leptin leptin leptin (from greek λεπτός leptos, "thin" or "light" or "small") is a hormone predominantly made by adipose cells and its primary role is likely to regulate long-term energy balance. not to be confused with lectin, lecithin, or lepton. lepavailable structurespdbortholog search: pdbe rcsb list of pdb id codes1ax8identifiersaliaseslep, lepd, ob, obs, leptinexternal idsomim: 164160 mgi: 104663 homologene: 193 genecards: lep gene location (human)chr.chromosome 7 (human)band7q32.1start128,241,278 bpend128,257,629 bpgene location (mouse)chr.chromosome 6 (mouse)band6 a3.3|6 12.3 cmstart29,060,219 bpend29,073,876 bprna expression patternbgeehumanmouse (ortholog)top expressed insubcutaneous adipose tissuelactiferous ductabdominal fatpericardiumplacentasynovial jointparotid glandsuperficial temporal arterysynovial membranecoronary arterytop expressed inwhite adipose tissuesubcutaneous adipose tissuebrown adipose tissueankleintercostal muscleskeletal muscle tissuezone of skinskin of backgreater petrosal nerveadrenal glandmore reference expression databiogpsmore reference expression datagene ontologymolecular function hormone activity peptide hormone receptor binding signaling receptor binding cellular component cytoplasm extracellular region extracellular space biological process regulation of protein phosphorylation response to dietary excess cellular response to retinoic acid positive regulation of developmental growth negative regulation of glucagon secretion placenta development cardiac muscle hypertrophy regulation of angiogenesis prostaglandin secretion regulation of intestinal cholesterol absorption t cell differentiation positive regulation of reactive oxygen species metabolic process central nervous system neuron development circadian rhythm positive regulation of ion transport angiogenesis glucose metabolic process positive regulation of peroxisome proliferator activated receptor signaling pathway positive regulation of hepatic stellate cell activation regulation of endothelial cell proliferation intestinal absorption response to ethanol negative regulation of autophagy positive regulation of p38mapk cascade positive regulation of protein kinase b signaling negative regulation of metabolic process negative regulation of vasoconstriction glucose homeostasis regulation of insulin secretion regulation of steroid biosynthetic process insulin secretion regulation of natural killer cell activation regulation of fat cell differentiation response to vitamin e response to nutrient levels bone mineralization involved in bone maturation positive regulation of t cell proliferation positive regulation of protein import into nucleus regulation of brown fat cell differentiation fatty acid beta-oxidation regulation of metabolic process hormone metabolic process positive regulation of mapk cascade positive regulation of tor signaling cellular response to l-ascorbic acid ovulation from ovarian follicle activation of protein kinase c activity sexual reproduction negative regulation of cartilage development response to nutrient negative regulation of glutamine transport leptin-mediated signaling pathway bile acid metabolic process female pregnancy negative regulation of apoptotic process cholesterol metabolic process positive regulation of follicle-stimulating hormone secretion negative regulation of transcription by rna polymerase ii negative regulation of appetite regulation of protein localization to nucleus regulation of blood pressure negative regulation of glucose import leukocyte tethering or rolling negative regulation of lipid storage adipose tissue development positive regulation of insulin receptor signaling pathway bone growth positive regulation of receptor signaling pathway via jak-stat glycerol biosynthetic process positive regulation of luteinizing hormone secretion fatty acid catabolic process regulation of gluconeogenesis response to estradiol intracellular signal transduction adult feeding behavior response to hypoxia regulation of natural killer cell proliferation eating behavior positive regulation of cytokine production regulation of cytokine production involved in inflammatory response regulation of nitric-oxide synthase activity response to activity cellular response to leptin stimulus regulation of cell cycle regulation of natural killer cell mediated cytotoxicity positive regulation of fat cell apoptotic process positive regulation of cell population proliferation regulation of lipoprotein lipid oxidation positive regulation of phosphatidylinositol 3-kinase signaling signal transduction regulation of bone remodeling lipid metabolism negative regulation of appetite by leptin-mediated signaling pathway interleukin-12 production positive regulation of tumor necrosis factor production interleukin-6 production response to insulin tyrosine phosphorylation of stat protein phagocytosis energy reserve metabolic process positive regulation of tyrosine phosphorylation of stat protein regulation of signaling receptor activity determination of adult lifespan regulation of lipid biosynthetic process positive regulation of cold-induced thermogenesis aorta development regulation of catalytic activity elastin metabolic process sources:amigo / quickgoorthologsspecieshumanmouseentrez395216846ensemblensg00000174697ensmusg00000059201uniprotp41159p41160refseq (mrna)nm_000230nm_008493refseq (protein)np_000221np_032519location (ucsc)chr 7: 128.24 – 128.26 mbchr 6: 29.06 – 29.07 mbpubmed searchwikidataview/edit humanview/edit mouse leptinstructure of the obese protein leptin-e100.identifierssymbolleptinpfampf02024pfam clancl0053interproipr000065scop21ax8 / scope / supfamavailable protein structures:pfam structures / ecod pdbrcsb pdb; pdbe; pdbjpdbsumstructure summarypdb1ax8​ as one of the major signals of energy status, leptin levels influence appetite, satiety, and motivated behaviors oriented towards the maintenance of energy reserves (e.g., feeding, foraging behaviors). the amount of circulating leptin correlates with the amount of energy reserves, mainly triglycerides stored in adipose tissue. high leptin levels are interpreted by the brain that energy reserves are high, whereas low leptin levels indicate that energy reserves are low, in the process adapting the organism to starvation through a variety of metabolic, endocrine, neurobiochemical, and behavioral changes. leptin is coded for by the lep gene. leptin receptors are expressed by a variety of brain and peripheral cell types. these include cell receptors in the arcuate and ventromedial nuclei, as well as other parts of the hypothalamus and dopaminergic neurons of the ventral tegmental area, consequently mediating feeding. although regulation of fat stores is deemed to be the primary function of leptin, it also plays a role in other physiological processes, as evidenced by its many sites of synthesis other than fat cells, and the many cell types beyond hypothalamic cells that have leptin receptors. many of these additional functions are yet to be fully defined. in obesity, a decreased sensitivity to leptin occurs (similar to insulin resistance in type 2 diabetes), resulting in an inability to detect satiety despite high energy stores and high levels of leptin. a synonym for lep is ob (for obese). effects a comparison of a mouse unable to produce leptin, resulting in obesity, constant hunger, and lethargy (left), and an active normal weight mouse (right) predominantly, the "energy expenditure hormone" leptin is made by adipose cells, and is thus labeled fat cell-specific. in the context of its effects, the short describing words central, direct and primary are not used interchangeably. in regard to the hormone leptin, central vs peripheral refers to the hypothalamic portion of the brain vs non-hypothalamic location of action of leptin; direct vs indirect refers to whether there is no intermediary, or there is an intermediary in the mode of action of leptin; and primary vs secondary is an arbitrary description of a particular function of leptin. location of actionthe central location of action (effect) of the fat cell-specific hormone leptin is the hypothalamus, a part of the brain, which is a part of the central nervous system. non-hypothalamic targets of leptin are referred to as peripheral targets. there is a different relative importance of central and peripheral leptin interactions under different physiologic states, and variations between species. mode of actionleptin acts directly on leptin receptors in the cell membrane of different types of cells in the human body in particular, and in vertebrates in general. the leptin receptor is found on a wide range of cell types. it is a single-transmembrane-domain type i cytokine receptor, a special class of cytokine receptors. further, leptin interacts with other hormones and energy regulators, indirectly mediating the effects of: insulin, glucagon, insulin-like growth factor, growth hormone, glucocorticoids, cytokines, and metabolites. functionthe primary function of the hormone leptin is the regulation of adipose tissue mass through central hypothalamus mediated effects on hunger, food energy use, physical exercise and energy balance. outside the brain, in the periphery of the body, leptin's secondary functions are: modulation of energy expenditure, modulation between fetal and maternal metabolism, and that of a permissive factor in puberty, activator of immune cells, activator of beta islet cells, and growth factor. central nervous system in vertebrates, the nervous system consists of two main parts, the central nervous system (cns) and the peripheral nervous system (pns). the primary effect of leptins is in the hypothalamus, a part of the central nervous system. leptin receptors are expressed not only in the hypothalamus but also in other brain regions, particularly in the hippocampus. thus some leptin receptors in the brain are classified as central (hypothalamic) and some as peripheral (non-hypothalamic). as scientifically known so far, the general effects of leptin in the central nervous system are: deficiency of leptin has been shown to alter brain proteins and neuronal functions of obese mice which can be restored by leptin injection. leptin receptor signaling in the hippocampus enhances learning and memory. treatment with leptin has been shown to enhance learning and memory in animal models. in humans, low circulating plasma leptin has been associated with cognitive changes associated with anorexia, depression, and alzheimer's disease. studies in transgenic mouse models of alzheimer's disease have shown that chronic administration of leptin can ameliorate brain pathology and improve cognitive performance, by reducing b-amyloid and hyperphosphorylated tau, two hallmarks of alzheimer's pathology. generally, leptin is thought to enter the brain at the choroid plexus, where the intense expression of a form of leptin receptor molecule could act as a transport mechanism. increased levels of melatonin causes a downregulation of leptin, however, melatonin also appears to increase leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping. partial sleep deprivation has also been associated with decreased leptin levels. mice with type 1 diabetes treated with leptin or leptin plus insulin, compared to insulin alone had better metabolic profiles: blood sugar did not fluctuate so much; cholesterol levels decreased; less body fat formed. hypothalamus leptin acts on receptors in the lateral hypothalamus to inhibit hunger and the medial hypothalamus to stimulate satiety. in the lateral hypothalamus, leptin inhibits hunger by counteracting the effects of neuropeptide y, a potent hunger promoter secreted by cells in the gut and in the hypothalamus counteracting the effects of anandamide, another potent hunger promoter that binds to the same receptors as thc in the medial hypothalamus, leptin stimulates satiety by promoting the synthesis of α-msh, a hunger suppressant thus, a lesion in the lateral hypothalamus causes anorexia (due to a lack of hunger signals) and a lesion in the medial hypothalamus causes excessive hunger (due to a lack of satiety signals). this appetite inhibition is long-term, in contrast to the rapid inhibition of hunger by cholecystokinin (cck) and the slower suppression of hunger between meals mediated by pyy3-36. the absence of leptin (or its receptor) leads to uncontrolled hunger and resulting obesity. fasting or following a very-low-calorie diet lowers leptin levels. leptin levels change more when food intake decreases than when it increases. the dynamics of leptin due to an acute change in energy balance may be related to appetite and eventually, to food intake rather than fat stores. it controls food intake and energy expenditure by acting on receptors in the mediobasal hypothalamus. leptin binds to neuropeptide y (npy) neurons in the arcuate nucleus in such a way as to decrease the activity of these neurons. leptin signals to the hypothalamus which produces a feeling of satiety. moreover, leptin signals may make it easier for people to resist the temptation of foods high in calories. leptin receptor activation inhibits neuropeptide y and agouti-related peptide (agrp), and activates α-melanocyte-stimulating hormone (α-msh). the npy neurons are a key element in the regulation of hunger; small doses of npy injected into the brains of experimental animals stimulates feeding, while selective destruction of the npy neurons in mice causes them to become anorexic. conversely, α-msh is an important mediator of satiety, and differences in the gene for the α-msh receptor are linked to obesity in humans. leptin interacts with six types of receptors (ob-ra–ob-rf, or lepra-leprf), which in turn are encoded by a single gene, lepr. ob-rb is the only receptor isoform that can signal intracellularly via the jak-stat and mapk signal transduction pathways, and is present in hypothalamic nuclei. once leptin has bound to the ob-rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to effect changes in gene expression, one of the main effects being the down-regulation of the expression of endocannabinoids, responsible for increasing hunger. in response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them. circulatory system the role of leptin/leptin receptors in modulation of t cell activity and the innate immune system was shown in experimentation with mice. it modulates the immune response to atherosclerosis, of which obesity is a predisposing and exercise a mitigating factor. exogenous leptin can promote angiogenesis by increasing vascular endothelial growth factor levels. hyperleptinemia produced by infusion or adenoviral gene transfer decreases blood pressure in rats. leptin microinjections into the nucleus of the solitary tract (nts) have