LEP_RAT
ID LEP_RAT Reviewed; 167 AA.
AC P50596;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=Leptin;
DE AltName: Full=Obesity factor;
DE Flags: Precursor;
GN Name=Lep; Synonyms=Ob;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Testis;
RX PubMed=7657834; DOI=10.1172/jci118204;
RA Ogawa Y., Masuzaki H., Isse N., Okazaki T., Mori K., Shigemoto M.,
RA Satoh N., Tamura N., Hosoda K., Yoshimasa Y., Jingami H., Kawada T.,
RA Nakao K.;
RT "Molecular cloning of rat obese cDNA and augmented gene expression in
RT genetically obese Zucker fatty (fa/fa) rats.";
RL J. Clin. Invest. 96:1647-1652(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Adipose tissue;
RX PubMed=7794258; DOI=10.1006/bbrc.1995.1837;
RA Funahashi T., Shimomura I., Hiraoka H., Arai T., Takahashi M., Nakamura T.,
RA Nozaki S., Yamashita S., Takemura K., Tokunaga K.;
RT "Enhanced expression of rat obese (ob) gene in adipose tissues of
RT ventromedial hypothalamus (VMH)-lesioned rats.";
RL Biochem. Biophys. Res. Commun. 211:469-475(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=OLETF, and Zucker; TISSUE=Adipose tissue;
RX PubMed=7733988; DOI=10.1006/bbrc.1995.1589;
RA Murakami T., Shima K.;
RT "Cloning of rat obese cDNA and its expression in obese rats.";
RL Biochem. Biophys. Res. Commun. 209:944-952(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 14-167.
RC STRAIN=Sprague-Dawley; TISSUE=Adipose tissue;
RA Donohoue P.A., Sivitz W.I., Bailey H.L.;
RL Submitted (FEB-1996) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP FUNCTION.
RX PubMed=9003024; DOI=10.1210/endo.138.2.5033;
RA Elmquist J.K., Ahima R.S., Maratos-Flier E., Flier J.S., Saper C.B.;
RT "Leptin activates neurons in ventrobasal hypothalamus and brainstem.";
RL Endocrinology 138:839-842(1997).
RN [6]
RP FUNCTION.
RX PubMed=10482243; DOI=10.1016/s0896-6273(01)80035-0;
RA Elias C.F., Aschkenasi C., Lee C., Kelly J., Ahima R.S., Bjorbaek C.,
RA Flier J.S., Saper C.B., Elmquist J.K.;
RT "Leptin differentially regulates NPY and POMC neurons projecting to the
RT lateral hypothalamic area.";
RL Neuron 23:775-786(1999).
RN [7]
RP FUNCTION.
RX PubMed=11460888; DOI=10.1038/emm.2001.17;
RA Park H.Y., Kwon H.M., Lim H.J., Hong B.K., Lee J.Y., Park B.E., Jang Y.,
RA Cho S.Y., Kim H.S.;
RT "Potential role of leptin in angiogenesis: leptin induces endothelial cell
RT proliferation and expression of matrix metalloproteinases in vivo and in
RT vitro.";
RL Exp. Mol. Med. 33:95-102(2001).
RN [8]
RP FUNCTION.
RX PubMed=11677594; DOI=10.1038/35101657;
RA Niswender K.D., Morton G.J., Stearns W.H., Rhodes C.J., Myers M.G. Jr.,
RA Schwartz M.W.;
RT "Intracellular signaling. Key enzyme in leptin-induced anorexia.";
RL Nature 413:794-795(2001).
RN [9]
RP REVIEW OF FUNCTION IN IMMUNITY.
RX PubMed=15122202; DOI=10.1038/nri1350;
RA La Cava A., Matarese G.;
RT "The weight of leptin in immunity.";
RL Nat. Rev. Immunol. 4:371-379(2004).
RN [10]
RP REVIEW OF FUNCTION.
RX PubMed=25232147; DOI=10.1530/joe-14-0404;
RA Allison M.B., Myers M.G. Jr.;
RT "20 years of leptin: connecting leptin signaling to biological function.";
RL J. Endocrinol. 223:T25-T35(2014).
CC -!- FUNCTION: Key player in the regulation of energy balance and body
CC weight control. Once released into the circulation, has central and
CC peripheral effects by binding LEPR, found in many tissues, which
CC results in the activation of several major signaling pathways (By
CC similarity) (PubMed:11677594). In the hypothalamus, acts as an
CC appetite-regulating factor that induces a decrease in food intake and
CC an increase in energy consumption by inducing anorexinogenic factors
CC and suppressing orexigenic neuropeptides, also regulates bone mass and
CC secretion of hypothalamo-pituitary-adrenal hormones. In the periphery,
CC increases basal metabolism, influences reproductive function, regulates
CC pancreatic beta-cell function and insulin secretion, is pro-angiogenic
CC for endothelial cell and affects innate and adaptive immunity (By
CC similarity) (PubMed:11460888, PubMed:10482243, PubMed:9003024,
CC PubMed:11677594). In the arcuate nucleus of the hypothalamus, activates
CC by depolarization POMC neurons inducing FOS and SOCS3 expression to
CC release anorexigenic peptides and inhibits by hyperpolarization NPY
CC neurons inducing SOCS3 with a consequent reduction on release of
CC orexigenic peptides (By similarity) (PubMed:10482243, PubMed:9003024).
CC In addition to its known satiety inducing effect, has a modulatory role
CC in nutrient absorption. In the intestine, reduces glucose absorption by
CC enterocytes by activating PKC and leading to a sequential activation of
CC p38, PI3K and ERK signaling pathways which exerts an inhibitory effect
CC on glucose absorption (By similarity). Acts as a growth factor on
CC certain tissues, through the activation of different signaling pathways
CC increases expression of genes involved in cell cycle regulation such as
CC CCND1, via JAK2-STAT3 pathway, or VEGFA, via MAPK1/3 and PI3K-AKT1
CC pathways (By similarity). May also play an apoptotic role via JAK2-
CC STAT3 pathway and up-regulation of BIRC5 expression (By similarity).
CC Pro-angiogenic, has mitogenic activity on vascular endothelial cells
CC and plays a role in matrix remodeling by regulating the expression of
CC matrix metalloproteinases (MMPs) and tissue inhibitors of
CC metalloproteinases (TIMPs) (PubMed:11460888). In innate immunity,
CC modulates the activity and function of neutrophils by increasing
CC chemotaxis and the secretion of oxygen radicals. Increases phagocytosis
CC by macrophages and enhances secretion of pro-inflammatory mediators.
CC Increases cytotoxic ability of NK cells (Probable). Plays a pro-
CC inflammatory role, in synergy with IL1B, by inducing NOS2 wich promotes
CC the production of IL6, IL8 and Prostaglandin E2, through a signaling
CC pathway that involves JAK2, PI3K, MAP2K1/MEK1 and MAPK14/p38 (By
CC similarity). In adaptive immunity, promotes the switch of memory T-
CC cells towards T helper-1 cell immune responses (By similarity).
CC Increases CD4(+)CD25(-) T-cell proliferation and reduces autophagy
CC during TCR (T-cell receptor) stimulation, through MTOR signaling
CC pathway activation and BCL2 up-regulation (By similarity).
CC {ECO:0000250|UniProtKB:P41159, ECO:0000250|UniProtKB:P41160,
CC ECO:0000269|PubMed:10482243, ECO:0000269|PubMed:11460888,
CC ECO:0000269|PubMed:11677594, ECO:0000269|PubMed:9003024,
CC ECO:0000305|PubMed:15122202, ECO:0000305|PubMed:25232147}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305|PubMed:25232147}.
CC -!- SIMILARITY: Belongs to the leptin family. {ECO:0000305}.
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DR EMBL; D45862; BAA08296.1; -; mRNA.
DR EMBL; S78586; AAB34657.2; -; mRNA.
DR EMBL; D49653; BAA08529.1; -; mRNA.
DR EMBL; U48849; AAC52514.1; -; mRNA.
DR PIR; PC4034; LTRT.
DR RefSeq; NP_037208.1; NM_013076.3.
DR RefSeq; XP_008760984.1; XM_008762762.2.
DR AlphaFoldDB; P50596; -.
DR SMR; P50596; -.
DR BioGRID; 247637; 5.
DR STRING; 10116.ENSRNOP00000066184; -.
DR PhosphoSitePlus; P50596; -.
DR PaxDb; P50596; -.
DR PRIDE; P50596; -.
DR Ensembl; ENSRNOT00000071926; ENSRNOP00000066184; ENSRNOG00000045797.
DR GeneID; 25608; -.
DR KEGG; rno:25608; -.
DR UCSC; RGD:3000; rat.
DR CTD; 3952; -.
DR RGD; 3000; Lep.
DR eggNOG; ENOG502S5K5; Eukaryota.
DR GeneTree; ENSGT00390000011772; -.
DR HOGENOM; CLU_132715_0_0_1; -.
DR InParanoid; P50596; -.
DR OMA; MRCGPLC; -.
DR OrthoDB; 1350528at2759; -.
DR PhylomeDB; P50596; -.
DR TreeFam; TF105086; -.
DR Reactome; R-RNO-381771; Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1).
DR Reactome; R-RNO-422085; Synthesis, secretion, and deacylation of Ghrelin.
DR PRO; PR:P50596; -.
DR Proteomes; UP000002494; Chromosome 4.
DR Bgee; ENSRNOG00000045797; Expressed in pancreas and 10 other tissues.
DR Genevisible; P50596; RN.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0005829; C:cytosol; IDA:ARUK-UCL.
DR GO; GO:0005615; C:extracellular space; IDA:HGNC-UCL.
DR GO; GO:0005125; F:cytokine activity; TAS:RGD.
DR GO; GO:0003677; F:DNA binding; ISO:RGD.
DR GO; GO:0008083; F:growth factor activity; ISO:RGD.
DR GO; GO:0005179; F:hormone activity; IDA:RGD.
DR GO; GO:1990460; F:leptin receptor binding; ISO:RGD.
DR GO; GO:0051428; F:peptide hormone receptor binding; IDA:RGD.
DR GO; GO:0005102; F:signaling receptor binding; IPI:RGD.
DR GO; GO:1990051; P:activation of protein kinase C activity; ISS:UniProtKB.
DR GO; GO:0060612; P:adipose tissue development; ISO:RGD.
DR GO; GO:0008343; P:adult feeding behavior; ISS:HGNC-UCL.
DR GO; GO:0001525; P:angiogenesis; ISO:RGD.
DR GO; GO:0035904; P:aorta development; ISO:RGD.
DR GO; GO:0008206; P:bile acid metabolic process; ISO:RGD.
DR GO; GO:0098868; P:bone growth; ISS:UniProtKB.
DR GO; GO:0035630; P:bone mineralization involved in bone maturation; IDA:RGD.
DR GO; GO:0019933; P:cAMP-mediated signaling; TAS:RGD.
DR GO; GO:0003300; P:cardiac muscle hypertrophy; IDA:RGD.
DR GO; GO:0032869; P:cellular response to insulin stimulus; ISO:RGD.
DR GO; GO:0071298; P:cellular response to L-ascorbic acid; IEP:RGD.
DR GO; GO:0044320; P:cellular response to leptin stimulus; ISO:RGD.
DR GO; GO:0071300; P:cellular response to retinoic acid; IEP:RGD.
DR GO; GO:0021954; P:central nervous system neuron development; ISO:RGD.
DR GO; GO:0008203; P:cholesterol metabolic process; ISO:RGD.
DR GO; GO:0007623; P:circadian rhythm; IEP:RGD.
DR GO; GO:0008340; P:determination of adult lifespan; ISO:RGD.
DR GO; GO:0042755; P:eating behavior; ISO:RGD.
DR GO; GO:0051541; P:elastin metabolic process; ISO:RGD.
DR GO; GO:0006112; P:energy reserve metabolic process; IDA:RGD.
DR GO; GO:0006635; P:fatty acid beta-oxidation; ISO:RGD.
DR GO; GO:0009062; P:fatty acid catabolic process; IDA:RGD.
DR GO; GO:0007565; P:female pregnancy; IEP:RGD.
DR GO; GO:0042593; P:glucose homeostasis; ISO:RGD.
DR GO; GO:0006006; P:glucose metabolic process; ISO:RGD.
DR GO; GO:0006114; P:glycerol biosynthetic process; IDA:RGD.
DR GO; GO:0042445; P:hormone metabolic process; ISO:RGD.
DR GO; GO:0030073; P:insulin secretion; ISO:RGD.
DR GO; GO:0050892; P:intestinal absorption; ISS:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IDA:RGD.
DR GO; GO:0033210; P:leptin-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0050901; P:leukocyte tethering or rolling; IDA:RGD.
DR GO; GO:0006629; P:lipid metabolic process; IEP:RGD.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:RGD.
DR GO; GO:0032099; P:negative regulation of appetite; ISS:HGNC-UCL.
DR GO; GO:0038108; P:negative regulation of appetite by leptin-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0010507; P:negative regulation of autophagy; ISS:UniProtKB.
DR GO; GO:0061037; P:negative regulation of cartilage development; IDA:RGD.
DR GO; GO:0070093; P:negative regulation of glucagon secretion; ISO:RGD.
DR GO; GO:0046325; P:negative regulation of glucose import; ISS:UniProtKB.
DR GO; GO:2000486; P:negative regulation of glutamine transport; IMP:RGD.
DR GO; GO:0010888; P:negative regulation of lipid storage; IDA:RGD.
DR GO; GO:0009892; P:negative regulation of metabolic process; IDA:RGD.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0045906; P:negative regulation of vasoconstriction; IDA:RGD.
DR GO; GO:0001542; P:ovulation from ovarian follicle; IDA:RGD.
DR GO; GO:0006909; P:phagocytosis; IDA:UniProtKB.
DR GO; GO:0001890; P:placenta development; ISO:RGD.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:RGD.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0001819; P:positive regulation of cytokine production; IEP:RGD.
DR GO; GO:0048639; P:positive regulation of developmental growth; ISO:RGD.
DR GO; GO:1904651; P:positive regulation of fat cell apoptotic process; IDA:RGD.
DR GO; GO:0046881; P:positive regulation of follicle-stimulating hormone secretion; IEP:RGD.
DR GO; GO:2000491; P:positive regulation of hepatic stellate cell activation; IDA:RGD.
DR GO; GO:0046628; P:positive regulation of insulin receptor signaling pathway; IDA:RGD.
DR GO; GO:0032735; P:positive regulation of interleukin-12 production; ISS:UniProtKB.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISS:UniProtKB.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; ISS:UniProtKB.
DR GO; GO:0043270; P:positive regulation of ion transport; IDA:RGD.
DR GO; GO:0033686; P:positive regulation of luteinizing hormone secretion; IEP:RGD.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:RGD.
DR GO; GO:0045639; P:positive regulation of myeloid cell differentiation; ISO:RGD.
DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; ISS:UniProtKB.
DR GO; GO:0035360; P:positive regulation of peroxisome proliferator activated receptor signaling pathway; IDA:RGD.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IDA:UniProtKB.
DR GO; GO:0042307; P:positive regulation of protein import into nucleus; ISO:RGD.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; ISS:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:RGD.
DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IDA:RGD.
DR GO; GO:0046427; P:positive regulation of receptor signaling pathway via JAK-STAT; IMP:RGD.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; ISS:UniProtKB.
DR GO; GO:0032008; P:positive regulation of TOR signaling; ISS:UniProtKB.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:UniProtKB.
DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; IMP:RGD.
DR GO; GO:0032310; P:prostaglandin secretion; ISS:UniProtKB.
DR GO; GO:0007259; P:receptor signaling pathway via JAK-STAT; TAS:RGD.
DR GO; GO:0045765; P:regulation of angiogenesis; ISS:UniProtKB.
DR GO; GO:0008217; P:regulation of blood pressure; IDA:RGD.
DR GO; GO:0046850; P:regulation of bone remodeling; ISS:UniProtKB.
DR GO; GO:0090335; P:regulation of brown fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0050790; P:regulation of catalytic activity; ISO:RGD.
DR GO; GO:0051726; P:regulation of cell cycle; ISS:UniProtKB.
DR GO; GO:1900015; P:regulation of cytokine production involved in inflammatory response; ISS:UniProtKB.
DR GO; GO:0001936; P:regulation of endothelial cell proliferation; ISS:UniProtKB.
DR GO; GO:0045598; P:regulation of fat cell differentiation; ISO:RGD.
DR GO; GO:0006111; P:regulation of gluconeogenesis; ISO:RGD.
DR GO; GO:0050796; P:regulation of insulin secretion; ISO:RGD.
DR GO; GO:0030300; P:regulation of intestinal cholesterol absorption; ISO:RGD.
DR GO; GO:0046890; P:regulation of lipid biosynthetic process; ISO:RGD.
DR GO; GO:0060587; P:regulation of lipoprotein lipid oxidation; IDA:RGD.
DR GO; GO:0019222; P:regulation of metabolic process; ISO:RGD.
DR GO; GO:0032814; P:regulation of natural killer cell activation; ISS:UniProtKB.
DR GO; GO:0042269; P:regulation of natural killer cell mediated cytotoxicity; ISS:UniProtKB.
DR GO; GO:0032817; P:regulation of natural killer cell proliferation; ISS:UniProtKB.
DR GO; GO:0050999; P:regulation of nitric-oxide synthase activity; ISS:UniProtKB.
DR GO; GO:1900180; P:regulation of protein localization to nucleus; ISO:RGD.
DR GO; GO:0001932; P:regulation of protein phosphorylation; ISO:RGD.
DR GO; GO:0050810; P:regulation of steroid biosynthetic process; ISO:RGD.
DR GO; GO:0014823; P:response to activity; IEP:RGD.
DR GO; GO:0002021; P:response to dietary excess; IMP:RGD.
DR GO; GO:0032355; P:response to estradiol; IEP:RGD.
DR GO; GO:0045471; P:response to ethanol; IEP:RGD.
DR GO; GO:0001666; P:response to hypoxia; IEP:RGD.
DR GO; GO:0032868; P:response to insulin; ISO:RGD.
DR GO; GO:0007584; P:response to nutrient; IEP:RGD.
DR GO; GO:0031667; P:response to nutrient levels; IEP:RGD.
DR GO; GO:0033197; P:response to vitamin E; IEP:RGD.
DR GO; GO:0019953; P:sexual reproduction; ISO:RGD.
DR GO; GO:0030217; P:T cell differentiation; ISS:UniProtKB.
DR GO; GO:0007260; P:tyrosine phosphorylation of STAT protein; ISO:RGD.
DR Gene3D; 1.20.1250.10; -; 1.
DR InterPro; IPR009079; 4_helix_cytokine-like_core.
DR InterPro; IPR000065; Leptin.
DR PANTHER; PTHR11724; PTHR11724; 1.
DR Pfam; PF02024; Leptin; 1.
DR PIRSF; PIRSF001837; Leptin; 1.
DR PRINTS; PR00495; LEPTIN.
DR SUPFAM; SSF47266; SSF47266; 1.
PE 1: Evidence at protein level;
KW Disulfide bond; Obesity; Reference proteome; Secreted; Signal.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..167
FT /note="Leptin"
FT /id="PRO_0000017690"
FT DISULFID 117..167
FT /evidence="ECO:0000250"
FT CONFLICT 32
FT /note="K -> T (in Ref. 2)"
FT /evidence="ECO:0000305"
FT CONFLICT 163
FT /note="L -> V (in Ref. 4; AAC52514)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 167 AA; 18866 MW; 3B5B563DA42EC84E CRC64;
MCWRPLCRFL WLWSYLSYVQ AVPIHKVQDD TKTLIKTIVT RINDISHTQS VSARQRVTGL
DFIPGLHPIL SLSKMDQTLA VYQQILTSLP SQNVLQIAHD LENLRDLLHL LAFSKSCSLP
QTRGLQKPES LDGVLEASLY STEVVALSRL QGSLQDILQQ LDLSPEC
