secretion in the estrogen primed OVX rat [54] and steroid implanted castrate male sheep [55]. Additionally, chronic ICV leptin treatment stimulated LH secretion in feed restricted OVX cows [43] and ewes [44]. In contrast, chronic ICV leptin treatment failed to stimulated LH secretion in well nourished OVX ewes with no steroid replacement [56], and in intact ewe lambs [42]. Leptin treatment stimulated basal and

Leptin and ovarian function

Leptin receptors have also been identified in both granulosa and theca cells of the human [103], [104] bovine [105], [106] and porcine [107] ovarian follicles. Several in vitro studies demonstrated that treatment with supraphysiological concentrations of leptin inhibited steroidogenesis in bovine granulosa [105], [108] and theca cells [106]. Similar results were reported for the human [109], [110], rat [111], sheep [112] and pig [113]. In contrast, physiological doses of leptin stimulated

Conclusion

Leptin is a key metabolic signal synthesized and secreted by fat cells that communicates information about body energy reserves, nutritional state, and metabolic shifts to the reproductive axis. Leptin can act peripherally at the ovary or centrally at the hypothalamus (Fig. 1) to augment reproductive function of females. Kisspeptin neurons are a key part of the central pathway by which leptin affects gonadotropin secretion. Hypogonadotropism and infertility observed in animal models with severe

Acknowledgments

We thank Linda Parnell for assisting in preparation of the manuscript.

References (119)

  • C.S. Whisnant et al.

    Effect of short-term feed restriction and refeeding on serum concentrations of leptin, luteinizing hormone and insulin in ovariectomized gilts

    Domest. Anim. Endocrinol.

    (2002)
  • L.A. Tartaglia

    The leptin receptor

    J. Biol. Chem.

    (1997)
  • J. Iqbal et al.

    Immunohistochemical characterization of localization of long-form leptin receptor (OB-Rb) in neurochemically defined cells in the ovine hypothalamus

    Brain Res.

    (2001)
  • K. Czaja et al.

    Distribution of neurons containing leptin receptors in the hypothalamus of the pig

    Biochem. Biophys. Res. Commun.

    (2002)
  • C.D. Morrison et al.

    Luteinizing hormone and growth hormone secretion in ewes infused intracerebroventricularly with neuropeptide Y

    Domest. Anim. Endocrinol.

    (2003)
  • M.G. Thomas et al.

    Injection of neuropeptide Y into the third cerebroventricle differentially influences pituitary secretion of luteinizing hormone and growth hormone in ovariectomized cows

    Domest. Anim. Endocrinol.

    (1999)
  • C.R. Barb et al.

    Biology of leptin in the pig

    Domest. Anim. Endocrinol.

    (2001)
  • M. Jang et al.

    Leptin rapidly inhibits hypothalamic neuropeptide Y secretion and stimulates corticotropin-releasing hormone secretion in adrenalectomized mice

    J. Nutr.

    (2000)
  • P.J. King et al.

    Regulation of neuropeptide Y release from hypothalamic slices by melanocortin-4 agonists and leptin

    Peptides

    (2000)
  • C.R. Barb et al.

    Role of leptin in modulating the hypothalamic-pituitary axis and luteinizing hormone secretion in the prepuberal gilt

    Domest. Anim. Endocrinol.

    (2004)
  • A. Morelli et al.

    Sex steroids and leptin regulate the "first Kiss" (KiSS 1/G-protein-coupled receptor 54 system) in human gonadotropin-releasing-hormone-secreting neuroblasts

    J. Sex. Med.

    (2008)
  • R.M. Cravo et al.

    Characterization of Kiss1 neurons using transgenic mouse models

    Neuroscience

    (2011)
  • R.S. Ahima

    Adipose tissue as an endocrine organ

    Obesity

    (2006)
  • H. Hauner

    Secretory factors from human adipose tissue and their functional role

    Proc. Nutr. Soc.

    (2005)
  • G.J. Hausman et al.

    Secreted proteins and genes in fetal and neonatal pig adipose tissue and stromal-vascular cells

    J. Anim. Sci.

    (2006)
  • G.N. Chaldakov et al.

    The adipose tissue: a new member of the diffuse neuroendocrine system?

    Adipobiology

    (2009)
  • G.N. Chaldakov et al.

    Neuroadipology: a novel component of neuroendocrinology

    Cell Biol. Int.

    (2010)
  • F. Sornelli et al.

    Adipose tissue-derived nerve growth factor and brain-derived neurotrophic factor: results from experimental stress and diabetes

    Gen. Physiol. Biophys.

    (2009)
  • A. Schäffler et al.

    The role of ’adipotropins’ and the clinical importance of a potential hypothalamic-pituitary-adipose axis

    Nat. Rev. Endocrinol.

    (2006)
  • R. De Matteis et al.

    TH-, NPY-, SP-, and CGRP-immunoreactive nerves in interscapular brown adipose tissue of adult rats acclimated at different temperatures: an immunohistochemical study

    J. Neurocytol.

    (1998)
  • A. Giordano et al.

    Tyrosine hydroxylase, neuropeptide Y, substance P, calcitonin gene-related peptide and vasoactive intestinal peptide in nerves of rat periovarian adipose tissue: an immunohistochemical and ultrastructural investigation

    J. Neurocytol.

    (1996)
  • L.E. Kuo et al.

    Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome

    Nat. Med.

    (2007)
  • G.J. Hausman et al.

    Patterns of gene expression in pig adipose tissue: transforming growth factors, interferons, interleukins, and apolipoproteins

    J. Anim. Sci.

    (2007)
  • Z. Zukowska-Grojec et al.

    Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium

    Circ. Res.

    (1998)
  • L.C. Turtzo et al.

    Cross-talk between sympathetic neurons and adipocytes in coculture

    Proc. Natl. Acad. Sci. USA

    (2001)
  • F. Hube et al.

    Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans

    Horm. Metab. Res.

    (1996)
  • B.C. Villafuerte et al.

    Expressions of leptin and insulin-like growth factor-I are highly correlated and region-specific in adipose tissue of growing rats

    Obes. Res.

    (2000)
  • T. Yamada et al.

    Fat depot-specific differences in angiogenic growth factor gene expression and its relation to adipocyte size in cattle

    J. Vet. Med. Sci.

    (2010)
  • C.T. Montague et al.

    Depot-related gene expression in human subcutaneous and omental adipocytes

    Diabetes

    (1998)
  • D.B. Hausman et al.

    The biology of white adipocyte proliferation

    Obes. Rev.

    (2001)
  • R.E. Frisch

    Body fat, puberty and fertility

    Biol. Rev. Camb. Philos. Soc.

    (1984)
  • J.L. Cameron et al.

    Metabolic changes during maturation of male monkeys: possible signals for onset of puberty

    Am. J. Physiol. Endocrinol. Metab.

    (1985)
  • C.R. Barb et al.

    Metabolic changes during the transition from the fed to the acute feed-deprived state in prepuberal and mature gilts

    J. Anim. Sci.

    (1997)
  • L.A. Campfield et al.

    Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks

    Science

    (1995)
  • I.A. Barash et al.

    Leptin is a metabolic signal to the reproductive system

    Endocrinology

    (1996)
  • R.S. Ahima et al.

    Leptin accelerates the onset of puberty in normal female mice

    J. Clin. Invest.

    (1997)
  • F.F. Chehab et al.

    Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin

    Nat. Genet.

    (1996)
  • F.F. Chehab et al.

    Early onset of reproductive function in normal female mice treated with leptin

    Science

    (1997)
  • M.R. Garcia et al.

    Serum leptin and its adipose gene expression during pubertal development, the estrous cycle, and different seasons in cattle

    J. Anim. Sci.

    (2002)
  • V. Matkovic et al.

    Leptin is inversely related to age at menarche in human females

    J. Clin. Endocrinol. Metab.

    (1997)
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