Current concepts concerning the role of leptin in reproductive function

Holness, Mark J.; Munns, Melinda J; Sugden, Mary C.

doi:10.1016/s0303-7207(99)00126-4

Cited by 75 publications

(44 citation statements)

References 88 publications

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“…The localization of the leptin receptor on the maternal side of the placenta supports the hypothesis that placenta leptin may have an autocrine role on the placenta itself as well as an endocrine role in the mother (Lea et al, 2000). The recent reports suggest that leptin may exert physiological effects on the placenta and conception, including fetal and placenta angiogenesis, fetal growth and development, embryonic hematopoiesis (Holness et al, 1999;Henson and Castracane, 2000).…”

Section: Introduction Introduction Introduction Introduction Introducsupporting

confidence: 57%

Association of leptin genetic polymorphism -2548 G/A with gestational diabetes mellitus

et al. 2006

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Section: Introduction Introduction Introduction Introduction Introducsupporting

confidence: 57%

Association of leptin genetic polymorphism -2548 G/A with gestational diabetes mellitus

et al. 2006

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“…The potency and reversibility of the superactive antagonist make it a prime tool for the study of the peripheral and central activities of leptin in adult animals in the steady state as well as in disease conditions. This tool is far superior to the current main research tool, the leptin-deficient mouse model, in which leptin deficiency in the embryonic and neonatal stages is associated with developmental aberrations that carry limited relevance to WT physiology (36,37). In addition, the superactive antagonists may be studied as potential future therapeutic agents in a myriad of disease conditions in which leptin signaling has been implicated, including solid tumors and auto-inflammatory disorders (38 -40).…”

Section: Discussionmentioning

confidence: 99%

Development and Characterization of High Affinity Leptins and Leptin Antagonists

Shpilman

Niv-Spector

Katz

et al. 2011

Journal of Biological Chemistry

124

117

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Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/ D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/ F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin.Leptin, a 16-kDa protein, is a central regulator of body weight (1), as well as a pleiotropic hormone whose involvement in many physiological processes has been well established (2). The three-dimensional structure of leptin was elucidated shortly after its discovery (3), but so far no structural information on its complex with leptin receptor has been published. Although several theoretical models of such a complex have been proposed (4 -6), lack of a valid crystallographic structure hampers reliable structural interpretation of any new leptin mutations. In the last decade, leptin has also been documented as a major regulator of the innate and adaptive immune response and a modulator of the onset and progression of autoimmunity in several animal models of disease (7), including rheumatoid arthritis, experimental autoimmune encephalomyelitis (4), and immune-mediated colitis (8). Work published from our and others' laboratories has also shown that leptin enhances thioacetamide-induced liver fibrosis (9) and liver inflammation in several mouse models (10). In addition, leptin acts as a mitogenic agent in many tissues and is suggested to promote cancer cell growth. In fact...

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“…In addition, leptin has a role stimulating myelopoiesis, erythropoiesis, lymphopoiesis, and thus, it may also promote maturation of the fetal immune system [140,154]. The presence of mature leptin protein in several tissues of the fetus contrasts with the absence of leptin in the corresponding adult tissues [140,155]. This suggests that leptin is a growth factor in fetal development, rather than acting as a signal of fetal energy stores to the fetal CNS, as it does in adults.…”

Section: Role Of Leptin In Fetal Developmentmentioning

confidence: 99%

Role of leptin in female reproduction

Pérez-Pérez

Sánchez-Jiménez

Maymó

et al. 2015

Clinical Chemistry and Laboratory Medicine (CCLM)

127

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Abstract:Reproductive function is dependent on energy resources. The role of weight, body composition, fat distribution and the effect of diet have been largely investigated in experimental female animals as well as in women. Any alteration in diet and/or weight may induce abnormalities in timing of sexual maturation and fertility. However, the cellular mechanisms involved in the fine coordination of energy balance and reproduction are largely unknown. The brain and hypothalamic structures receive endocrine and/or metabolic signals providing information on the nutritional status and the degree of fat stores. Adipose tissue acts both as a store of energy and as an active endocrine organ, secreting a large number of biologically important molecules termed adipokines. Adipokines have been shown to be involved in regulation of the reproductive functions. The first adipokine described was leptin. Extensive research over the last 10 years has shown that leptin is not only an adipose tissue-derived messenger of the amount of energy stores to the brain, but also a crucial hormone/cytokine for a number of diverse physiological processes, such as inflammation, angiogenesis, hematopoiesis, immune function, and most importantly, reproduction. Leptin plays an integral role in the normal physiology of the reproductive system with complex interactions at all levels of the hypothalamic-pituitary gonadal (HPG) axis. In addition, leptin is also produced by placenta, where it plays an important autocrine function. Observational studies have demonstrated that states of leptin excess, deficiency, or resistance can be associated with abnormal reproductive function. This review focuses on the leptin action in female reproduction.

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Current concepts concerning the role of leptin in reproductive function

Cited by 75 publications

References 88 publications

Association of leptin genetic polymorphism -2548 G/A with gestational diabetes mellitus

Association of leptin genetic polymorphism -2548 G/A with gestational diabetes mellitus

Development and Characterization of High Affinity Leptins and Leptin Antagonists

Role of leptin in female reproduction

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