Leptin – Neuigkeiten von einem alten Bekannten

Zusammenfassung

Leptin ist ein Hormon des weißen Fettgewebes. Seine Konzentration im Blut spiegelt die Energiereserven des Körpers wider. Es reguliert die Nahrungsaufnahme, das Sättigungsgefühl sowie den Energieverbrauch und beeinflusst ferner den Blutdruck, den Glukose- und Lipidstoffwechsel, das Immunsystem und die Fruchtbarkeit.

Homozygote Mutationen im Leptin-Gen äußern sich im Auftreten einer kongenitalen Leptindefizienz. Betroffene Kinder fallen nach der Geburt durch ein mangelndes Sättigungsgefühl, eine ausgeprägte Hyperphagie und eine sich folgend entwickelnde extreme Adipositas auf. Begleitend kommt es zu schweren metabolischen, hormonellen und immunologischen Störungen. Nur bei korrekter Diagnose kann eine effektive Hormonersatztherapie mit rekombinantem humanen Leptin erfolgen. Aufgrund des unterschiedlichen biologischen Verhaltens einzelner Mutationen kann eine solche Diagnose sich jedoch als schwierig erweisen.

Summary

Leptin is a white adipose tissue hormone whose circulating levels reflect the energy stores of the body. It has a pivotal role in the regulation of food intake, satiety and energy expenditure. It furthermore exerts an influence on blood pressure, glucose and lipid metabolism, immunity and fertility.

Homozygous mutations of the leptin gene result in congenital leptin deficiency. Affected children show massive hyperphagia and severe early-onset obesity, but also pronounced metabolic, hormonal, and immunological derangements. Patients can be treated with daily injections of recombinant human leptin. However, diagnosis of the disease is challenging because different mutations come along with distinct biological behaviors of the mutant proteins.

Schlüsselwörter

Leptin - kongenitale Leptindefizienz - bioinaktives Hormon

Keywords

Leptin - congenital leptin deficiency - bioinactive hormone

• Literatur

• 1 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372 (6505): 425-432.
• 2 Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y. et al. Leptin levels in human and ro dent: measurement of plasma leptin and ob RNA in obese and weightreduced subjects. Nature medicine 1995; 01 (11) 1155-1161.
• 3 Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR. et al. Serum im munoreactiveleptin concentrations in normal weight and obese humans. The New England jour nal of medicine 1996; 334 (05) 292-295.
• 4 Zhang Y, Guo KY, Diaz PA, Heo M, Leibel RL. De terminants of leptin gene expression in fat depots of lean mice. American journal of physiology Regulatory, integrative and comparative physiol ogy 2002; 282 (01) R226-234.
• 5 Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, MaratosFlier E. et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996; 382 (6588) 250-252.
• 6 Munzberg H, Morrison CD. Structure, production and signaling of leptin. Metabolism: clinical and experimental 2015; 64 (01) 13-23.
• 7 La Cava A, Matarese G. The weight of leptin in im munity. Nature reviews Immunology 2004; 04 (05) 371-379.
• 8 Chehab FF. 20 years of leptin: leptin and reproduc tion: past milestones, present undertakings, and future endeavors. The Journal of endocrinology 2014; 223 (01) T37-48.
• 9 Turner RT, Kalra SP, Wong CP, Philbrick KA, Lindenmaier LB, Boghossian S. et al. Peripheral leptin regulates bone formation. Journal of bone and mineral research 2013; 28 (01) 22-34.
• 10 SierraHonigmann MR, Nath AK, Murakami C, Garcia-Cardena G, Papapetropoulos A, Sessa WC. et al. Biological action of leptin as an angiogenic factor. Science 1998; 281 (5383) 1683-1686.
• 11 Frank S, Stallmeyer B, Kampfer H, Kolb N, Pfeilschifter J. Leptin enhances wound reepithelializ ation and constitutes a direct function of leptin in skin repair. The Journal of clinical investigation 2000; 106 (04) 501-509.
• 12 Bennett BD, Solar GP, Yuan JQ, Mathias J, Thomas GR, Matthews W. A role for leptin and its cognate receptor in hematopoiesis. Current biology 1996; 06 (09) 1170-1180.
• 13 Harris RB. Direct and indirect effects of leptin on adipocyte metabolism. Biochimica et biophysica acta 2014; 01 842 (03) 414-23.
• 14 Dodd GT, Decherf S, Loh K, Simonds SE, Wiede F, Balland E. et al. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 2015; 160 (1–2): 88-104.
• 15 Lindstrom P. The physiology of obese-hyperglycemic mice [ob/ob mice]. TheScientificWorldJournal 2007; 07: 666-685.
• 16 Moon BC, Friedman JM. The molecular basis of the obese mutation in ob2J mice. Genomics 1997; 42 (01) 152-156.
• 17 Santoro A, Mattace GRaso, Meli R. Drug targeting of leptin resistance. Life sciences. 2015
• 18 Simonds SE, Pryor JT, Ravussin E, Greenway FL, Dileone R, Allen AM. et al. Leptin mediates the increase in blood pressure associated with obesity. Cell 2014; 159 (06) 1404-1416.
• 19 Knight ZA, Hannan KS, Greenberg ML, Friedman JM. Hyperleptinemia is required for the development of leptin resistance. PloS one 2010; 05 (06) e11376.
• 20 Liu J, Lee J, Salazar MAHernandez, Mazitschek R, Ozcan U. Treatment of obesity with celastrol. Cell 2015; 161 (05) 999-1011.
• 21 Ravussin Y, Leibel RL, Ferrante Jr AW. A missing link in body weight homeostasis: the catabolic signal of the overfed state. Cell metabolism 2014; 20 (04) 565-572.
• 22 Ottaway N, Mahbod P, Rivero B, Norman LA, Gertler A, D’Alessio DA. et al. Diet-induced obese mice retain endogenous leptin action. Cell metabolism 2015; 21 (06) 877-882.
• 23 Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387 (6636) 903-908.
• 24 Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nature genetics 1998; 18 (03) 213-215.
• 25 Chekhranova MK, Karpova SK, Yatsyshina SB, Pankov JA. A new mutation c.422C>G (p.S141C) in homoand heterozygous forms of the human leptin gene. Russian Journal of Bioorganic Chemistry 2008; 34 (06) 768-770.
• 26 Mazen I, El-Gammal M, Abdel-Hamid M, Amr K. A novel homozygous missense mutation of the leptin gene (N103K) in an obese Egyptian patient. Molecular genetics and metabolism 2009; 97 (04) 305-308.
• 27 Fischer-Posovszky P, von Schnurbein J, Moepps B, Lahr G, Strauss G, Barth TF. et al. A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T cell responsiveness. The Journal of clinical endocrinology and metabolism 2010; 95 (06) 2836-2840.
• 28 Fatima W, Shahid A, Imran M, Manzoor J, Hasnain S, Rana S. et al. Leptin deficiency and leptin gene mutations in obese children from Pakistan. International journal of pediatric obesity 2011; 06 (5–6): 419-427.
• 29 Thakur S, Kumar A, Dubey S, Saxena R, Peters A, Singhal A. A novel mutation of the leptin gene in an Indian patient. Clinical genetics. 2013
• 30 Wabitsch M, Funcke JB, Lennerz B, Kuhnle-Krahl U, Lahr G, Debatin KM. et al. Biologically inactive leptin and early-onset extreme obesity. The New England journal of medicine 2015; 372 (01) 48-54.
• 31 Wabitsch M, Funcke JB, von Schnurbein J, Denzer F, Lahr G, Mazen I. et al. Severe earlyonset obesity due to bioinactive leptin caused by a p.N103K mutation in the leptin gene. The Journal of clinical endocrinology and metabolism 2015; jc20152263.
• 32 Mazen I, Khalda A, Tantawy S, Farooqi IS, El-Gammal M. A novel mutation in the leptin gene (W121X) in an Egyptian family. Molecular Gen etics and Metabolism Reports 2014; 01: 474-476.
• 33 Ozata M, Ozdemir IC, Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. The Journal of clinical endocrinology and metabolism 1999; 84 (10) 3686-3695.
• 34 Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C. et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. The Journal of clinical investigation 2002; 110 (08) 1093-103.
• 35 von Schnurbein J, Heni M, Moss A, Nagel SA, Machann J, Muehleder H. et al. Rapid improvement of hepatic steatosis after initiation of leptin substitution in a leptin-deficient girl. Hormone research in paediatrics 2013; 79 (05) 310-317.
• 36 von Schnurbein J, Moss A, Nagel SA, Muehleder H, Debatin KM, Farooqi IS. et al. Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogon-adotropic hypogonadism. Hormone research in paediatrics 2012; 77 (02) 127-133.
• 37 Zhang F, Basinski MB, Beals JM, Briggs SL, Churgay LM, Clawson DK. et al. Crystal structure of the obese protein leptin-E100. Nature 1997; 387 (6629) 206-209.
• 38 Park HK, Ahima RS. Leptin signaling. F1000prime reports 2014; 06: 73.
• 39 Peelman F, Van Beneden K, Zabeau L, Iserentant H, Ulrichts P, Defeau D. et al. Mapping of the lep tin binding sites and design of a leptin antagonist. The Journal of biological chemistry 2004; 279 (39) 41038-41046.
• 40 Niv-Spector L, Gonen-Berger D, Gourdou I, Biener E, Gussakovsky EE, Benomar Y. et al. Identification of the hydrophobic strand in the A-B loop of leptin as major binding site III: implications for largescale preparation of potent recombinant human and ovine leptin antagonists. The Biochemical journal 2005; 391 (Pt 2): 221-230.
• 41 Peelman F, Zabeau L, Moharana K, Savvides SN, Tavernier J. 20 years of leptin: insights into signaling assemblies of the leptin receptor. The Journal of endocrinology 2014; 223 (01) T9-23.
• 42 Rau H, Reaves BJ, O’Rahilly S, Whitehead JP. Truncated human leptin (delta133) associated with extreme obesity undergoes proteasomal degradation after defective intracellular transport. Endocrinology 1999; 140 (04) 1718-1723.
• 43 Boute N, Zilberfarb V, Camoin L, Bonnafous S, Le Marchand-Brustel Y, Issad T. The formation of an intrachain disulfide bond in the leptin protein is necessary for efficient leptin secretion. Biochemie 2004; 86 (06) 351-356.
• 44 Farooqi IS. The severely obese patient--a genetic work-up. Nature clinical practice Endocrinology & metabolism 2006; 02 (03) 172-177. quiz following 7.
• 45 Kratzsch J, Berthold A, Lammert A, Reuter W, Keller E, Kiess W. A rapid, quantitative immunofunctional assay for measuring human leptin. Hormone research 2002; 57 (3–4): 127132.