LEP

Summary

LEP (leptin, HGNC:6553) is a protein-coding gene on chromosome 7q32.1, encoding Leptin (P41159). Key player in the regulation of energy balance and body weight control.

This gene encodes a protein that is secreted by white adipocytes into the circulation and plays a major role in the regulation of energy homeostasis. Circulating leptin binds to the leptin receptor in the brain, which activates downstream signaling pathways that inhibit feeding and promote energy expenditure. This protein also has several endocrine functions, and is involved in the regulation of immune and inflammatory responses, hematopoiesis, angiogenesis, reproduction, bone formation and wound healing. Mutations in this gene and its regulatory regions cause severe obesity and morbid obesity with hypogonadism in human patients. A mutation in this gene has also been linked to type 2 diabetes mellitus development.

Source: NCBI Gene 3952 — RefSeq curated summary.

At a glance

• Gene–disease (curated): obesity due to congenital leptin deficiency (Definitive, GenCC)
• GWAS associations: 38
• Clinical variants (ClinVar): 121 total — 6 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 26
• MANE Select transcript: NM_000230

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6553
Approved symbol	LEP
Name	leptin
Location	7q32.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000174697
Ensembl biotype	protein_coding
OMIM	164160
Entrez	3952

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000308868, ENST00000965599

RefSeq mRNA: 1 — MANE Select: NM_000230 NM_000230

CCDS: CCDS5800

Canonical transcript exons

ENST00000308868 — 3 exons

Exon	Start	End
ENSE00001208755	128254404	128257629
ENSE00001303768	128251991	128252162
ENSE00001422382	128241278	128241306

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 95.06.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.2748 / max 373.3742, expressed in 91 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80913	1.0933	76
80912	0.1816	38

Top tissues by expression

270 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skin of hip	UBERON:0001554	95.06	gold quality
buccal mucosa cell	CL:0002336	94.25	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.99	gold quality
adipose tissue	UBERON:0001013	93.26	gold quality
connective tissue	UBERON:0002384	91.25	gold quality
thoracic mammary gland	UBERON:0005200	88.24	gold quality
mammary gland	UBERON:0001911	88.20	gold quality
mammary duct	UBERON:0001765	88.18	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.10	gold quality
omental fat pad	UBERON:0010414	87.46	gold quality
peritoneum	UBERON:0002358	87.33	gold quality
epithelium of mammary gland	UBERON:0003244	85.98	gold quality
pericardium	UBERON:0002407	84.43	gold quality
placenta	UBERON:0001987	81.10	gold quality
synovial joint	UBERON:0002217	80.52	gold quality
parotid gland	UBERON:0001831	78.29	silver quality
superficial temporal artery	UBERON:0001614	75.78	silver quality
decidua	UBERON:0002450	73.30	silver quality
layer of synovial tissue	UBERON:0007616	71.21	gold quality
endometrium epithelium	UBERON:0004811	70.74	gold quality
endothelial cell	CL:0000115	68.69	gold quality
tendon of biceps brachii	UBERON:0008188	68.51	gold quality
frontal pole	UBERON:0002795	68.45	gold quality
paraflocculus	UBERON:0005351	68.07	gold quality
middle frontal gyrus	UBERON:0002702	68.02	gold quality
diaphragm	UBERON:0001103	67.73	gold quality
coronary artery	UBERON:0001621	67.31	gold quality
left coronary artery	UBERON:0001626	67.20	gold quality
Brodmann (1909) area 10	UBERON:0013541	65.46	gold quality
left ventricle myocardium	UBERON:0006566	65.19	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ARID5B, ARNT, CEBPA, CEBPB, CEBPD, CEBPG, CREB1, CTNNB1, ESR1, FOSL2, GFI1, HIF1A, HMGA1, IKZF1, KHDRBS1, NCOA1, NCOR2, NFATC4, NFKB1, NFKB, NHLH2, NKX3-1, NR3C2, NR4A1, NR4A3, PARP1, POU1F1, POU2F1, PPARA, PPARD, PPARG, RELA, SMAD3, SMAD4, SON, SP1, SREBF1, STAT3, STAT5A

miRNA regulators (miRDB)

93 targeting LEP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-1251-3P	99.64	67.21	1408
HSA-MIR-298	99.63	67.56	1916

Literature-anchored findings (GeneRIF, showing 40)

• data reveal the presence of leptin in term human milk (PMID:11787735)
• evaluation of the relative contributions of existing obesity and a family history of obesity (FHOB) to blood pressure (BP) level, sympathetic activity, plasma leptin and insulin levels in young men without a family history of hypertension. (PMID:11800057)
• leptin level was significantly lower in the CDGP (constitutional delay of growth and puberty)group (PMID:11822578)
• Human follicular papilla cells carry out nonadipose tissue production (PMID:11886494)
• in obese women serum leptin level and the occurrence of binge eating are unrelated; relationship between serum leptin level and restraint of food intake observed in eating disordered patients and in overweight preadolescent girls is shared by obese women (PMID:11890967)
• Fetal Down syndrome or Edwards syndrome does not seem to alter maternal leptin concentration (PMID:11920898)
• leptin concentration experience delayed reduction in systemic circulation after acute resistance exercise; decline likely associated with disruption in metabolic homeostasis created by energy expenditure & excess post oxygen consumption from the exercise (PMID:11932568)
• leptin upregulates ET-1 production in HUVECs via a mechanism potentially involving jun binding members of the bZIP family (PMID:11934840)
• Results support the involvement of NGF, BDNF, leptin, and mast cells in human coronary atherosclerosis and metabolic syndrome, implying neuroimmune and adipoimmune pathways in the pathobiology of these cardiovascular disorders. (PMID:11935372)
• microsatellite polymorphism in exon 3 of POMC is associated with elevated serum leptin levels (PMID:11979399)
• the differential distribution of mRNA for leptin and its receptor suggests an important autocrine and paracrine role for leptin in human endometriosis. (PMID:11994543)
• Results indicate that leptin, after binding its receptor, leads to activation of Grb2 and several pathways for signal transduction that might lead to mitogenic effects. (PMID:11997181)
• Data show that pro-inflammatory cytokines dose-dependently decrease the production and release of leptin from adipose tissue fragments in vitro. (PMID:11997182)
• Higher serum leptin level in women than in men with type 1 diabetes. (PMID:12003376)
• Leptin levels were not higher in patients with PCOS compared to the control group; the leptin level was correlated with the amount of fat tissue not only in patients with PCOS but also in healthy women. (PMID:12009346)
• Novel human and mouse genes encoding an acid phosphatase family member and its downregulation in W/Wv mouse jejunum [ACPL1] (PMID:12010881)
• Leptin increased acute myelogenous leukemia blast release of IL-1beta, IL6, tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor, and increased spontaneous AML blast proliferation (PMID:12031914)
• leptin 3’-tetranucleotide repeat is associated with high body mass index(BMI) in adult Samoans with allele 226 having a low frequency in the high BMI group (PMID:12037648)
• rose in glucose metabolism in type 2 diabetes (review) (PMID:12047393)
• Leptin gene polymorphism is associated with hypertension independent of obesity. (PMID:12050272)
• The role of leptin in satiety and sex maturation, regulation of leptin secretion, and its possible therapeutic use in obesity are reviewed. (PMID:12053815)
• mediates a proliferative response in human MCF7 breast cancer cells (PMID:12054648)
• polymorphism found to be associated with exercise-mediated improvement in glucose tolerance and leptin resistance in healthy Japanese men (PMID:12062855)
• Genetic diversity and evolution of the human leptin locus tetranucleotide repeat (PMID:12073010)
• induction of leptin gene expression by hypoxia and HIF1 (PMID:12084725)
• serum level affects regulation of circulating soluble leptin reeptor levels, depending on gender, adiposity (PMID:12086939)
• These results support the hypothesis of leptin as a stimulatory cytokine and point to a possible role for leptin in the pathophysiology of human HIV infection. (PMID:12100031)
• during weight loss leptin levels decreased, whereas soluble leptin receptor levels and the receptor bound fraction of leptin increased (PMID:12105280)
• a quantitative trait locus on chromosome 22 may influence the level of leptin adjusted for testosterone (PMID:12105281)
• The changes in plasma leptin, insulin and proinsulin levels in obese adolescents (PMID:12133430)
• modifications in circulating levels across the eating disorder spectrum (PMID:12140788)
• anti-CD3-driven proliferation of memory T cells was inhibited by leptin, whereas that of naive T cells was markedly enhanced; despite the inhibition of proliferation of the memory T cells, their production of interferon-gamma was substantially increased (PMID:12149424)
• inverse correlation found between adiponectin and leptin with serum leptin concentrations increased in women with high body mass index (PMID:12153737)
• AHSG, TNF-alpha and leptin may contribute to insulin resistance during normal pregnancy and gestational diabetes (PMID:12153747)
• study showed release of free and protein-bound leptin, and leptin receptor from adipose tissue was increased in obese compared with lean subjects (PMID:12161541)
• polymorphism in the leptin promoter region (-2548 G/A) influences gene expression and adipose tissue secretion of leptin (PMID:12189581)
• a key role in metabolic syndrome, especially in the obesity (PMID:12189588)
• Serum leptin and leptin binding activity in children and adolescents with hypothalamic dysfunction. (PMID:12199340)
• leptin has a role in advanced lung cancer, but is not causative in cancer cachexia or anorexia (PMID:12200109)
• the sex-dependent specificity of the relationship between leptin and bone mineral density (BMD) in human studies could be caused by serum leptin levels that are two- to threefold higher in women than in men (PMID:12211425)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Lep	ENSMUSG00000059201
rattus_norvegicus	Lep	ENSRNOG00000045797

Protein

Protein identifiers

Leptin — P41159 (reviewed: P41159)

Alternative names: Obese protein, Obesity factor

All UniProt accessions (2): A4D0Y8, P41159

UniProt curated annotations — full annotation on UniProt →

Function. Key player in the regulation of energy balance and body weight control. Once released into the circulation, has central and peripheral effects by binding LEPR, found in many tissues, which results in the activation of several major signaling pathways. In the hypothalamus, acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones. In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic for endothelial cell and affects innate and adaptive immunity. In the arcuate nucleus of the hypothalamus, activates by depolarization POMC neurons inducing FOS and SOCS3 expression to release anorexigenic peptides and inhibits by hyperpolarization NPY neurons inducing SOCS3 with a consequent reduction on release of orexigenic peptides. In addition to its known satiety inducing effect, has a modulatory role in nutrient absorption. In the intestine, reduces glucose absorption by enterocytes by activating PKC and leading to a sequential activation of p38, PI3K and ERK signaling pathways which exerts an inhibitory effect on glucose absorption. Acts as a growth factor on certain tissues, through the activation of different signaling pathways increases expression of genes involved in cell cycle regulation such as CCND1, via JAK2-STAT3 pathway, or VEGFA, via MAPK1/3 and PI3K-AKT1 pathways. May also play an apoptotic role via JAK2-STAT3 pathway and up-regulation of BIRC5 expression. Pro-angiogenic, has mitogenic activity on vascular endothelial cells and plays a role in matrix remodeling by regulating the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). In innate immunity, modulates the activity and function of neutrophils by increasing chemotaxis and the secretion of oxygen radicals. Increases phagocytosis by macrophages and enhances secretion of pro-inflammatory mediators. Increases cytotoxic ability of NK cells. Plays a pro-inflammatory role, in synergy with IL1B, by inducing NOS2 which promotes the production of IL6, IL8 and Prostaglandin E2, through a signaling pathway that involves JAK2, PI3K, MAP2K1/MEK1 and MAPK14/p38. In adaptive immunity, promotes the switch of memory T-cells towards T helper-1 cell immune responses. Increases CD4(+)CD25(-) T-cell proliferation and reduces autophagy during TCR (T-cell receptor) stimulation, through MTOR signaling pathway activation and BCL2 up-regulation.

Subunit / interactions. Interacts with SIGLEC6.

Subcellular location. Secreted.

Tissue specificity. Adipose tissue is the main source of leptin. It is also produced by other peripheral tissues such as the skeletal muscle. Expressed by intercalated and striated tracts of submandibular and parotid salivary gland intralobular ducts. Detected by fundic epithelium of the gastric mucosa. Secreted into blood and gastric juice.

Disease relevance. Leptin deficiency (LEPD) [MIM:614962] A rare disease characterized by low levels of serum leptin, severe hyperphagia and intractable obesity from an early age. The disease is caused by variants affecting the gene represented in this entry.

Induction. Induced by secretin.

Similarity. Belongs to the leptin family.

RefSeq proteins (1): NP_000221* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000065	Leptin	Family
IPR009079	4_helix_cytokine-like_core	Homologous_superfamily

Pfam: PF02024

UniProt features (17 total): helix 7, sequence variant 5, signal peptide 1, chain 1, turn 1, disulfide bond 1, sequence conflict 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
1AX8	X-RAY DIFFRACTION	2.4
9PUO	X-RAY DIFFRACTION	3.1
8X85	ELECTRON MICROSCOPY	3.58
7Z3Q	X-RAY DIFFRACTION	3.62
8X81	ELECTRON MICROSCOPY	3.77
8X80	ELECTRON MICROSCOPY	3.88
8AVE	ELECTRON MICROSCOPY	5.62
8AVF	ELECTRON MICROSCOPY	6.45
8AVO	ELECTRON MICROSCOPY	6.84
8K6Z	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41159-F1	81.28	0.42

Antibody-complex structures (SAbDab): 1 — 9PUO

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (1): 117–167

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-2586552	Signaling by Leptin
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-381771	Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)
R-HSA-422085	Synthesis, secretion, and deacylation of Ghrelin
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-2980736	Peptide hormone metabolism
R-HSA-392499	Metabolism of proteins
R-HSA-400508	Incretin synthesis, secretion, and inactivation
R-HSA-9843745	Adipogenesis

MSigDB gene sets: 672 (showing top): GOBP_CIRCADIAN_RHYTHM, REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_LIPID_MODIFICATION, GOBP_DIGESTION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_RESPONSE_TO_ETHANOL, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_REGULATION_OF_LIPID_STORAGE, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION

GO Biological Process (107): negative regulation of transcription by RNA polymerase II (GO:0000122), angiogenesis (GO:0001525), ovulation from ovarian follicle (GO:0001542), response to hypoxia (GO:0001666), placenta development (GO:0001890), regulation of endothelial cell proliferation (GO:0001936), response to dietary excess (GO:0002021), cardiac muscle hypertrophy (GO:0003300), glucose metabolic process (GO:0006006), regulation of gluconeogenesis (GO:0006111), energy reserve metabolic process (GO:0006112), glycerol biosynthetic process (GO:0006114), lipid metabolic process (GO:0006629), fatty acid beta-oxidation (GO:0006635), phagocytosis (GO:0006909), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), female pregnancy (GO:0007565), circadian rhythm (GO:0007623), cholesterol metabolic process (GO:0008203), bile acid metabolic process (GO:0008206), regulation of blood pressure (GO:0008217), determination of adult lifespan (GO:0008340), adult feeding behavior (GO:0008343), negative regulation of autophagy (GO:0010507), negative regulation of lipid storage (GO:0010888), response to activity (GO:0014823), sexual reproduction (GO:0019953), central nervous system neuron development (GO:0021954), insulin secretion (GO:0030073), T cell differentiation (GO:0030217), regulation of intestinal cholesterol absorption (GO:0030300), positive regulation of TOR signaling (GO:0032008), negative regulation of appetite (GO:0032099), prostaglandin secretion (GO:0032310), response to estradiol (GO:0032355), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-6 production (GO:0032755), positive regulation of interleukin-8 production (GO:0032757), positive regulation of tumor necrosis factor production (GO:0032760), regulation of natural killer cell activation (GO:0032814)

GO Molecular Function (6): DNA binding (GO:0003677), hormone activity (GO:0005179), peptide hormone receptor binding (GO:0051428), leptin receptor binding (GO:1990460), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Peptide hormone metabolism	2
Signal Transduction	1
Adipogenesis	1
Incretin synthesis, secretion, and inactivation	1
Metabolism of proteins	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
female gonad development	1
ovulation cycle process	1
ovulation	1
response to stress	1
response to decreased oxygen levels	1
animal organ development	1
endothelial cell proliferation	1
regulation of epithelial cell proliferation	1
response to nutrient levels	1
energy homeostasis	1
striated muscle hypertrophy	1
hexose metabolic process	1
gluconeogenesis	1
regulation of glucose metabolic process	1
regulation of carbohydrate biosynthetic process	1
energy derivation by oxidation of organic compounds	1
glycerol metabolic process	1
alditol biosynthetic process	1
primary metabolic process	1
fatty acid catabolic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
endocytosis	1
cell surface receptor signaling pathway via STAT	1
multi-organism reproductive process	1
multi-multicellular organism process	1
rhythmic process	1
sterol metabolic process	1
secondary alcohol metabolic process	1
steroid metabolic process	1
monocarboxylic acid metabolic process	1
nucleic acid binding	1
receptor ligand activity	1
hormone receptor binding	1

Protein interactions and networks

STRING

4520 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LEP	LEPR	P48357	999
LEP	NPY	P01303	996
LEP	POMC	P01189	992
LEP	INS	P01308	986
LEP	ADIPOQ	Q15848	983
LEP	GHRL	Q9UBU3	978
LEP	AGRP	O00253	975
LEP	ADIPOR1	Q96A54	949
LEP	MC4R	P32245	945
LEP	JAK2	O60674	936
LEP	KISS1	Q15726	936
LEP	SIGLEC6	O43699	931
LEP	HCRT	O43612	930
LEP	IRS1	P35568	928
LEP	RETN	Q9HD89	925

IntAct

19 interactions, top by confidence:

A	B	Type	Score
LEPR	LEP	psi-mi:“MI:0407”(direct interaction)	0.700
LEP	LEPR	psi-mi:“MI:0914”(association)	0.700
LEPR	LEP	psi-mi:“MI:0915”(physical association)	0.700
LEP	LEPR	psi-mi:“MI:0915”(physical association)	0.700
ISLR2	LEP	psi-mi:“MI:0915”(physical association)	0.590
ISLR2	LEP	psi-mi:“MI:0407”(direct interaction)	0.590
ISLR2	LEP	psi-mi:“MI:0403”(colocalization)	0.590
HSF2BP	LEP	psi-mi:“MI:0915”(physical association)	0.560
LEP	Islr2	psi-mi:“MI:0407”(direct interaction)	0.540
Islr2	LEP	psi-mi:“MI:0915”(physical association)	0.540
LEP	SIGLEC6	psi-mi:“MI:0407”(direct interaction)	0.440
LEP	SIGLEC5	psi-mi:“MI:0407”(direct interaction)	0.440
LEP	CD33	psi-mi:“MI:0407”(direct interaction)	0.440
LEP	IL1RAPL2	psi-mi:“MI:0915”(physical association)	0.400
PSG9	LEP	psi-mi:“MI:0915”(physical association)	0.400
LEP	HSPA5	psi-mi:“MI:0914”(association)	0.350
LEP	HSF2BP	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (17): LEP (Reconstituted Complex), LEP (Two-hybrid), LEP (Reconstituted Complex), LEP (Affinity Capture-RNA), LEPR (Affinity Capture-MS), GLB1L (Affinity Capture-MS), COL6A1 (Affinity Capture-MS), NMU (Affinity Capture-MS), IDUA (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), TOR3A (Affinity Capture-MS), POMGNT2 (Affinity Capture-MS), S100P (Reconstituted Complex), S100A6 (Reconstituted Complex), LEP (Two-hybrid)

ESM2 similar proteins: A0A140LIA7, B6CKP4, O02720, O02750, O08987, O42164, P04141, P04401, P05113, P08700, P20109, P35225, P41159, P41160, P42203, P46652, P46685, P47966, P48093, P50595, P50596, P51492, P51748, P61126, Q0MUT8, Q1XG29, Q257X2, Q28504, Q28603, Q28809, Q29406, Q4KM46, Q588G0, Q5I6E4, Q5J732, Q62575, Q6EBC2, Q706D0, Q706D1, Q864V6

Diamond homologs: O02720, O02750, O42164, O93416, P41159, P41160, P50595, P50596, Q1XG29, Q257X2, Q28504, Q28603, Q29406, Q5J732, Q706D0, Q706D1, Q95189, Q95234, Q9N2C1, Q9TU09, Q9XSW9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
LEP	up-regulates	LEPR	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

121 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	2
Uncertain significance	63
Likely benign	33
Benign	8

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1074122	NM_000230.3(LEP):c.73C>T (p.Gln25Ter)	Pathogenic
13986	NM_000230.3(LEP):c.398del (p.Gly133fs)	Pathogenic
13987	NM_000230.3(LEP):c.313C>T (p.Arg105Trp)	Pathogenic
162430	NM_000230.3(LEP):c.298G>T (p.Asp100Tyr)	Pathogenic
2428497	NM_000230.3(LEP):c.175G>A (p.Gly59Ser)	Pathogenic
2428498	NM_000230.3(LEP):c.190C>T (p.Pro64Ser)	Pathogenic
2735087	NM_000230.3(LEP):c.309C>A (p.Asn103Lys)	Likely pathogenic
448905	NM_000230.3(LEP):c.461T>C (p.Leu154Pro)	Likely pathogenic

SpliceAI

324 predictions. Top by Δscore:

Variant	Effect	Δscore
7:128244472:A:G	acceptor_gain	1.0000
7:128254397:T:A	acceptor_gain	1.0000
7:128254400:A:AG	acceptor_gain	1.0000
7:128254401:T:G	acceptor_gain	1.0000
7:128254402:A:AG	acceptor_gain	1.0000
7:128254403:G:GG	acceptor_gain	1.0000
7:128254403:GCA:G	acceptor_gain	1.0000
7:128241304:AAGG:A	donor_loss	0.9900
7:128241305:AGGTA:A	donor_loss	0.9900
7:128241306:GGTA:G	donor_loss	0.9900
7:128241307:GTA:G	donor_loss	0.9900
7:128244471:A:AG	acceptor_gain	0.9900
7:128251989:A:AG	acceptor_gain	0.9900
7:128251990:G:GG	acceptor_gain	0.9900
7:128252159:CACGG:C	donor_loss	0.9900
7:128252163:G:GG	donor_gain	0.9900
7:128252164:T:TC	donor_loss	0.9900
7:128254399:CATA:C	acceptor_loss	0.9900
7:128254400:ATAG:A	acceptor_loss	0.9900
7:128254402:AGC:A	acceptor_loss	0.9900
7:128254403:G:GA	acceptor_loss	0.9900
7:128254403:GC:G	acceptor_gain	0.9900
7:128254403:GCAGT:G	acceptor_gain	0.9900
7:128241307:G:GG	donor_gain	0.9800
7:128241308:T:G	donor_loss	0.9800
7:128251985:TTTCA:T	acceptor_loss	0.9800
7:128251986:TTCA:T	acceptor_loss	0.9800
7:128251987:TCAG:T	acceptor_loss	0.9800
7:128251988:CAGGC:C	acceptor_loss	0.9800
7:128251989:AGGC:A	acceptor_loss	0.9800

AlphaMissense

1083 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:128254570:T:C	L104P	0.982
7:128254558:A:T	D100V	0.980
7:128254558:A:C	D100A	0.979
7:128254558:A:G	D100G	0.979
7:128254557:G:C	D100H	0.972
7:128254561:T:C	L101P	0.972
7:128254708:T:C	L150P	0.967
7:128254549:T:A	I97K	0.965
7:128254570:T:A	L104H	0.965
7:128254559:C:A	D100E	0.963
7:128254559:C:G	D100E	0.963
7:128252141:G:C	R41S	0.959
7:128252141:G:T	R41S	0.959
7:128254549:T:G	I97R	0.957
7:128254720:T:C	L154P	0.955
7:128254443:T:C	F62L	0.952
7:128254445:C:A	F62L	0.952
7:128254445:C:G	F62L	0.952
7:128252119:T:C	L34P	0.951
7:128254579:T:C	L107P	0.951
7:128254549:T:C	I97T	0.944
7:128254557:G:T	D100Y	0.944
7:128254570:T:G	L104R	0.943
7:128252140:G:T	R41M	0.938
7:128254573:G:C	R105P	0.935
7:128252119:T:A	L34H	0.934
7:128254503:T:G	Y82D	0.928
7:128254568:C:A	N103K	0.927
7:128254568:C:G	N103K	0.927
7:128254495:T:C	L79P	0.924

dbSNP variants (sampled 300 via entrez): RS1000056221 (7:128251110 T>G), RS1000169849 (7:128240556 G>C), RS1001147962 (7:128252952 C>A,G), RS1001433165 (7:128254310 G>A), RS1001545671 (7:128247855 G>C), RS1001617773 (7:128247707 A>T), RS1001816864 (7:128241598 A>G), RS1001826740 (7:128242962 G>T), RS1001992378 (7:128249634 T>C,G), RS1002027482 (7:128247413 C>T), RS1002732856 (7:128239388 G>C), RS1003015860 (7:128240121 A>T), RS1003432809 (7:128257042 A>C), RS1003523014 (7:128244083 T>C), RS1003544001 (7:128250702 A>G,T)

Disease associations

OMIM: gene MIM:164160 | disease phenotypes: MIM:614962

GenCC curated gene-disease

Disease	Classification	Inheritance
obesity due to congenital leptin deficiency	Definitive	Autosomal recessive

Mondo (2): obesity due to congenital leptin deficiency (MONDO:0013991), monogenic diabetes (MONDO:0015967)

Orphanet (2): Obesity due to congenital leptin deficiency (Orphanet:66628), Rare genetic diabetes mellitus (Orphanet:183625)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000054	Micropenis
HP:0000135	Hypogonadism
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000815	Hypergonadotropic hypogonadism
HP:0000831	Insulin-resistant diabetes mellitus
HP:0000842	Hyperinsulinemia
HP:0001513	Obesity
HP:0002155	Hypertriglyceridemia
HP:0002591	Polyphagia
HP:0002788	Recurrent upper respiratory tract infections
HP:0003292	Decreased serum leptin
HP:0004926	Orthostatic hypotension due to autonomic dysfunction
HP:0005419	Decreased T cell activation
HP:0005616	Accelerated skeletal maturation
HP:0006532	Recurrent pneumonia
HP:0008187	Absence of secondary sex characteristics
HP:0008214	Decreased serum estradiol
HP:0008245	Pituitary hypothyroidism
HP:0008724	Hypoplasia of the ovary
HP:0008734	Decreased testicular size
HP:0011463	Childhood onset
HP:0032218	Decreased CD4+ T cell proportion
HP:0040171	Decreased serum testosterone concentration
HP:0410018	Recurrent ear infections

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST002128_14	Type 2 diabetes	3.000000e-13
GCST003367_1	circulating leptin levels	9.000000e-06
GCST003367_9	circulating leptin levels	4.000000e-06
GCST003368_1	circulating leptin levels adjusted for BMI	2.000000e-12
GCST003368_8	circulating leptin levels adjusted for BMI	1.000000e-09
GCST003400_40	Type 2 diabetes	8.000000e-08
GCST006005_4	High density lipoprotein cholesterol levels	2.000000e-11
GCST009293_3	BMI at 8 months old	6.000000e-06
GCST009295_4	BMI at 1.5 years old	1.000000e-08
GCST010118_156	Type 2 diabetes	5.000000e-105
GCST010989_127	Body size at age 10	2.000000e-11
GCST012438_2	Interleukin-6 levels in non-alcoholic fatty liver disease x mastiha supplementation interaction	4.000000e-08
GCST90007307_6	circulating leptin levels	3.000000e-13
GCST90007307_7	circulating leptin levels	1.000000e-10
GCST90007308_3	circulating leptin levels	3.000000e-06
GCST90007309_4	circulating leptin levels	3.000000e-12
GCST90007309_5	circulating leptin levels	2.000000e-06
GCST90007310_6	circulating leptin levels	1.000000e-09
GCST90007312_4	circulating leptin levels	8.000000e-09
GCST90007313_4	circulating leptin levels	7.000000e-10
GCST90007315_2	circulating leptin levels	2.000000e-08
GCST90007316_3	circulating leptin levels	6.000000e-08
GCST90007318_1	circulating leptin levels	2.000000e-06
GCST90007319_6	circulating leptin levels adjusted for BMI	1.000000e-23
GCST90007319_7	circulating leptin levels adjusted for BMI	2.000000e-16
GCST90007320_4	circulating leptin levels adjusted for BMI	7.000000e-08
GCST90007320_5	circulating leptin levels adjusted for BMI	1.000000e-09
GCST90007321_3	circulating leptin levels adjusted for BMI	4.000000e-20
GCST90007321_4	circulating leptin levels adjusted for BMI	6.000000e-09
GCST90007322_4	circulating leptin levels adjusted for BMI	5.000000e-19

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0005000	leptin measurement
EFO:0007793	BMI-adjusted leptin measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004340	body mass index
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004810	interleukin-6 measurement
EFO:0600067	mastiha supplement exposure measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4731426	Toxicity	3	olanzapine	Schizophrenia
rs7799039	Toxicity	3	antipsychotics;risperidone	Autism Spectrum Disorder;Mood Disorder

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2071045	LEP		0.00	0
rs2167270	LEP		0.00	0
rs4731426	LEP	3	2.50	1	olanzapine
rs7799039	LEP	3	6.00	1	antipsychotics;risperidone
rs10244329	LEP		0.00	0
rs12706832	LEP		0.00	0

CTD chemical–gene interactions

149 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases activity, decreases reaction, decreases expression, increases reaction (+2 more)	8
Rosiglitazone	increases secretion, affects cotreatment, decreases reaction, increases expression, decreases expression	8
Dexamethasone	increases secretion, increases reaction, affects cotreatment, increases expression, decreases reaction (+1 more)	8
1-Methyl-3-isobutylxanthine	increases expression, decreases reaction, increases reaction, affects cotreatment	5
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases activity, decreases expression, decreases response to substance, decreases reaction, increases expression (+1 more)	4
sodium arsenite	decreases expression, increases abundance, increases expression	3
Troglitazone	affects cotreatment, decreases secretion, decreases reaction, increases expression, increases secretion (+1 more)	3
Arsenic	affects expression, increases abundance, increases expression	3
monobutyl phthalate	increases abundance, increases secretion, decreases secretion	2
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide	decreases reaction, increases chemical synthesis, increases expression, decreases response to substance	2
perfluorooctane sulfonic acid	affects expression, increases expression	2
candesartan	decreases expression, increases expression, increases reaction	2
SB 203580	decreases reaction, increases expression, decreases response to substance	2
alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide	decreases reaction, increases expression, affects cotreatment, decreases activity, decreases expression	2
mono-isobutyl phthalate	decreases secretion, increases abundance, increases secretion	2
Olanzapine	increases expression	2
Resveratrol	decreases expression	2
Hydrogen Peroxide	affects expression, decreases expression	2
Indomethacin	affects cotreatment, increases expression, decreases reaction	2
Oxygen	increases expression, increases secretion	2
Progesterone	decreases reaction, increases chemical synthesis, affects reaction, decreases secretion	2
Zinc	affects reaction, decreases expression, decreases abundance	2
Ramipril	decreases expression, increases expression, increases reaction	2
Amlodipine	decreases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
1,2-linoleoylphosphatidylcholine	increases expression, decreases reaction	1
propylparaben	decreases expression	1
diphenyleneiodonium	decreases expression, decreases reaction	1
sodium arsenate	increases abundance, increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1XA	Abcam A-549 LEP KO	Cancer cell line	Male
CVCL_D2BJ	Abcam HCT 116 LEP KO	Cancer cell line	Male

Clinical trials (associated diseases)

10 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT06976658	PHASE2	RECRUITING	Glucokinase Activator in Monogenic Diabetes
NCT01795144	PHASE1	COMPLETED	Incretin Regulation of Insulin Secretion in Monogenic Diabetes
NCT04063488	Not specified	COMPLETED	The Effects of Metreleptin in Congenital Leptin Deficiency
NCT04409795	PHASE2/PHASE3	COMPLETED	Oral Hypoglycemic Therapy for Monogenic Variant Carriers of the Joslin Medalist Study
NCT03988764	Not specified	RECRUITING	Monogenic Diabetes Misdiagnosed as Type 1
NCT05586594	Not specified	NOT_YET_RECRUITING	Identifying Maturity-onset Diabetes of the Young in Emirati Patients
NCT06478121	Not specified	RECRUITING	Understanding Beta Cell Disorders Through the Study of Rare Genotypes (ENDURE)
NCT06746610	Not specified	RECRUITING	Screening and Molecular Diagnosis-based Individualized Precision Management of Monogenic Diabetes
NCT07492004	Not specified	RECRUITING	China Monogenic Diabetes Registry
NCT07564518	Not specified	NOT_YET_RECRUITING	Application of FreeStyle Libre 2 for Evaluating Glycemic Variability Characteristics in Patients With Extreme Glucose Metabolism Phenotypes