The leptin receptor, like the hormone that binds to it : leptin, allows the regulation of body weight by balancing food intake. It also plays a role in reproduction, immunity and bone metabolism.
Here, we give an overview of the current structural knowledge of the receptor and its main functions, without omitting its activation, its regulation and its link with some pathologies.
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 [1] [2]. 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 [2].
The extracellular part is itself subdivided into 5 functional domains [3]:
- 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, dorsomedial and ventromedial nuclei, and in the paraventricular nucleus (PVN) [4] [5] [6]. 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[2] [7].
Short-form leptin receptors are located primarily in the lungs, kidneys and islets of Langerhans [4]. 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 [5].
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 [8]. 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 [9].
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 [3] is done through the CRH2, IGD and FN III domains [10].
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, Leu13 and Leu86 of leptin interact with Leu504 (pink in viewer) in CRH2 forming a bond via hydrophobic interactions[11]. In contrast, the receptor functionality is hardly affected when the CRH1 domain is deleted.
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. However, the receptor is completely devoid of biological activity.
In the FN III domains, there are two conserved cysteines (Cys-672 and Cys-751 [12]) that are crucial for the activation of the receptor.
Moreover, in order to form an activated 2:4 leptin:ObR complex., 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 [13]. 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 [14]. 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 [15] of the receptor is thought to increase the risk of diseases during pregnancy such as miscarriages, gestational diabetes, or even breast cancer.
