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General informations

Structure

Leptin receptors belong to the family of class 1 cytokine receptors.

The leptin receptor protein is a molecule that exists in different forms : short or long. It consists of an extracellular chain of 816 amino acids, a transmembrane domain of 23 amino acids and a cytoplasmic domain. This cytoplasmic domain is made up of 34 amino acids for the short form of the leptin receptor and 303 amino acids for the long form.

The extracellular part is itself subdivided into 5 functional domains :

- distal membrane homology of the first cytokine receptor (CRH1)

- immunoglobulin-like domain (IGD)

- second homology of the cytokine receptor (CRH2)

- two membrane proximal fibronectine type-III (FNIII) domains

Location

Leptin receptors are found in different regions depending on the short or long form of the protein.

The long form (Ob-Rl) is mainly present in the hypothalamus, notably in the arcuate nucleus, dorsomedian and ventromedian nuclei, and in the paraventricular nucleus (PVN). It is also found in lesser amounts in the islets of Langerhans in mouses, as well as in the liver, spleen, heart, white fat, lymph node, jejunum and hematopoietic stem cells.

Short-form leptin receptors are located primarily in the lungs, kidneys and islets of Langerhans. In ovaries, only this short form of the protein can be found. The short form Ob-Ra is also present in smaller quantities in the brain at the hypothalamus.

Important functions of the protein

Leptin and, therefore, its receptor, have multiple roles. Most of these roles have been little developed or are being researched or simply have not been found. However, we do know that it is necessary for the proper development of the human course, as well as its good health.

Its main function is linked to the feeling of satiety. This therefore makes it possible not to overeat. It also plays an important role in the use of energy provided by nutrition. Its main role is therefore linked to its production, since the level of leptin depends on the body mass of the person. The stronger a person is, the more leptin they produce. It therefore has a strong link with obesity.

The second important role of the leptin receptor is the development of the body for reproduction and then during pregnancy. Regarding reproduction, studies have shown in mice that the absence of leptin had an impact on their fertility. In particular, because they do not produce enough primary follicles, the size of the uterus is smaller than normal in women, and there is too little sperm production in men due to poor regulation.For pregnancy, there are two phenomenas, one in the mother and the other in the fetus. In the mother, there is a significant increase in leptin production throughout pregnancy and then a return to normal just before childbirth. This increase is due to the production of leptin in the placenta, the produced leptin is transmitted thanks to its receptor which is on the wall. For the child, a small amount is transmitted by the placenta but the fetus is able to manufacture leptin in the same way as adults, that is to say according to their fat mass.

Interactions of the protein

Activation

The activation of the leptin receptor is done through the CRH2, IGD and FN III domains. The CRH2 domain is the main leptin binding site on the receptor. This domain is required for the activation of the receptor. It is composed of a region of four consecutive hydrophobic residues. The IGD domain has no affinity for leptin but is nevertheless required for receptor activation. In the absence of this domain, the result is a receptor with a wild-type affinity for leptin, but completely devoid of biological activity. In the FN III domains, there are two conserved cysteines that are crucial for the activation of the receptor. In contrast, the receptor functionality is hardly affected when the CRH1 domain is deleted.

Signaling pathways

The leptin receptor has cytokine receptor characteristics. The transduction of the signal by this type of receptor involves the formation of multimeric complexes. This leads to the recruitment of tyrosine kinases, in particular those of the JAK family, which will phosphorylate STAT-like transcription factors at the cytoplasmic tail of the receptor. Recruitment and activation of secondary signalling molecules enable the lept signalling via the MAPK, PI3K, AMPK and mTOR pathways.

Regulation

The best known regulation of the leptin receptor is negative regulation by OB-RGRP. The gene encoding the leptin receptor (OB-R) also encodes a second transcript called OB-R gene related protein (OB-RGRP). Stopping the expression of the OB-RGRP gene by interfering RNAs increases the sensitivity of the cells' receptors to leptin. This prevents the development of obesity despite a diet that may be high in fat.

Disease

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