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   02-SEP-2026, entry version 176.
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:10482243, PubMed:11460888, PubMed:11677594,
CC       PubMed:9003024). 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 which
CC       promotes the production of IL6, IL8 and Prostaglandin E2, through a
CC       signaling pathway that involves JAK2, PI3K, MAP2K1/MEK1 and MAPK14/p38
CC       (By 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   AlphaFoldDB; P50596; -.
DR   SMR; P50596; -.
DR   BioGRID; 247637; 5.
DR   FunCoup; P50596; 11.
DR   STRING; 10116.ENSRNOP00000066184; -.
DR   PhosphoSitePlus; P50596; -.
DR   PaxDb; 10116-ENSRNOP00000066184; -.
DR   Ensembl; ENSRNOT00000071926.3; ENSRNOP00000066184.1; ENSRNOG00000045797.3.
DR   Ensembl; ENSRNOT00055036716; ENSRNOP00055029816; ENSRNOG00055021484.
DR   Ensembl; ENSRNOT00060048713; ENSRNOP00060040626; ENSRNOG00060028054.
DR   Ensembl; ENSRNOT00065043064; ENSRNOP00065035263; ENSRNOG00065025045.
DR   GeneID; 25608; -.
DR   KEGG; rno:25608; -.
DR   UCSC; RGD:3000; rat.
DR   AGR; RGD:3000; -.
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; 9872512at2759; -.
DR   PhylomeDB; P50596; -.
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 cell types or tissues.
DR   ExpressionAtlas; P50596; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR   GO; GO:0005829; C:cytosol; IDA:ARUK-UCL.
DR   GO; GO:0005576; C:extracellular region; IDA:HGNC-UCL.
DR   GO; GO:0043235; C:signaling receptor complex; IEA:Ensembl.
DR   GO; GO:0005125; F:cytokine activity; TAS:RGD.
DR   GO; GO:0003677; F:DNA binding; 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:0003300; P:cardiac muscle hypertrophy; IDA:RGD.
DR   GO; GO:0007259; P:cell surface receptor signaling pathway via JAK-STAT; ISO:RGD.
DR   GO; GO:0097696; P:cell surface receptor signaling pathway via STAT; ISO: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:0097009; P:energy homeostasis; 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; ISO: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:0046325; P:negative regulation of D-glucose import across plasma membrane; ISS:UniProtKB.
DR   GO; GO:0070093; P:negative regulation of glucagon secretion; ISO:RGD.
DR   GO; GO:2000486; P:negative regulation of glutamine transport; IMP:RGD.
DR   GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; ISO:RGD.
DR   GO; GO:0010888; P:negative regulation of lipid storage; 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: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:0043270; P:positive regulation of monoatomic ion transport; IDA: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:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IDA:UniProtKB.
DR   GO; GO:0042307; P:positive regulation of protein import into nucleus; ISO:RGD.
DR   GO; GO:0031401; P:positive regulation of protein modification process; IMP: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:0032310; P:prostaglandin secretion; ISS:UniProtKB.
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: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: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:0030217; P:T cell differentiation; ISS:UniProtKB.
DR   FunFam; 1.20.1250.10:FF:000008; Leptin; 1.
DR   Gene3D; 1.20.1250.10; -; 1.
DR   InterPro; IPR009079; 4_helix_cytokine-like_core.
DR   InterPro; IPR000065; Leptin.
DR   PANTHER; PTHR11724; LEPTIN; 1.
DR   PANTHER; PTHR11724:SF1; LEPTIN; 1.
DR   Pfam; PF02024; Leptin; 1.
DR   PIRSF; PIRSF001837; Leptin; 1.
DR   PRINTS; PR00495; LEPTIN.
DR   SUPFAM; SSF47266; 4-helical cytokines; 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
//