LEP (leptin)

Gene

• Entrez ID: 3952
• Gene name: Leptin
• Gene symbol: LEP
• Synonyms: LEPD, OB, OBS
• Chromosome: 7
• Chromosome location: 7q32.1
• Summary: 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. [provided by RefSeq, Aug 2017]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs104894023	C>T	Pathogenic	Missense variant, coding sequence variant
rs201523305	C>T	Uncertain-significance, conflicting-interpretations-of-pathogenicity	Synonymous variant, coding sequence variant
rs724159998	G>A,T	Pathogenic	Coding sequence variant, missense variant
rs1554394014	T>C	Likely-pathogenic	Coding sequence variant, missense variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT784155	hsa-miR-208a-3p	HITS-CLIP	27418678
MIRT784162	hsa-miR-208b-3p	HITS-CLIP	27418678
MIRT785041	hsa-miR-3658	HITS-CLIP	27418678
MIRT786921	hsa-miR-499a-5p	HITS-CLIP	27418678
MIRT789609	hsa-miR-7856-5p	HITS-CLIP	27418678

Transcription factors

Transcription factor	Regulation	Reference
CEBPA	Activation	21983012
HIF1A	Activation	18559540
HIF1A	Unknown	19080496
KHDRBS1	Activation	21672929
SP1	Activation	18559540
STAT3	Activation	18242580;19492417

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	IEA
GO:0001525	Process	Angiogenesis	IDA	19910644, 21771332
GO:0001542	Process	Ovulation from ovarian follicle	IEA
GO:0001666	Process	Response to hypoxia	IEA
GO:0001890	Process	Placenta development	IDA	17957153
GO:0001934	Process	Positive regulation of protein phosphorylation	IDA	27037668
GO:0001936	Process	Regulation of endothelial cell proliferation	IDA	11460888
GO:0002021	Process	Response to dietary excess	IEA
GO:0003300	Process	Cardiac muscle hypertrophy	IEA
GO:0003677	Function	DNA binding	IEA
GO:0005179	Function	Hormone activity	IBA	21873635
GO:0005515	Function	Protein binding	IPI	32296183
GO:0005576	Component	Extracellular region	TAS
GO:0005615	Component	Extracellular space	IBA	21873635
GO:0005615	Component	Extracellular space	ISS
GO:0005829	Component	Cytosol	ISS
GO:0006006	Process	Glucose metabolic process	IEA
GO:0006111	Process	Regulation of gluconeogenesis	IEA
GO:0006112	Process	Energy reserve metabolic process	IBA	21873635
GO:0006114	Process	Glycerol biosynthetic process	IEA
GO:0006629	Process	Lipid metabolic process	IBA	21873635
GO:0006635	Process	Fatty acid beta-oxidation	IEA
GO:0006909	Process	Phagocytosis	IEA
GO:0007260	Process	Tyrosine phosphorylation of STAT protein	IBA	21873635
GO:0007565	Process	Female pregnancy	IEA
GO:0007623	Process	Circadian rhythm	IEA
GO:0008203	Process	Cholesterol metabolic process	IEA
GO:0008206	Process	Bile acid metabolic process	IEA
GO:0008217	Process	Regulation of blood pressure	IEA
GO:0008340	Process	Determination of adult lifespan	IEA
GO:0008343	Process	Adult feeding behavior	ISS
GO:0010507	Process	Negative regulation of autophagy	IDA	25060689
GO:0010888	Process	Negative regulation of lipid storage	IEA
GO:0014068	Process	Positive regulation of phosphatidylinositol 3-kinase signaling	IBA	21873635
GO:0014068	Process	Positive regulation of phosphatidylinositol 3-kinase signaling	IDA	24340098
GO:0014068	Process	Positive regulation of phosphatidylinositol 3-kinase signaling	ISS
GO:0014823	Process	Response to activity	IEA
GO:0019953	Process	Sexual reproduction	IMP	8589726
GO:0021954	Process	Central nervous system neuron development	IEA
GO:0030073	Process	Insulin secretion	IEA
GO:0030217	Process	T cell differentiation	ISS
GO:0030300	Process	Regulation of intestinal cholesterol absorption	IEA
GO:0032008	Process	Positive regulation of TOR signaling	IBA	21873635
GO:0032008	Process	Positive regulation of TOR signaling	IDA	25060689
GO:0032099	Process	Negative regulation of appetite	ISS
GO:0032310	Process	Prostaglandin secretion	IDA	19688109
GO:0032355	Process	Response to estradiol	IEA
GO:0032635	Process	Interleukin-6 production	IDA	19688109
GO:0032637	Process	Interleukin-8 production	IDA	19688109
GO:0032760	Process	Positive regulation of tumor necrosis factor production	IEA
GO:0032814	Process	Regulation of natural killer cell activation	IDA	12504075
GO:0032817	Process	Regulation of natural killer cell proliferation	IDA	12504075
GO:0032868	Process	Response to insulin	IBA	21873635
GO:0032869	Process	Cellular response to insulin stimulus	IEA
GO:0033197	Process	Response to vitamin E	IEA
GO:0033210	Process	Leptin-mediated signaling pathway	ISS
GO:0033686	Process	Positive regulation of luteinizing hormone secretion	IEA
GO:0035360	Process	Positive regulation of peroxisome proliferator activated receptor signaling pathway	IEA
GO:0035556	Process	Intracellular signal transduction	IEA
GO:0035630	Process	Bone mineralization involved in bone maturation	IEA
GO:0035904	Process	Aorta development	IEA
GO:0038108	Process	Negative regulation of appetite by leptin-mediated signaling pathway	IBA	21873635
GO:0038108	Process	Negative regulation of appetite by leptin-mediated signaling pathway	ISS
GO:0042102	Process	Positive regulation of T cell proliferation	IDA	25060689
GO:0042269	Process	Regulation of natural killer cell mediated cytotoxicity	IDA	12504075
GO:0042307	Process	Positive regulation of protein import into nucleus	IEA
GO:0042445	Process	Hormone metabolic process	IEA
GO:0042531	Process	Positive regulation of tyrosine phosphorylation of STAT protein	IEA
GO:0042593	Process	Glucose homeostasis	IEA
GO:0042755	Process	Eating behavior	IEA
GO:0043066	Process	Negative regulation of apoptotic process	IEA
GO:0043410	Process	Positive regulation of MAPK cascade	IDA	24340098
GO:0043410	Process	Positive regulation of MAPK cascade	ISS
GO:0044320	Process	Cellular response to leptin stimulus	IDA	17344214
GO:0045471	Process	Response to ethanol	IEA
GO:0045765	Process	Regulation of angiogenesis	IDA	11460888
GO:0045906	Process	Negative regulation of vasoconstriction	IEA
GO:0046325	Process	Negative regulation of glucose import	IDA	24340098
GO:0046427	Process	Positive regulation of receptor signaling pathway via JAK-STAT	IBA	21873635
GO:0046427	Process	Positive regulation of receptor signaling pathway via JAK-STAT	IDA	17344214
GO:0046628	Process	Positive regulation of insulin receptor signaling pathway	IEA
GO:0046850	Process	Regulation of bone remodeling	ISS
GO:0046881	Process	Positive regulation of follicle-stimulating hormone secretion	IEA
GO:0048639	Process	Positive regulation of developmental growth	IDA	17957153
GO:0050796	Process	Regulation of insulin secretion	IEA
GO:0050810	Process	Regulation of steroid biosynthetic process	IEA
GO:0050892	Process	Intestinal absorption	IDA	24340098
GO:0050901	Process	Leukocyte tethering or rolling	IEA
GO:0050999	Process	Regulation of nitric-oxide synthase activity	IDA	15899045
GO:0051428	Function	Peptide hormone receptor binding	IBA	21873635
GO:0051541	Process	Elastin metabolic process	IEA
GO:0051726	Process	Regulation of cell cycle	IDA	17344214
GO:0051897	Process	Positive regulation of protein kinase B signaling	ISS
GO:0060587	Process	Regulation of lipoprotein lipid oxidation	IEA
GO:0060612	Process	Adipose tissue development	IEA
GO:0061037	Process	Negative regulation of cartilage development	IEA
GO:0070093	Process	Negative regulation of glucagon secretion	IEA
GO:0071298	Process	Cellular response to L-ascorbic acid	IEA
GO:0071300	Process	Cellular response to retinoic acid	IEA
GO:0090335	Process	Regulation of brown fat cell differentiation	ISS
GO:0098868	Process	Bone growth	ISS
GO:0120162	Process	Positive regulation of cold-induced thermogenesis	ISS	27986616
GO:1900015	Process	Regulation of cytokine production involved in inflammatory response	IDA	19688109
GO:1900745	Process	Positive regulation of p38MAPK cascade	IBA	21873635
GO:1900745	Process	Positive regulation of p38MAPK cascade	IDA	24340098
GO:1904651	Process	Positive regulation of fat cell apoptotic process	IEA
GO:1990051	Process	Activation of protein kinase C activity	IBA	21873635
GO:1990051	Process	Activation of protein kinase C activity	IDA	24340098
GO:1990460	Function	Leptin receptor binding	IDA	27037668
GO:2000379	Process	Positive regulation of reactive oxygen species metabolic process	IEA
GO:2000486	Process	Negative regulation of glutamine transport	IEA
GO:2000491	Process	Positive regulation of hepatic stellate cell activation	IEA

Other IDs

• MIM: 164160
• HGNC: 6553
• e!Ensembl: ENSG00000174697

Protein

• UniProt ID: P41159
• Protein name: Leptin (Obese protein) (Obesity factor)
• Protein 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 (PubMed:17344214, PubMed:15899045, PubMed:19688109). 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 (By similarity) (PubMed:8589726, PubMed:11460888, PubMed:19688109, PubMed:24340098, PubMed:25060689). 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 (By similarity). 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 (PubMed:24340098). 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 (By similarity) (PubMed:17344214). May also play an apoptotic role via JAK2-STAT3 pathway and up-regulation of BIRC5 expression (PubMed:18242580). 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) (PubMed:11460888). 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 (PubMed:12504075). Plays a pro-inflammatory role, in synergy with IL1B, by inducing NOS2 wich promotes the production of IL6, IL8 and Prostaglandin E2, through a signaling pathway that involves JAK2, PI3K, MAP2K1/MEK1 and MAPK14/p38 (PubMed:15899045, PubMed:19688109). In adaptive immunity, promotes the switch of memory T-cells towards T helper-1 cell immune responses (By similarity). Increases CD4(+)CD25(-) T-cell proliferation and reduces autophagy during TCR (T-cell receptor) stimulation, through MTOR signaling pathway activation and BCL2 up-regulation (PubMed:25060689).
• PDB: 1AX8
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF02024	Leptin	23 → 167	Leptin	Domain

• Sequence:

  MHWGTLCGFLWLWPYLFYVQAVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGL
  DFIPGLHPILTLSKMDQTLAVYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLP
  WASGLETLDSLGGVLEASGYSTEVVALSRLQGSLQDMLWQLDLSPGC

• Sequence length: 167