The Leptin System in Patients with Classical Galactosaemia - Putative Role and Clinical Consequences
Main Article Content
Abstract
The hormone leptin is a polypeptide of 146 amino acids which is predominantly secreted by adipose tissue. Leptin has distinct effects on energy homeostasis, metabolism, neuroendocrine function and other systems through its interactive effects on the central nervous system (CNS) and peripheral tissues. It has a critical role on regulation of body weight, fat reserves and reproductive function. The leptin receptor (LepR, Ob-R) is expressed in different isoforms, with the main signaling carried out by its long glycosylated isoform, Ob-Rb. Soluble leptin receptor (sOb-R) represents the main binding protein for leptin in human blood and increases its bioavailability. There are numerous N-glycosylation sites which are of physiological relevance for receptor function. Galactose and other sugar moieties are physiologically relevant for glycosylation of complex molecules for a wide range of biological processes.
This review considers how leptin signaling pathways are dysregulated in the rare inherited disorder of carbohydrate metabolism, Classical Galactosaemia. This disease is caused by profound deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT). Classical Galactosaemia may cause significant morbidity and even mortality in neonates and long-term complications later in life, including pubertal delay and primary ovarian insufficiency (POI). The immediate removal of galactose from the diet is lifesaving in affected infants. The pathophysiology of its long-term complications is incompletely understood. Underlying mechanisms comprise intoxication with galactose and its metabolites together with altered glycosylation pathways and disruption of signaling pathways.
Here we discuss how interaction of leptin with the hypothalamic pituitary gonadal axis (HPG) and other circuits is potentially dysregulated in Classical Galactosaemia with clinical consequences for puberty and reproductive capacity, particularly in females. We have identified defective N-glycosylation as a major factor implicated in disrupted leptin-HPG signaling resulting from distorted receptor function. Finally, we speculate how leptin dysregulation may affect cognitive function and neuroprotection in patients with Classical Galactosaemia.
Article Details
How to Cite
COLHOUN, Hugh Owen et al.
The Leptin System in Patients with Classical Galactosaemia - Putative Role and Clinical Consequences.
Medical Research Archives, [S.l.], v. 2, n. 4, nov. 2015.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/391>. Date accessed: 18 apr. 2024.
Keywords
Leptin; Leptin Receptor; Classical Galactosaemia; Glycosylation; Primary Ovarian Insufficiency
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
[1] Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994; 372(6505):425-32.
[2] Wauters M, Considine RV, Chagnon M, et al. Leptin levels, leptin receptor gene polymorphisms, and energy metabolism in women. Obesity research. 2002; 10(5):394-400.
[3] Kratzsch J, Lammert A, Bottner A, et al. Circulating soluble leptin receptor and free leptin index during childhood, puberty, and adolescence. The Journal of clinical endocrinology and metabolism. 2002; 87(10):4587-94.
[4] Otero M, Lago R, Lago F, et al. Leptin, from fat to inflammation: old questions and new insights. FEBS letters. 2005; 579(2):295-301.
[5] Karsenty G. Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab. 2006; 4(5):341-8.
[6] Young EA, Midgley AR, Carlson NE, et al. Alteration in the hypothalamic-pituitary-ovarian axis in depressed women. Archives of general psychiatry. 2000; 57(12):1157-62.
[7] Meissner U, Hanisch C, Ostreicher I, et al. Differential regulation of leptin synthesis in rats during short-term hypoxia and short-term carbon monoxide inhalation. Endocrinology. 2005; 146(1):215-20.
[8] Maffei M, Halaas J, Ravussin E, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature medicine. 1995; 1(11):1155-61.
[9] Chou SH, Chamberland JP, Liu X, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proceedings of the National Academy of Sciences of the United States of America. 2011; 108(16):6585-90.
[10] Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet (London, England). 2005; 366(9479):74-85.
[11] Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. The New England journal of medicine. 2004; 351(10):987-97.
[12] Knerr I, Herzog D, Rauh M, et al. Leptin and ghrelin expression in adipose tissues and serum levels in gastric banding patients. European journal of clinical investigation. 2006; 36(6):389-94.
[13] Nobili V, Manco M, Ciampalini P, et al. Leptin, free leptin index, insulin resistance and liver fibrosis in children with non-alcoholic fatty liver disease. European journal of endocrinology / European Federation of Endocrine Societies. 2006; 155(5):735-43.
[14] Goumenou AG, Matalliotakis IM, Koumantakis GE, et al. The role of leptin in fertility. European journal of obstetrics, gynecology, and reproductive biology. 2003; 106(2):118-24.
[15] Myers MG, Jr. Leptin receptor signaling and the regulation of mammalian physiology. Recent progress in hormone research. 2004; 59:287-304.
[16] Hughes J, Ryan S, Lambert D, et al. Outcomes of siblings with classical galactosemia. J Pediatr. 2009; 154(5):721-6.
[17] Schwartz N. Neuroendocrine Regulation of Reproductive Cyclicity. In: Conn PM, Freeman M, eds. Neuroendocrinology in Physiology and Medicine: Humana Press; 2000. p. 135-45.
[18] Fink G. Neuroendocrine Regulation of Pituitary Function. In: Conn PM, Freeman M, eds. Neuroendocrinology in Physiology and Medicine: Humana Press; 2000. p. 107-33.
[19] Fernandez-Fernandez R, Martini AC, Navarro VM, et al. Novel signals for the integration of energy balance and reproduction. Molecular and Cellular Endocrinology. 2006; 254–255:127-32.
[20] Casanueva FF, Dieguez C. Neuroendocrine Regulation and Actions of Leptin. Frontiers in Neuroendocrinology. 1999; 20(4):317-63.
[21] Mantzoros CS, Magkos F, Brinkoetter M, et al. Leptin in human physiology and pathophysiology. American journal of physiology Endocrinology and metabolism. 2011; 301(4):E567-84.
[22] Tena-Sempere M. Roles of ghrelin and leptin in the control of reproductive function. Neuroendocrinology. 2007; 86(3):229-41.
[23] Cheung CC, Thornton JE, Kuijper JL, et al. Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology. 1997; 138(2):855-8.
[24] Ahima RS, Dushay J, Flier SN, et al. Leptin accelerates the onset of puberty in normal female mice. The Journal of clinical investigation. 1997; 99(3):391-5.
[25] Chehab FF, Mounzih K, Lu R, et al. Early onset of reproductive function in normal female mice treated with leptin. Science (New York, NY). 1997; 275(5296):88-90.
[26] Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. The New England journal of medicine. 1999; 341(12):879-84.
[27] Barash IA, Cheung CC, Weigle DS, et al. Leptin is a metabolic signal to the reproductive system. Endocrinology. 1996; 137(7):3144-7.
[28] Castellano JM, Roa J, Luque RM, et al. KiSS-1/kisspeptins and the metabolic control of reproduction: physiologic roles and putative physiopathological implications. Peptides. 2009; 30(1):139-45.
[29] Donato J, Jr., Cravo RM, Frazao R, et al. Hypothalamic sites of leptin action linking metabolism and reproduction. Neuroendocrinology. 2011; 93(1):9-18.
[30] Elias CF, Purohit D. Leptin signaling and circuits in puberty and fertility. Cellular and molecular life sciences : CMLS. 2013; 70(5):841-62.
[31] Trinko R, Gan G, Gao X-B, et al. Erk1/2 Mediates Leptin Receptor Signaling in the Ventral Tegmental Area. PloS one. 2011; 6(11):e27180.
[32] Lavens D, Piessevaux J, Tavernier J. Review: Negative regulation of leptin receptor signalling. European cytokine network. 2006; 17(3):211-9.
[33] Coss KP, Treacy EP, Cotter EJ, et al. Systemic gene dysregulation in classical Galactosaemia: Is there a central mechanism? Molecular genetics and metabolism. 2014; 113(3):177-87.
[34] Knerr I, Coss KP, Kratzsch J, et al. Effects of temporary low-dose galactose supplements in children aged 5-12 y with classical galactosemia: a pilot study. Pediatr Res. 2015; 78(3):272-9.
[35] Coss KP, Doran PP, Owoeye C, et al. Classical Galactosaemia in Ireland: incidence, complications and outcomes of treatment. J Inherit Metab Dis. 2013; 36(1):21-7.
[36] Coman DJ, Murray DW, Byrne JC, et al. Galactosemia, a single gene disorder with epigenetic consequences. Pediatr Res. 2010; 67 286-92.
[37] Coss KP, Byrne JC, Coman DJ, et al. IgG N-glycans as potential biomarkers for determining galactose tolerance in Classical Galactosaemia. Mol Genet Metab. 2012; 105(2):212-20.
[38] Fridovich-Keil JL, Walter JH. Galactosaemia Chapter 72. The Online Metabolic and Molecular Bases of Inherited Disease, OMMBID. New York: McGraw Hill; 2008: New York: McGraw Hill; 2008
[39] Rubio-Gozalbo ME, Gubbels CS, Bakker JA, et al. Gonadal function in male and female patients with classic galactosemia. Human reproduction update. 2010; 16(2):177-88.
[40] Garcia-Mayor RV, Andrade MA, Rios M, et al. Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage. The Journal of clinical endocrinology and metabolism. 1997; 82(9):2849-55.
[41] Plant TM, Durrant AR. Circulating leptin does not appear to provide a signal for triggering the initiation of puberty in the male rhesus monkey (Macaca mulatta). Endocrinology. 1997; 138(10):4505-8.
[42] Mantzoros CS, Flier JS, Rogol AD. A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty. The Journal of clinical endocrinology and metabolism. 1997; 82(4):1066-70.
[43] Vazquez MJ, Romero-Ruiz A, Tena-Sempere M. Roles of leptin in reproduction, pregnancy and polycystic ovary syndrome: consensus knowledge and recent developments. Metabolism. 2015; 64(1):79-91.
[44] Watanobe H. Leptin directly acts within the hypothalamus to stimulate gonadotropin-releasing hormone secretion in vivo in rats. The Journal of physiology. 2002; 545(Pt 1):255-68.
[45] Herbison AE, Pape JR. New evidence for estrogen receptors in gonadotropin-releasing hormone neurons. Frontiers in neuroendocrinology. 2001; 22(4):292-308.
[46] Quennell JH, Mulligan AC, Tups A, et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology. 2009; 150(6):2805-12.
[47] Magni P, Vettor R, Pagano C, et al. Expression of a leptin receptor in immortalized gonadotropin-releasing hormone-secreting neurons. Endocrinology. 1999; 140(4):1581-5.
[48] Williams KW, Elmquist JK. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nature neuroscience. 2012; 15(10):1350-5.
[49] Xu Y, Faulkner LD, Hill JW. Cross-Talk between Metabolism and Reproduction: The Role of POMC and SF1 Neurons. Frontiers in endocrinology. 2011; 2:98.
[50] Roa J, Herbison AE. Direct regulation of GnRH neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice. Endocrinology. 2012; 153(11):5587-99.
[51] Balthasar N, Coppari R, McMinn J, et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron. 2004; 42(6):983-91.
[52] Hill JW, Elias CF, Fukuda M, et al. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell metabolism. 2010; 11(4):286-97.
[53] Wu Q, Whiddon BB, Palmiter RD. Ablation of neurons expressing agouti-related protein, but not melanin concentrating hormone, in leptin-deficient mice restores metabolic functions and fertility. Proc Natl Acad Sci U S A. 2012; 109(8):3155-60.
[54] Erickson JC, Hollopeter G, Palmiter RD. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science (New York, NY). 1996; 274(5293):1704-7.
[55] Elias CF. Leptin action in pubertal development: recent advances and unanswered questions. Trends in endocrinology and metabolism: TEM. 2012; 23(1):9-15.
[56] Navarro VM, Tena-Sempere M. Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility. Nature reviews Endocrinology. 2012; 8(1):40-53.
[57] Oakley AE, Clifton DK, Steiner RA. Kisspeptin signaling in the brain. Endocrine reviews. 2009; 30(6):713-43.
[58] d'Anglemont de Tassigny X, Colledge WH. The role of kisspeptin signaling in reproduction. Physiology (Bethesda, Md). 2010; 25(4):207-17.
[59] Cravo RM, Margatho LO, Osborne-Lawrence S, et al. Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience. 2011; 173:37-56.
[60] Smith JT, Acohido BV, Clifton DK, et al. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. Journal of neuroendocrinology. 2006; 18(4):298-303.
[61] Backholer K, Smith JT, Rao A, et al. Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells. Endocrinology. 2010; 151(5):2233-43.
[62] Gubbels CS, Kuppens SMI, Bakker JA, et al. Pregnancy in classic galactosemia despite undetectable anti-Müllerian hormone. Fertility and Sterility. 2009; 91(4):1293.e13-.e16.
[63] Millar RP, Lu ZL, Pawson AJ, et al. Gonadotropin-releasing hormone receptors. Endocrine reviews. 2004; 25(2):235-75.
[64] Moult PR, Harvey J. Hormonal regulation of hippocampal dendritic morphology and synaptic plasticity. Cell adhesion & migration. 2008; 2(4):269-75.
[65] Schlichting ML, Mumford JA, Preston AR. Learning-related representational changes reveal dissociable integration and separation signatures in the hippocampus and prefrontal cortex. Nature communications. 2015; 6:8151.
[66] Knerr I, Coss KP, Doran PP, et al. Leptin levels in children and adults with classic Galactosaemia. JIMD reports. 2013; 9:125-31.
[67] Messinis IE, Kariotis I, Milingos S, et al. Treatment of normal women with oestradiol plus progesterone prevents the decrease of leptin concentrations induced by ovariectomy. Hum Reprod. 2000; 15(11):2383-7.
[68] Hamm ML, Bhat GK, Thompson WE, et al. Folliculogenesis is impaired and granulosa cell apoptosis is increased in leptin-deficient mice. Biol Reprod. 2004; 71(1):66-72.
[69] El-Eshmawy MM, Abdel Aal IA, El Hawary AK. Association of ghrelin and leptin with reproductive hormones in constitutional delay of growth and puberty. Reprod Biol Endocrinol. 2010; 8:153.
[70] Gubbels CS, Welt CK, Dumoulin JC, et al. The male reproductive system in classic galactosemia: cryptorchidism and low semen volume. J Inherit Metab Dis. 2012.
[71] Holden KF, Lindquist K, Tylavsky FA, et al. Serum leptin level and cognition in the elderly: Findings from the Health ABC Study. Neurobiology of aging. 2009; 30(9):1483-9.
[72] Paz-Filho GJ, Babikian T, Asarnow R, et al. Leptin replacement improves cognitive development. PloS one. 2008; 3(8):e3098.
[73] Greco SJ, Sarkar S, Johnston JM, et al. Leptin reduces Alzheimer's disease-related tau phosphorylation in neuronal cells. Biochemical and biophysical research communications. 2008; 376(3):536-41.
[74] Paz-Filho G, Wong ML, Licinio J. Ten years of leptin replacement therapy. Obesity reviews : an official journal of the International Association for the Study of Obesity. 2011; 12(5):e315-23.
[75] Matochik JA, London ED, Yildiz BO, et al. Effect of leptin replacement on brain structure in genetically leptin-deficient adults. The Journal of clinical endocrinology and metabolism. 2005; 90(5):2851-4.
[2] Wauters M, Considine RV, Chagnon M, et al. Leptin levels, leptin receptor gene polymorphisms, and energy metabolism in women. Obesity research. 2002; 10(5):394-400.
[3] Kratzsch J, Lammert A, Bottner A, et al. Circulating soluble leptin receptor and free leptin index during childhood, puberty, and adolescence. The Journal of clinical endocrinology and metabolism. 2002; 87(10):4587-94.
[4] Otero M, Lago R, Lago F, et al. Leptin, from fat to inflammation: old questions and new insights. FEBS letters. 2005; 579(2):295-301.
[5] Karsenty G. Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab. 2006; 4(5):341-8.
[6] Young EA, Midgley AR, Carlson NE, et al. Alteration in the hypothalamic-pituitary-ovarian axis in depressed women. Archives of general psychiatry. 2000; 57(12):1157-62.
[7] Meissner U, Hanisch C, Ostreicher I, et al. Differential regulation of leptin synthesis in rats during short-term hypoxia and short-term carbon monoxide inhalation. Endocrinology. 2005; 146(1):215-20.
[8] Maffei M, Halaas J, Ravussin E, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature medicine. 1995; 1(11):1155-61.
[9] Chou SH, Chamberland JP, Liu X, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proceedings of the National Academy of Sciences of the United States of America. 2011; 108(16):6585-90.
[10] Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet (London, England). 2005; 366(9479):74-85.
[11] Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. The New England journal of medicine. 2004; 351(10):987-97.
[12] Knerr I, Herzog D, Rauh M, et al. Leptin and ghrelin expression in adipose tissues and serum levels in gastric banding patients. European journal of clinical investigation. 2006; 36(6):389-94.
[13] Nobili V, Manco M, Ciampalini P, et al. Leptin, free leptin index, insulin resistance and liver fibrosis in children with non-alcoholic fatty liver disease. European journal of endocrinology / European Federation of Endocrine Societies. 2006; 155(5):735-43.
[14] Goumenou AG, Matalliotakis IM, Koumantakis GE, et al. The role of leptin in fertility. European journal of obstetrics, gynecology, and reproductive biology. 2003; 106(2):118-24.
[15] Myers MG, Jr. Leptin receptor signaling and the regulation of mammalian physiology. Recent progress in hormone research. 2004; 59:287-304.
[16] Hughes J, Ryan S, Lambert D, et al. Outcomes of siblings with classical galactosemia. J Pediatr. 2009; 154(5):721-6.
[17] Schwartz N. Neuroendocrine Regulation of Reproductive Cyclicity. In: Conn PM, Freeman M, eds. Neuroendocrinology in Physiology and Medicine: Humana Press; 2000. p. 135-45.
[18] Fink G. Neuroendocrine Regulation of Pituitary Function. In: Conn PM, Freeman M, eds. Neuroendocrinology in Physiology and Medicine: Humana Press; 2000. p. 107-33.
[19] Fernandez-Fernandez R, Martini AC, Navarro VM, et al. Novel signals for the integration of energy balance and reproduction. Molecular and Cellular Endocrinology. 2006; 254–255:127-32.
[20] Casanueva FF, Dieguez C. Neuroendocrine Regulation and Actions of Leptin. Frontiers in Neuroendocrinology. 1999; 20(4):317-63.
[21] Mantzoros CS, Magkos F, Brinkoetter M, et al. Leptin in human physiology and pathophysiology. American journal of physiology Endocrinology and metabolism. 2011; 301(4):E567-84.
[22] Tena-Sempere M. Roles of ghrelin and leptin in the control of reproductive function. Neuroendocrinology. 2007; 86(3):229-41.
[23] Cheung CC, Thornton JE, Kuijper JL, et al. Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology. 1997; 138(2):855-8.
[24] Ahima RS, Dushay J, Flier SN, et al. Leptin accelerates the onset of puberty in normal female mice. The Journal of clinical investigation. 1997; 99(3):391-5.
[25] Chehab FF, Mounzih K, Lu R, et al. Early onset of reproductive function in normal female mice treated with leptin. Science (New York, NY). 1997; 275(5296):88-90.
[26] Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. The New England journal of medicine. 1999; 341(12):879-84.
[27] Barash IA, Cheung CC, Weigle DS, et al. Leptin is a metabolic signal to the reproductive system. Endocrinology. 1996; 137(7):3144-7.
[28] Castellano JM, Roa J, Luque RM, et al. KiSS-1/kisspeptins and the metabolic control of reproduction: physiologic roles and putative physiopathological implications. Peptides. 2009; 30(1):139-45.
[29] Donato J, Jr., Cravo RM, Frazao R, et al. Hypothalamic sites of leptin action linking metabolism and reproduction. Neuroendocrinology. 2011; 93(1):9-18.
[30] Elias CF, Purohit D. Leptin signaling and circuits in puberty and fertility. Cellular and molecular life sciences : CMLS. 2013; 70(5):841-62.
[31] Trinko R, Gan G, Gao X-B, et al. Erk1/2 Mediates Leptin Receptor Signaling in the Ventral Tegmental Area. PloS one. 2011; 6(11):e27180.
[32] Lavens D, Piessevaux J, Tavernier J. Review: Negative regulation of leptin receptor signalling. European cytokine network. 2006; 17(3):211-9.
[33] Coss KP, Treacy EP, Cotter EJ, et al. Systemic gene dysregulation in classical Galactosaemia: Is there a central mechanism? Molecular genetics and metabolism. 2014; 113(3):177-87.
[34] Knerr I, Coss KP, Kratzsch J, et al. Effects of temporary low-dose galactose supplements in children aged 5-12 y with classical galactosemia: a pilot study. Pediatr Res. 2015; 78(3):272-9.
[35] Coss KP, Doran PP, Owoeye C, et al. Classical Galactosaemia in Ireland: incidence, complications and outcomes of treatment. J Inherit Metab Dis. 2013; 36(1):21-7.
[36] Coman DJ, Murray DW, Byrne JC, et al. Galactosemia, a single gene disorder with epigenetic consequences. Pediatr Res. 2010; 67 286-92.
[37] Coss KP, Byrne JC, Coman DJ, et al. IgG N-glycans as potential biomarkers for determining galactose tolerance in Classical Galactosaemia. Mol Genet Metab. 2012; 105(2):212-20.
[38] Fridovich-Keil JL, Walter JH. Galactosaemia Chapter 72. The Online Metabolic and Molecular Bases of Inherited Disease, OMMBID. New York: McGraw Hill; 2008: New York: McGraw Hill; 2008
[39] Rubio-Gozalbo ME, Gubbels CS, Bakker JA, et al. Gonadal function in male and female patients with classic galactosemia. Human reproduction update. 2010; 16(2):177-88.
[40] Garcia-Mayor RV, Andrade MA, Rios M, et al. Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage. The Journal of clinical endocrinology and metabolism. 1997; 82(9):2849-55.
[41] Plant TM, Durrant AR. Circulating leptin does not appear to provide a signal for triggering the initiation of puberty in the male rhesus monkey (Macaca mulatta). Endocrinology. 1997; 138(10):4505-8.
[42] Mantzoros CS, Flier JS, Rogol AD. A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty. The Journal of clinical endocrinology and metabolism. 1997; 82(4):1066-70.
[43] Vazquez MJ, Romero-Ruiz A, Tena-Sempere M. Roles of leptin in reproduction, pregnancy and polycystic ovary syndrome: consensus knowledge and recent developments. Metabolism. 2015; 64(1):79-91.
[44] Watanobe H. Leptin directly acts within the hypothalamus to stimulate gonadotropin-releasing hormone secretion in vivo in rats. The Journal of physiology. 2002; 545(Pt 1):255-68.
[45] Herbison AE, Pape JR. New evidence for estrogen receptors in gonadotropin-releasing hormone neurons. Frontiers in neuroendocrinology. 2001; 22(4):292-308.
[46] Quennell JH, Mulligan AC, Tups A, et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology. 2009; 150(6):2805-12.
[47] Magni P, Vettor R, Pagano C, et al. Expression of a leptin receptor in immortalized gonadotropin-releasing hormone-secreting neurons. Endocrinology. 1999; 140(4):1581-5.
[48] Williams KW, Elmquist JK. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nature neuroscience. 2012; 15(10):1350-5.
[49] Xu Y, Faulkner LD, Hill JW. Cross-Talk between Metabolism and Reproduction: The Role of POMC and SF1 Neurons. Frontiers in endocrinology. 2011; 2:98.
[50] Roa J, Herbison AE. Direct regulation of GnRH neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice. Endocrinology. 2012; 153(11):5587-99.
[51] Balthasar N, Coppari R, McMinn J, et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron. 2004; 42(6):983-91.
[52] Hill JW, Elias CF, Fukuda M, et al. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell metabolism. 2010; 11(4):286-97.
[53] Wu Q, Whiddon BB, Palmiter RD. Ablation of neurons expressing agouti-related protein, but not melanin concentrating hormone, in leptin-deficient mice restores metabolic functions and fertility. Proc Natl Acad Sci U S A. 2012; 109(8):3155-60.
[54] Erickson JC, Hollopeter G, Palmiter RD. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science (New York, NY). 1996; 274(5293):1704-7.
[55] Elias CF. Leptin action in pubertal development: recent advances and unanswered questions. Trends in endocrinology and metabolism: TEM. 2012; 23(1):9-15.
[56] Navarro VM, Tena-Sempere M. Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility. Nature reviews Endocrinology. 2012; 8(1):40-53.
[57] Oakley AE, Clifton DK, Steiner RA. Kisspeptin signaling in the brain. Endocrine reviews. 2009; 30(6):713-43.
[58] d'Anglemont de Tassigny X, Colledge WH. The role of kisspeptin signaling in reproduction. Physiology (Bethesda, Md). 2010; 25(4):207-17.
[59] Cravo RM, Margatho LO, Osborne-Lawrence S, et al. Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience. 2011; 173:37-56.
[60] Smith JT, Acohido BV, Clifton DK, et al. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. Journal of neuroendocrinology. 2006; 18(4):298-303.
[61] Backholer K, Smith JT, Rao A, et al. Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells. Endocrinology. 2010; 151(5):2233-43.
[62] Gubbels CS, Kuppens SMI, Bakker JA, et al. Pregnancy in classic galactosemia despite undetectable anti-Müllerian hormone. Fertility and Sterility. 2009; 91(4):1293.e13-.e16.
[63] Millar RP, Lu ZL, Pawson AJ, et al. Gonadotropin-releasing hormone receptors. Endocrine reviews. 2004; 25(2):235-75.
[64] Moult PR, Harvey J. Hormonal regulation of hippocampal dendritic morphology and synaptic plasticity. Cell adhesion & migration. 2008; 2(4):269-75.
[65] Schlichting ML, Mumford JA, Preston AR. Learning-related representational changes reveal dissociable integration and separation signatures in the hippocampus and prefrontal cortex. Nature communications. 2015; 6:8151.
[66] Knerr I, Coss KP, Doran PP, et al. Leptin levels in children and adults with classic Galactosaemia. JIMD reports. 2013; 9:125-31.
[67] Messinis IE, Kariotis I, Milingos S, et al. Treatment of normal women with oestradiol plus progesterone prevents the decrease of leptin concentrations induced by ovariectomy. Hum Reprod. 2000; 15(11):2383-7.
[68] Hamm ML, Bhat GK, Thompson WE, et al. Folliculogenesis is impaired and granulosa cell apoptosis is increased in leptin-deficient mice. Biol Reprod. 2004; 71(1):66-72.
[69] El-Eshmawy MM, Abdel Aal IA, El Hawary AK. Association of ghrelin and leptin with reproductive hormones in constitutional delay of growth and puberty. Reprod Biol Endocrinol. 2010; 8:153.
[70] Gubbels CS, Welt CK, Dumoulin JC, et al. The male reproductive system in classic galactosemia: cryptorchidism and low semen volume. J Inherit Metab Dis. 2012.
[71] Holden KF, Lindquist K, Tylavsky FA, et al. Serum leptin level and cognition in the elderly: Findings from the Health ABC Study. Neurobiology of aging. 2009; 30(9):1483-9.
[72] Paz-Filho GJ, Babikian T, Asarnow R, et al. Leptin replacement improves cognitive development. PloS one. 2008; 3(8):e3098.
[73] Greco SJ, Sarkar S, Johnston JM, et al. Leptin reduces Alzheimer's disease-related tau phosphorylation in neuronal cells. Biochemical and biophysical research communications. 2008; 376(3):536-41.
[74] Paz-Filho G, Wong ML, Licinio J. Ten years of leptin replacement therapy. Obesity reviews : an official journal of the International Association for the Study of Obesity. 2011; 12(5):e315-23.
[75] Matochik JA, London ED, Yildiz BO, et al. Effect of leptin replacement on brain structure in genetically leptin-deficient adults. The Journal of clinical endocrinology and metabolism. 2005; 90(5):2851-4.