LEPR — Leptin Receptor

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LEPR — Leptin Receptor

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Leptin Receptor</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>LEPR</td></tr>
<tr><td><strong>Full Name</strong></td><td>Leptin Receptor</td></tr>
<tr><td><strong>Alias</strong></td><td>OB-R, LEPR, CD295</td></tr>
<tr><td><strong>Chromosome</strong></td><td>1p31.3</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[3953](https://www.ncbi.nlm.nih.gov/gene/3953)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[164380](https://www.omim.org/entry/164380)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000116678</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P48471](https://www.uniprot.org/uniprot/P48471)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/obesity" style="color:#ef9a9a">Obesity</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">24 edges</a></td>
</tr>
</table>
</div>

Overview

...

LEPR — Leptin Receptor

Overview

The LEPR (Leptin Receptor) gene encodes a cytokine receptor family member that mediates the effects of leptin on energy homeostasis, metabolism, and neuroendocrine function. Located on chromosome 1p31.3 in humans, LEPR is expressed in multiple tissues including the hypothalamus, pituitary, liver, and immune cells. The leptin receptor is a critical bridge between peripheral energy stores and central nervous system regulation of feeding, metabolism, and cognitive function.

The discovery of LEPR and its ligand leptin established one of the most important hormonal axes in mammalian physiology. The leptin-LEPR signaling pathway has since been implicated in numerous aspects of brain function beyond energy balance, including synaptic plasticity, neuroprotection, and more recently, neurodegeneration.

Gene Structure and Isoforms

Genomic Organization

Chromosomal location: 1p31.3
Genomic span: ~170 kb, 20 exons
Promoter: Tissue-specific, regulated by nutritional status

Alternative Splicing

LEPR produces multiple splice variants generating diverse isoforms:

| Isoform | Structure | Expression | Signaling |
|---------|-----------|------------|-----------|
| Ob-Rb | Full-length, long form | Hypothalamus, brainstem | Competent |
| Ob-Ra | Short form | Choroid plexus, liver | Limited |
| Ob-Rc | Short form | Multiple tissues | Limited |
| Ob-Re | Soluble form | Blood, CSF | None |
| Ob-Rf | Truncated | Testis | Limited |

The Ob-Rb (long form) is the signaling-competent isoform primarily expressed in the [hypothalamus](/brain-regions/hypothalamus) and other brain regions. It contains the full intracellular domain required for JAK-STAT signaling.

Protein Structure

The leptin receptor is a single transmembrane receptor belonging to the class I cytokine receptor family (gp130 family):

Leptin Receptor Domain Structure:
├── Extracellular Domain (~800 aa)
│ ├── N-terminal signal peptide
│ ├── Cytokine receptor homology (CRH) domain (CNN motifs)
│ ├── Ig-like domain
│ ├── Fibronectin type III domain
│ └── Membrane-proximal domain
├── Transmembrane Domain (~40 aa)
│ └── Single alpha-helix
└── Intracellular Domain (~300 aa)
├── JAK2 binding motifs
├── STAT3 recruitment site
└── Multiple tyrosine phosphorylation sites

Key Structural Features

CRH domain — contains the leptin binding site
JAK2 docking site — box1 and box2 motifs for JAK2 association
STAT3 activation site — YXXQ motif for STAT3 phosphorylation
Multiple tyrosine residues — serve as docking sites for SH2-containing proteins

Signaling Pathways

JAK-STAT Pathway (Primary)

The major signaling cascade for LEPR:

Mermaid diagram (expand to render)

Leptin binding — induces LEPR homodimerization

JAK2 activation — associated JAK2 kinases undergo autophosphorylation

STAT3 phosphorylation — STAT3 binds phospho-tyrosine motifs, is phosphorylated

Dimerization — p-STAT3 forms dimers

Nuclear translocation — STAT3 dimers enter nucleus

Gene transcription — regulates SOCS3, POMC, NPY, and other targets

PI3K/Akt Pathway

JAK2 can activate PI3K via IRS proteins
Leads to Akt activation
Promotes cell survival and metabolic effects
Important for neuroprotective actions

MAPK/ERK Pathway

JAK2 activates Ras-MAPK cascade
Involved in growth, differentiation
Synaptic plasticity modulation

AMPK Activation

LEPR signaling can activate AMPK
Energy sensing function
May mediate metabolic effects in brain

Expression Patterns

Central Nervous System

[Hypothalamus](/brain-regions/hypothalamus) — highest expression in arcuate nucleus
POMC neurons (anorexigenic)
NPY/AgRP neurons (orexigenic)
Ventromedial hypothalamus — energy balance integration
Dorsal vagal complex — peripheral signal integration
Choroid plexus — Ob-Ra for leptin transport into CSF
Hippocampus — modulates synaptic plasticity and memory
Cortex — lower but significant expression

Peripheral Tissues

Liver — metabolic regulation
Adipose tissue — autocrine/paracrine effects
Immune cells — cytokine signaling
Kidney, lung, heart — lower expression

Clinical Significance

Obesity

LEPR mutations cause monogenic obesity[@lepra]:

Recessive LEPR deficiency — severe early-onset obesity
Dominant-negative mutations — partial dysfunction
Common variants — contribute to polygenic BMI variation
Leptin resistance — functional impairment in common obesity

Alzheimer's Disease

LEPR signaling is impaired in AD and represents a therapeutic target[@leptin][@farr2022]:

Reduced LEPR expression in AD hippocampus
Impaired JAK-STAT signaling in AD brain
Leptin resistance — similar to insulin resistance
Amyloid-beta effects — Aβ reduces LEPR signaling
Neuroprotection — leptin protects against Aβ toxicity
Clinical trials — leptin analog therapy in early AD[@nichols2023]

Parkinson's Disease

LEPR dysfunction contributes to PD pathogenesis[@rose2021]:

Reduced LEPR in substantia nigra of PD patients
Impaired dopaminergic signaling via LEPR
Metabolic dysfunction — LEPR regulates mitochondrial function
Therapeutic potential — leptin agonists under investigation

Other Associations

Type 2 diabetes — LEPR variants affect metabolic risk
Cardiovascular disease — LEPR affects blood pressure
Immune dysfunction — LEPR modulates inflammation

Therapeutic Approaches

Target Strategy

| Approach | Mechanism | Status |
|----------|-----------|--------|
| Leptin analogs | Bypass leptin resistance | Clinical (rare obesity) |
| LEPR agonists | Direct receptor activation | Preclinical |
| JAK2 inhibitors | Modulate excessive signaling | Research |
| STAT3 modulators | Fine-tune transcription | Research |

Clinical Applications

Metreleptin — FDA-approved for congenital leptin deficiency
Combination therapy — LEPR + amyloid-targeting in AD
Neuroprotective strategies — enhancing LEPR signaling

Animal Models

Knockout Models

Lepr−/− mice — severe obesity, infertility, shortened lifespan
Ob/Ob mice — leptin-deficient, similar phenotype
Brain-specific knockout — metabolic and cognitive phenotypes

Transgenic Models

LEPR overexpression — protected against neurodegeneration
Human LEPR mutations — knock-in models for obesity

External Links

[NCBI Gene: 3953](https://www.ncbi.nlm.nih.gov/gene/3953)
[UniProt: P48471](https://www.uniprot.org/uniprot/P48471)
[Ensembl: ENSG00000116678](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000116678)
[Human Protein Atlas](https://www.proteinatlas.org/ENSG00000116678-LEPR)
[OMIM: 164380](https://www.omim.org/entry/164380)

References

[NCBI Gene, LEPR gene description (n.d.)](https://www.ncbi.nlm.nih.gov/gene/3953)

[Montague et al., LEPR mutations and obesity (1997)](https://pubmed.ncbi.nlm.nih.gov/9006001/)

[Sheng et al., Leptin in Alzheimer's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31102901/)

[Rose et al., Leptin signaling in Parkinson's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34547921/)

[Farr et al., Leptin and cognitive function in aging (2022)](https://pubmed.ncbi.nlm.nih.gov/35644567/)

[Marwar et al., Leptin receptor deficiency and neurodegeneration (2022)](https://pubmed.ncbi.nlm.nih.gov/35672389/)

[Nichols et al., Leptin analog as AD therapeutic (2023)](https://pubmed.ncbi.nlm.nih.gov/37892345/)

Pathway Diagram

The following diagram shows the key molecular relationships involving LEPR — Leptin Receptor discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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LEPR — Leptin Receptor

LEPR — Leptin Receptor

Overview

LEPR — Leptin Receptor

Overview

Gene Structure and Isoforms

Genomic Organization

Alternative Splicing

Protein Structure

Key Structural Features

Signaling Pathways

JAK-STAT Pathway (Primary)

PI3K/Akt Pathway

MAPK/ERK Pathway

AMPK Activation

Expression Patterns

Central Nervous System

Peripheral Tissues

Clinical Significance

Obesity

Alzheimer's Disease

Parkinson's Disease

Other Associations

Therapeutic Approaches

Target Strategy

Clinical Applications

Animal Models

Knockout Models

Transgenic Models

See Also

External Links

References

Pathway Diagram