The leptin receptor also known as LEP-R or OB-R is a protein encoded by the LEPR gene. It’s a molecule that receives and transmits signals from leptin, a digestive peptide hormone mostly produced in adipocytes and responsible for the feeling of satiety.

Thus, the interaction between the hormone and the leptin receptor allows the regulation of body weight and the preservation of energy homeostasis by balancing food intake. It also plays a role in reproduction, immunity and bone metabolism. Leptin receptors belong to the family of class 1 cytokine receptors.

General informations

Structure

The leptin receptor protein exists in different forms. Up to now, six ObR isoforms are known named ObRa to ObRf. They are produced by alternative splicing or ectodomain shedding ^[1] . It consists of an extracellular chain of 816 amino acids, a transmembrane domain of 23 amino acids and a cytoplasmic domain ^{[2] [3]}. These proteins exists in a long form and in a short forms with a cytoplasmic domain of variable size : 302 amino acids for the long form ObRb and 30-40 amino acids for short forms ObRa, ObRc, ObRd, ObRf. There is also a soluble form ObRe ^[1] . All isoforms have an identical extracellular domain containing 6 functional domains :

- an N-terminal domain (NTD)

- two CRH domains (a distal membrane homology of the first cytokine receptor CHR1 and a second homology of the cytokine receptor CRH2)

- an immunoglobuline-like domain (IGD ( and )) ^{[4] [5]}

- two additional membrane-proximal fibronectin type III (FN III ( or )) domains ^{[6] [1] [4]}.

ObR is heavily glycosylated causing an increase of 30-70 kDa in molecular weight ^[1] .

Location

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

The long form (Ob-Rb) is mainly present in the hypothalamus, notably in the arcuate nucleus, dorsomedial and ventromedial nuclei, and in the paraventricular nucleus (PVN) ^{[5] [7] [8]}. It is also found in lesser amounts in the islets of Langerhans in mice, as well as in the liver, spleen, heart, white fat, lymph node, jejunum and hematopoietic stem cells^{[3] [9]}.

The short-form (Ob-Ra) is located primarily in the lungs, kidneys and islets of Langerhans ^[5]. It is also present in smaller quantities in the brain at the hypothalamus.^[7] Ob-Ra is the only form of the protein found in ovaries. Short form facilitates the passage of leptin across the blood cerebrospinal fluid barrier.

Leptin receptors play a role in the regulation of body weight and blunt the drive for food intake, so they are found in adipocytes, muscles, hypothalamus. Leptin receptors intervene in gonads to support fertility especially in Leydig cells in mice, in bone marrow to promote hematopoiesis and actions in capillary endothelium to increase angiogenesis ^[9].

Important functions

The leptin receptor helps regulate the release of leptin in the body. Leptin playing a large number of roles, its receptor allows the regulation and proper functioning of all these tasks ^[10]. Its role in immunity and bone metabolism is secondary.

Leptin is necessary for the proper development of the human body. Its main function is related to the feeling of satiety. It plays an important role in the use of energy provided by nutrition. The main role of the receptor is linked to its release in the body and therefore to its upstream production by the white fatty tissue, since the level of leptin depends on the body mass of the person.

The second important role of the leptin receptor is the development of the body for reproduction and pregnancy. Regarding reproduction, studies have shown in mice that the absence of leptin, and therefore the proper functioning of its receptor, had an impact on their fertility ^[11].

During pregnancy, women have an increase of leptin production. The leptin receptor is located on the wall of the placenta. Placental leptin is, therefore, transmitted to the mother in addition to the normal release which also increases with fat gain. The foetus recovers very little leptin through this pathway, but already uses the receptor which is on the hypothalamus.

The leptin receptor also plays a secondary role in bone metabolism. It is also useful for immunity since it is part of the cytokine family.

Interactions of the protein

Activation

The activation of the leptin receptor is done through the CRH2, IGD and FN III domains ^[12].

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. In particular, and of leptin interact with in CRH2 forming a bond via hydrophobic interactions^[13]. In contrast, the receptor functionality is hardly affected when the CRH1 domain is deleted.

The IGD ( and ) 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. However, the receptor is completely devoid of biological activity ^[4] .

In the domains, there are two conserved cysteines (Cys-672 and Cys-751 ^[14]) that are crucial for the activation of the receptor ^[4].

Moreover, in order to form an ., the leptin clusters two pre-formed ObR dimers.

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 leptin receptor signalling via the MAPK,AMPK, PI3K 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 ^[15]. This prevents the development of obesity despite a diet that may be high in fat.

Disease

Some disease are due to an abnormality of the receptor or everywhere in the body which prevent leptin from reaching the receptor.

Obesityis partly due to the too weak uptake of leptin by the receptor, the individual does not feel the feeling of satiety. Too few recipients, a mutation of the latter, or an inability for leptin to pass the blood-brain barrier are the causes of this resistance ^[16]. recent studies have shown that the dysfunction of the receptor linked to diabetes, could also cause, in some cases, Alzheimer's disease. It is indeed the binding between the leptin receptor and the Aβ peptides that would cause the dysfunction of Alzheimer disease.

Pregnancy diabetes would also be due to the overproduction of the receptor on the wall of the placenta, which would lead to an overproduction of leptin. The LEP-2548G / A gene and the polymorphism A223G ^[17] of the receptor is thought to increase the risk of diseases during pregnancy such as miscarriages, gestational diabetes, or even breast cancer.