Leptin

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Leptin
Leptin
Leptin according to PDB  1ax8

Existing structure data : PDB  1ax8

Properties of human protein
Mass / length primary structure 146 amino acids , 16.026 kDa
Precursor 167 amino acids; 18.64 kDa
Identifier
Gene names LEP  ; IF; OBS
External IDs
Occurrence
Parent taxon Euteleostomi
Orthologue
human mouse
Entrez 3952 16846
Ensemble ENSG00000174697 ENSMUSG00000059201
UniProt P41159 Q544U0
Refseq (mRNA) NM_000230 NM_008493
Refseq (protein) NP_000221 NP_032519
Gene locus Chr 7: 127.67 - 127.68 Mb Chr 6: 01/29 - 02/29 Mb
PubMed search 3952 16846

Leptin (from Greek: λεπτός leptos = 'thin', synonymous with obese protein ) is a proteohormone that was discovered in 1994 by the molecular biologist Jeffrey Friedman .

description

Leptin is the "obese" encoding gene and mainly of adipocytes ( "fat cells") expressed in small amounts also in the placenta , the gastric mucosa , the bone marrow , the breast epithelium , the skeletal muscles , the pituitary gland and the hypothalamus . In the course of the secretion of leptin, its signal sequence of 21 amino acids is split off, creating the biologically active leptin with 146 amino acids. Leptin inhibits feelings of hunger and plays an important role in regulating the fat metabolism in humans and other mammals .

Receptors for leptin (Ob-Rs) could be identified in two different populations of neurons in the nucleus arcuatus and nucleus paraventricularis of the hypothalamus . The first group of these neurons produces the appetite-stimulating neuropeptides AgRP (agouti-related protein) and NPY (neuropeptide Y), which are suppressed by leptin. The second population produces POMC (Proopiomelanocortin) and cocaine- and amphetamine-regulated transcript (CART), both transmitter substances that have an appetite suppressant effect. These are activated by leptin. As the body's fat deposits are reduced, the concentration of leptin in the bloodstream also decreases, which in turn causes an increase in appetite.

By stimulating the sympathetic nervous system , leptin also increases blood pressure , heart rate and thermogenesis by decoupling cell respiration from ATP synthesis.

Use as a drug

Metreleptin

In the USA, the drug Metreleptin ( Myalept ) was approved by the American regulatory authority (FDA) for leptin replacement therapy in 2014 . Metreleptin is a recombinant analog of human leptin, which for the treatment of very rare disease ( orphan disease ) lipodystrophy is used. Metreleptin was approved in the EU in July 2018.

Appetite suppressants

Leptin satiety
Video: Three Important Hormones For Metabolism (Leptin, Insulin And Ghreli)

Hopes that leptin might prove to be a powerful appetite suppressant drug were initially dashed when it was discovered that most obese people had high levels of this hormone. These often hungry patients are not lacking in leptin (leptin deficiency ), but rather suffer from what is known as leptin resistance . In this state, the physiological effect of leptin on the target neurons does not occur. The underlying mechanism is not yet clear. Recent research shows a modulating effect or an interaction of nitric oxide and leptin. According to previous studies, however, nitric oxide alone has an appetite suppressant effect. In addition, nitrogen monoxide has a thirst-reducing effect.

Alternative to insulin

A new study in mice shows that leptin could also prove to be an alternative to insulin in people with type 1 diabetes. The advantage over insulin is: Leptin is apparently a better antagonist of glucagon and therefore lowers blood sugar levels more precisely. Other disadvantages of insulin therapy may be eliminated. Clinical studies should test these hypotheses.

See also

literature

Individual evidence

  1. ^ Y. Zhang, R. Proenca, M. Maffei, M. Barone, L. Leopold, JM Friedman: Positional cloning of the mouse obese gene and its human homologue. In: Nature . Volume 372, Number 6505, December 1994, pp. 425-432, doi : 10.1038 / 372425a0 . PMID 7984236 .
  2. Jump up ↑ A. Bado, S. Levasseur, S. Attoub, S. Kermorgant, JP Laigneau, MN Bortoluzzi, L. Moizo, T. Lehy, M. Guerre-Millo, Y. Le Marchand-Brustel, MJ Lewin: The stomach is a source of leptin. In: Nature. Volume 394, number 6695, August 1998, pp. 790-793, doi : 10.1038 / 29547 . PMID 9723619 .
  3. ↑ H. Masuzaki, Y. Ogawa, N. Sagawa, K. Hosoda, T. Matsumoto, H. Mise, H. Nishimura, Y. Yoshimasa, I. Tanaka, T. Mori, K. Nakao: Nonadipose tissue production of leptin : leptin as a novel placenta-derived hormone in humans. In: Nature medicine . Volume 3, Number 9, September 1997, pp. 1029-1033, PMID 9288733 .
  4. ↑ B. Morash, A. Li et al. a .: Leptin gene expression in the brain and pituitary gland. In: Endocrinology. Volume 140, Number 12, December 1999, pp. 5995-5998, PMID 10579368 .
  5. ↑ David Nelson, Michael Cox: Lehninger Principles of Biochemistry . 4th edition, WH Freeman, New York, 2005, ISBN 0-7167-4339-6 .
  6. ↑ Drugs @ FDA: FDA Approved Drug Products , FDA: Approval Date (s) and History, Letters, Labels, Reviews for BLA 125390, accessed January 11, 2019.
  7. ↑ Drugs @ FDA: FDA Approved Drug Products , FDA: Approval Date (s) and History, Letters, Labels, Reviews for BLA 125390, accessed July 20, 2017.
  8. ↑ Myalepta-Metreleptin , EPAR from EMA, accessed on January 11, 2019.
  9. ↑ Novelion Therapeutics Announces Marketing Authorization for MYALEPTA® (metreleptin) in the European Union to Treat Generalized and Partial Lipodystrophy , PM Novelion of December 21, 2016, accessed on January 11, 2019.
  10. ↑ Novelion Therapeutics' Subsidiary Files for European Approval for Metreleptin as a treatment for Generalized Lipodystrophy and a Subset of Patients with Partial Lipodystrophy , PM Novelion, December 21, 2016, accessed January 11, 2019.
  11. ↑ SJ Yang, DM Denbow: Interaction of leptin and nitric oxide on food intake in broilers and Leghorns. In: Physiology & behavior. Volume 92, number 4, November 2007, pp. 651-657, doi : 10.1016 / j.physbeh.2007.05.009 . PMID 17631366 .
  12. ↑ JE Morley, MM Alshaher, SA Farr, JF Flood, VB Kumar: leptin and neuropeptide Y (NPY) modulate nitric oxide synthase: Further evidence for a role of nitric oxide in feeding. In: Peptides . Volume 20, Number 5, 1999, pp. 595-600, PMID 10465511 .
  13. ↑ YH Choi, M. Furuse, J. Okumura, DM Denbow: Nitric oxide controls feeding behavior in the chicken. In: Brain research. Volume 654, Number 1, August 1994, pp. 163-166, PMID 7982091 .
  14. ↑ G. Calapai, AP Caputi: Nitric oxide and drinking behavior. In: Regulatory peptides. Volume 66, Number 1-2, October 1996, pp. 117-121, PMID 8899905 .
  15. ↑ MY Wang, L. Chen, GO Clark, Y. Lee, RD Stevens, OR Ilkayeva, BR Wenner, JR Bain, MJ Charron, CB Newgard, RH Unger: Leptin therapy in insulin-deficient type I diabetes. In: PNAS . Volume 107, Number 11, March 2010, pp. 4813-4819, doi : 10.1073 / pnas.0909422107 . PMID 20194735 . PMC 2841945 (free full text).

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