Leptin - wikipedia Leptin Not to be confused with Lectin or Lecithin. LEP Available structures PDB Ortholog search : PDBe RCSB show List of PDB id codes 1AX8 Identifiers Aliases LEP, LEPD, OB, OBS, leptin External IDs OMIM : 164160 MGI : 104663 HomoloGene : 193 GeneCards : LEP hide Gene location ( Human ) Chr. Chromosome 7 ( human ) Band 7q32. 1 Start 128,241,284 bp End 128,257,628 bp show Gene location ( Mouse ) Chr. Chromosome 6 ( mouse ) Band 6 A3. 3 6 12.3 cM Start 29,060,220 bp End 29,073,877 bp hide RNA expression pattern More reference expression data show Gene ontology Molecular function hormone activity peptide hormone receptor binding 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 from RNA polymerase II promoter 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 JAK - STAT cascade 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 interleukin - 6 secretion positive regulation of cell proliferation interleukin - 8 secretion regulation of lipoprotein lipid oxidation positive regulation of phosphatidylinositol 3 - kinase signaling signal transduction regulation of bone remodeling lipid metabolic process 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 receptor activity Sources : Amigo / QuickGO Orthologs Species Human Mouse Entrez 3952 16846 Ensembl ENSG00000174697 ENSMUSG00000059201 UniProt P41159 P41160 RefSeq ( mRNA ) NM_000230 NM_008493 RefSeq ( protein ) NP_000221 NP_032519 Location ( UCSC ) Chr 7 : 128.24 -- 128.26 Mb Chr 6 : 29.06 -- 29.07 Mb PubMed search Wikidata View / Edit Human View / Edit Mouse Leptin Structure of the obese protein leptin - E100. Identifiers Symbol Leptin Pfam PF02024 Pfam clan CL0053 InterPro IPR000065 SCOP 1ax8 SUPERFAMILY 1ax8 show Available protein structures : Pfam structures PDB RCSB PDB ; PDBe ; PDBj PDBsum structure summary Leptin ( from Greek λεπτός leptos, `` thin '' ), `` the hormone of energy expenditure '', is a hormone predominantly made by adipose cells that helps to regulate energy balance by inhibiting hunger. Leptin is opposed by the actions of the hormone ghrelin, the `` hunger hormone ''. Both hormones act on receptors in the arcuate nucleus of the hypothalamus. 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. 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 beside hypothalamic cells that have leptin receptors. Many of these additional functions are yet to be defined. Contents 1 Identification of the encoding gene 2 Recognition of scientific advances 3 Location of gene and structure of hormone 4 Mutations 4.1 Nonsense 4.2 Frameshift 4.3 Polymorphisms 4.4 Transversion 5 Sites of synthesis 6 Blood levels 6.1 Physiologic variation 6.2 In specific conditions 6.3 Mutant leptins 7 Effects 7.1 Central nervous system 7.1. 1 Hypothalamus 7.2 Circulatory system 7.3 Fetal lung 7.4 Reproductive system 7.4. 1 Ovulatory cycle 7.4. 2 Pregnancy 7.4. 3 Lactation 7.4. 4 Puberty 7.5 Bone 7.6 Immune system 8 Role in obesity and weight loss 8.1 Obesity 8.2 Response to weight loss 9 Role in joint problems and obesity 9.1 Obesity and osteoarthritis 9.2 Leptin and osteoarthritis 10 Therapeutic use 10.1 Leptin 10.2 Analog metreleptin 11 See also 12 Notes 13 References 14 External links Identification of the encoding gene In 1949, a non-obese mouse colony being studied at the Jackson Laboratory produced a strain of obese offspring, suggesting that a mutation had occurred in a hormone regulating hunger and energy expenditure. Mice homozygous for the so - called ob mutation ( ob / ob ) ate voraciously and were massively obese. In the 1960s, a second mutation causing obesity and a similar phenotype was identified by Douglas Coleman, also at the Jackson Laboratory, and was named diabetes ( db ), as both ob / ob and db / db were obese. In 1990 Rudolph Leibel and Jeffrey M. Friedman reported mapping of the db gene. Consistent with Coleman 's and Leibel 's hypothesis, several subsequent studies from Leibel 's and Friedman 's labs and other groups confirmed that the ob gene encoded a novel hormone that circulated in blood and that could suppress food intake and body weight in ob and wild type mice, but not in db mice. In 1994, Friedman 's laboratory reported the identification of the gene. In 1995, Jose F. Caro 's laboratory provided evidence that the mutations in the mouse ob gene did not occur in humans. Furthermore, since ob gene expression was increased, not decreased, in human obesity, it suggested resistance to leptin to be a possibility. At the suggestion of Roger Guillemin, Friedman named this new hormone `` leptin '' from the Greek lepto meaning thin. Leptin was the first fat cell - derived hormone ( adipokine ) to be discovered. Subsequent studies in 1995 confirmed that the db gene encodes the leptin receptor, and that it is expressed in the hypothalamus, a region of the brain known to regulate the sensation of hunger and body weight. Recognition of scientific advances Coleman and Friedman have been awarded numerous prizes acknowledging their roles in discovery of leptin, including the Gairdner Foundation International Award ( 2005 ), the Shaw Prize ( 2009 ), the Lasker Award, the BBVA Foundation Frontiers of Knowledge Award and the King Faisal International Prize, Leibel has not received the same level of recognition from the discovery because he was omitted as a co-author of a scientific paper published by Friedman that reported the discovery of the gene. The various theories surrounding Friedman 's omission of Leibel and others as co-authors of this paper have been presented in a number of publications, including Ellen Ruppel Shell 's 2002 book The Hungry Gene. The discovery of leptin also is documented in a series of books including Fat : Fighting the Obesity Epidemic by Robert Pool, The Hungry Gene by Ellen Ruppel Shell, and Rethinking Thin : The New Science of Weight Loss and the Myths and Realities of Dieting by Gina Kolata. Fat : Fighting the Obesity Epidemic and Rethinking Thin : The New Science of Weight Loss and the Myths and Realities of Dieting review the work in the Friedman laboratory that led to the cloning of the ob gene, while The Hungry Gene draws attention to the contributions of Leibel. Location of gene and structure of hormone The Ob ( Lep ) gene ( Ob for obese, Lep for leptin ) is located on chromosome 7 in humans. Human leptin is a 16 - kDa protein of 167 amino acids. Mutations A human mutant leptin was first described in 1997, and subsequently six additional mutations were described. All of those affected were from Eastern countries ; and all had variants of leptin not detected by the standard immunoreactive technique, so leptin levels were low or undetectable. The most recently described eighth mutation reported in January 2015, in a child with Turkish parents, is unique in that it is detected by the standard immunoreactive technique, where leptin levels are elevated ; but the leptin does not turn on the leptin receptor, hence the patient has functional leptin deficiency. These eight mutations all cause extreme obesity in infancy, with hyperphagia. Nonsense A nonsense mutation in the leptin gene that results in a stop codon and lack of leptin production was first observed in mice in 1950. In the mouse gene, arginine - 105 is encoded by CGA and only requires one nucleotide change to create the stop codon TGA. The corresponding amino acid in humans is encoded by the sequence CGG and would require two nucleotides to be changed to produce a stop codon, which is much less likely to happen. Frameshift A recessive frameshift mutation resulting in a reduction of leptin has been observed in two consanguineous children with juvenile obesity. Polymorphisms A Human Genome Equivalent ( HuGE ) review in 2004 looked at studies of the connection between genetic mutations affecting leptin regulation and obesity. They reviewed a common polymorphism in the leptin gene ( A19G ; frequency 0.46 ), three mutations in the leptin receptor gene ( Q223R, K109R and K656N ) and two mutations in the PPARG gene ( P12A and C161T ). They found no association between any of the polymorphisms and obesity. A 2006 study found a link between the common LEP - 2548 G / A genotype and morbid obesity in Taiwanese aborigines, but a 2014 meta - analysis did not, however, this polymorphism has been associated with weight gain in patients taking antipsychotics. The LEP - 2548 G / A polymorphism has been linked with an increased risk of prostate cancer, gestational diabetes, and osteoporosis. Other rare polymorphisms have been found but their association with obesity are not consistent. Transversion A single case of a homozygous transversion mutation of the gene encoding for leptin was reported in January 2015. It leads to functional leptin deficiency with high leptin levels in circulation. The transversion of ( c. 298G → T ) changed aspartic acid to tyrosine at position 100 ( p. D100Y ). The mutant leptin could neither bind to nor activate the leptin receptor in vitro, nor in leptin - deficient mice in vivo. It was found in a two - year - old boy with extreme obesity with recurrent ear and pulmonary infections. Treatment with metreleptin led to `` rapid change in eating behavior, a reduction in daily energy intake, and substantial weight loss ''. Sites of synthesis Leptin is produced primarily in the adipocytes of white adipose tissue. It also is produced by brown adipose tissue, placenta ( syncytiotrophoblasts ), ovaries, skeletal muscle, stomach ( the lower part of the fundic glands ), mammary epithelial cells, bone marrow, gastric chief cells and P / D1 cells. Blood levels Leptin circulates in blood in free form and bound to proteins. Physiologic variation Leptin levels vary exponentially, not linearly, with fat mass. Leptin levels in blood are higher between midnight and early morning, perhaps suppressing appetite during the night. The diurnal rhythm of blood leptin levels may be modified by meal - timing. In specific conditions In humans, many instances are seen where leptin dissociates from the strict role of communicating nutritional status between body and brain and no longer correlates with body fat levels : Leptin plays a critical role in the adaptive response to starvation. Leptin level is decreased after short - term fasting ( 24 -- 72 hours ), even when changes in fat mass are not observed. Serum level of leptin is reduced by sleep deprivation. Leptin levels are paradoxically increased in obesity. Leptin level is increased by emotional stress. Leptin level is chronically reduced by physical exercise training. Leptin level is decreased by increases in testosterone levels and increased by increases in estrogen levels. Leptin level is increased by insulin. Leptin release is increased by dexamethasone. In obese patients with obstructive sleep apnea, leptin level is increased, but decreased after the administration of continuous positive airway pressure. In non-obese individuals, however, restful sleep ( i.e., 8 -- 12 hours of unbroken sleep ) can increase leptin to normal levels. Mutant leptins All known leptin mutations except one are associated with low to undetectable immunoreactive leptin blood levels. The exception is a mutant leptin reported in January 2015 which is not functional, but is detected with standard immunoreactive methods. It was found in a massively obese 2 - 1 / 2 - year - old boy who had high levels of circulating leptin which had no effect on leptin receptors, so he was functionally leptin - deficient. Effects Main articles : Leptin receptor and Energy expenditure 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, thus it is labeled fat cell - specific. In the context of its effects, it is important to recognize that the short describing words direct, central, 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 action Leptin 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. Mode of action The 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. Function The 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. 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 in the immune system was shown in experimentation with mice. It modulates the immune response to atherosclerosis, of which obesity is a predisposing 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 been shown to elicit sympathoexcitatory responses, and potentiate the cardiovascular responses to activation of the chemoreflex. Fetal lung In fetal lung, leptin is induced in the alveolar interstitial fibroblasts ( `` lipofibroblasts '' ) by the action of PTHrP secreted by formative alveolar epithelium ( endoderm ) under moderate stretch. The leptin from the mesenchyme, in turn, acts back on the epithelium at the leptin receptor carried in the alveolar type II pneumocytes and induces surfactant expression, which is one of the main functions of these type II pneumocytes. Reproductive system Ovulatory cycle In mice, and to a lesser extent in humans, leptin is required for male and female fertility. Ovulatory cycles in females are linked to energy balance ( positive or negative depending on whether a female is losing or gaining weight ) and energy flux ( how much energy is consumed and expended ) much more than energy status ( fat levels ). When energy balance is highly negative ( meaning the woman is starving ) or energy flux is very high ( meaning the woman is exercising at extreme levels, but still consuming enough calories ), the ovarian cycle stops and females stop menstruating. Only if a female has an extremely low body fat percentage does energy status affect menstruation. Leptin levels outside an ideal range may have a negative effect on egg quality and outcome during in vitro fertilization. Leptin is involved in reproduction by stimulating gonadotropin - releasing hormone from the hypothalamus. Pregnancy The placenta produces leptin. Leptin levels rise during pregnancy and fall after childbirth. Leptin is also expressed in fetal membranes and the uterine tissue. Uterine contractions are inhibited by leptin. Leptin plays a role in hyperemesis gravidarum ( severe morning sickness of pregnancy ), in polycystic ovary syndrome and hypothalamic leptin is implicated in bone growth in mice. Lactation Immunoreactive leptin has been found in human breast milk ; and leptin from mother 's milk has been found in the blood of suckling infant animals. Puberty Leptin along with kisspeptin controls the onset of puberty. High levels of leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche. This may eventually lead to shorter stature as oestrogen secretion starts during menarche and causes early closure of epiphyses. Bone Leptin 's ability to regulate bone mass was first recognized in 2000. Leptin can affect bone metabolism via direct signalling from the brain. Leptin decreases cancellous bone, but increases cortical bone. This `` cortical - cancellous dichotomy '' may represent a mechanism for enlarging bone size, and thus bone resistance, to cope with increased body weight. Bone metabolism can be regulated by central sympathetic outflow, since sympathetic pathways innervate bone tissue. A number of brain - signalling molecules ( neuropeptides and neurotransmitters ) have been found in bone, including adrenaline, noradrenaline, serotonin, calcitonin gene - related peptide, vasoactive intestinal peptide and neuropeptide Y. Leptin binds to its receptors in the hypothalamus, where it acts through the sympathetic nervous system to regulate bone metabolism. Leptin may also act directly on bone metabolism via a balance between energy intake and the IGF - I pathway. There is a potential for treatment of diseases of bone formation - such as impaired fracture healing - with leptin. Immune system Factors that acutely affect leptin levels are also factors that influence other markers of inflammation, e.g., testosterone, sleep, emotional stress, caloric restriction, and body fat levels. While it is well - established that leptin is involved in the regulation of the inflammatory response, it has been further theorized that leptin 's role as an inflammatory marker is to respond specifically to adipose - derived inflammatory cytokines. In terms of both structure and function, leptin resembles IL - 6 and is a member of the cytokine superfamily. Circulating leptin seems to affect the HPA axis, suggesting a role for leptin in stress response. Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women. Similar to what is observed in chronic inflammation, chronically elevated leptin levels are associated with obesity, overeating, and inflammation - related diseases, including hypertension, metabolic syndrome, and cardiovascular disease. While leptin is associated with body fat mass, however, the size of individual fat cells, and the act of overeating, it is interesting that it is not affected by exercise ( for comparison, IL - 6 is released in response to muscular contractions ). Thus, it is speculated that leptin responds specifically to adipose - derived inflammation. Leptin is a pro-angiogenic, pro-inflammatory and mitogenic factor, the actions of which are reinforced through crosstalk with IL - 1 family cytokines in cancer. Taken as such, increases in leptin levels ( in response to caloric intake ) function as an acute pro-inflammatory response mechanism to prevent excessive cellular stress induced by overeating. When high caloric intake overtaxes the ability of fat cells to grow larger or increase in number in step with caloric intake, the ensuing stress response leads to inflammation at the cellular level and ectopic fat storage, i.e., the unhealthy storage of body fat within internal organs, arteries, and / or muscle. The insulin increase in response to the caloric load provokes a dose - dependent rise in leptin, an effect potentiated by high cortisol levels. ( This insulin - leptin relationship is notably similar to insulin 's effect on the increase of IL - 6 gene expression and secretion from preadipocytes in a time - and dose - dependent manner. ) Furthermore, plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis, concurrent hypocaloric dieting and weight loss notwithstanding. Such findings appear to demonstrate high caloric loads in excess of storage rate capacities of fat cells lead to stress responses that induce an increase in leptin, which then operates as an adipose - derived inflammation stopgap signaling for the cessation of food intake so as to prevent adipose - derived inflammation from reaching elevated levels. This response may then protect against the harmful process of ectopic fat storage, which perhaps explains the connection between chronically elevated leptin levels and ectopic fat storage in obese individuals. Role in obesity and weight loss Obesity Leptin and Ghrelin on the metabolism control Although leptin reduces appetite as a circulating signal, obese individuals generally exhibit a higher circulating concentration of leptin than normal weight individuals due to their higher percentage body fat. These people show resistance to leptin, similar to resistance of insulin in type 2 diabetes, with the elevated levels failing to control hunger and modulate their weight. A number of explanations have been proposed to explain this. An important contributor to leptin resistance is changes to leptin receptor signalling, particularly in the arcuate nucleus, however, deficiency of, or major changes to, the leptin receptor itself are not thought to be a major cause. Other explanations suggested include changes to the way leptin crosses the blood brain barrier ( BBB ) or alterations occurring during development. Studies on leptin cerebrospinal fluid ( CSF ) levels provide evidence for the reduction in leptin crossing the BBB and reaching obesity - relevant targets, such as the hypothalamus, in obese people. In humans it has been observed that the ratio of leptin in the CSF compared to the blood is lower in obese people than in people of a normal weight. The reason for this may be high levels of triglycerides affecting the transport of leptin across the BBB or due to the leptin transporter becoming saturated. Although deficits in the transfer of leptin from the plasma to the CSF is seen in obese people, they are still found to have 30 % more leptin in their CSF than lean individuals. These higher CSF levels fail to prevent their obesity. Since the amount and quality of leptin receptors in the hypothalamus appears to be normal in the majority of obese humans ( as judged from leptin - mRNA studies ), it is likely that the leptin resistance in these individuals is due to a post leptin - receptor deficit, similar to the post-insulin receptor defect seen in type 2 diabetes. When leptin binds with the leptin receptor, it activates a number of pathways. Leptin resistance may be caused by defects in one or more part of this process, particularly the JAK / STAT pathway. Mice with a mutation in the leptin receptor gene that prevents the activation of STAT3 are obese and exhibit hyperphagia. The PI3K pathway may also be involved in leptin resistance, as has been demonstrated in mice by artificial blocking of PI3K signalling. The PI3K pathway also is activated by the insulin receptor and is therefore an important area where leptin and insulin act together as part of energy homeostasis. The insulin - pI3K pathway can cause POMC neurons to become insensitive to leptin through hyperpolarization. The consumption of a high fructose diet from birth has been associated with a reduction in leptin levels and reduced expression of leptin receptor mRNA in rats. Long - term consumption of fructose in rats has been shown to increase levels of triglycerides and trigger leptin and insulin resistance, however, another study found that leptin resistance only developed in the presence of both high fructose and high fat levels in the diet. A third study found that high fructose levels reversed leptin resistance in rats given a high fat diet. The contradictory results mean that it is uncertain whether leptin resistance is caused by high levels of carbohydrates or fats, or if an increase of both, is needed. Leptin is known to interact with amylin, a hormone involved in gastric emptying and creating a feeling of fullness. When both leptin and amylin were given to obese, leptin - resistant rats, sustained weight loss was seen. Due to its apparent ability to reverse leptin resistance, amylin has been suggested as possible therapy for obesity. It has been suggested that the main role of leptin is to act as a starvation signal when levels are low, to help maintain fat stores for survival during times of starvation, rather than a satiety signal to prevent overeating. Leptin levels signal when an animal has enough stored energy to spend it in pursuits besides acquiring food. This would mean that leptin resistance in obese people is a normal part of mammalian physiology and possibly, could confer a survival advantage. Leptin resistance ( in combination with insulin resistance and weight gain ) is seen in rats after they are given unlimited access to palatable, energy - dense foods. This effect is reversed when the animals are put back on a low - energy diet. This also may have an evolutionary advantage : allowing energy to be stored efficiently when food is plentiful would be advantageous in populations where food frequently may be scarce. Response to weight loss Dieters who lose weight, particularly those with an overabundance of fat cells, experience a drop in levels of circulating leptin. This drop causes reversible decreases in thyroid activity, sympathetic tone, and energy expenditure in skeletal muscle, and increases in muscle efficiency and parasympathetic tone. Many of these changes are reversed by peripheral administration ( ⁠ ⁠ intravenously into the veins of the arms, hands, legs, or feet ⁠ ⁠ ) of recombinant leptin to restore pre-diet levels. A decline in levels of circulating leptin also changes brain activity in areas involved in the regulatory, emotional, and cognitive control of appetite that are reversed by administration of leptin. Role in joint problems and obesity Obesity and osteoarthritis Osteoarthritis and obesity are closely linked. Obesity is one of the most important preventable factors for the development of osteoarthritis. Originally, the relationship between osteoarthritis and obesity was considered to be exclusively biomechanically based, according to which the excess weight caused the joint to become worn down more quickly. However, today we recognise that there is also a metabolic component which explains why obesity is a risk factor for osteoarthritis, not only for weight - bearing joints ( for example, the knees ), but also for joints that do not bear weight ( for example, the hands ). Consequently, it has been shown that decreasing body fat lessens osteoarthritis to a greater extent than weight loss per se. This metabolic component related with the release of systemic factors, of a pro-inflammatory nature, by the adipose tissues, which frequently are critically associated with the development of osteoarthritis. Thus, the deregulated production of adipokines and inflammatory mediators, hyperlipidaemia, and the increase of systemic oxidative stress are conditions frequently associated with obesity which can favour joint degeneration. Furthermore, many regulation factors have been implicated in the development, maintenance and function, both of adipose tissues, as well as of the cartilage and other joint tissues. Alterations in these factors can be the additional link between obesity and osteoarthritis. Leptin and osteoarthritis Adipocytes interact with other cells through producing and secreting a variety of signalling molecules, including the cell signalling proteins known as adipokines. Certain adipokines can be considered as hormones, as they regulate the functions of organs at a distance, and several of them have been specifically involved in the physiopathology of joint diseases. In particular, there is one, leptin, which has been the focus of attention for research in recent years. The circulating leptin levels are positively correlated with the Body Mass Index ( BMI ), more specifically with fatty mass, and obese individuals have higher leptin levels in their blood circulation, compared with non-obese individuals. In obese individuals, the increased circulating leptin levels induce unwanted responses, that is, reduced food intake or losing body weight does not occur as there is a resistance to leptin ( ref 9 ). In addition to the function of regulating energy homeostasis, leptin carries out a role in other physiological functions such as neuroendocrine communication, reproduction, angiogenesis and bone formation. More recently, leptin has been recognised as a cytokine factor as well as with pleiotropic actions also in the immune response and inflammation. For example, leptin can be found in the synovial fluid in correlation with the body mass index, and the leptin receptors are expressed in the cartilage, where leptin mediates and modulates many inflammatory responses that can damage cartilage and other joint tissues. Leptin has thus emerged as a candidate to link obesity and osteoarthritis and serves as an apparent objective as a nutritional treatment for osteoarthritis. As in the plasma, the leptin levels in the synovial fluid are positively correlated with BMI. The leptin of the synovial fluid is synthesised at least partially in the joint and may originate in part in the circulation. Leptin has been shown to be produced by chondrocytes, as well as by other tissues in the joints, including the synovial tissue, osteophytes, the meniscus and bone. An infrapatellar fat pad located extrasynovially within the knee joint is also adjacent to the synovial membrane and cartilage, and has recently been highly appreciated as an important source of leptin, as well as other adipokines and mediators which contribute to the pathogenesis of osteoarthritis The risk of suffering osteoarthritis can be decreased with weight loss. This reduction of risk is related in part with the decrease of the load on the joint, but also in the decrease of fatty mass, the central adipose tissue and the low - level inflammation associated with obesity and systemic factors. This growing evidence points to leptin as a cartilage degradation factor in the pathogenesis of osteoarthritis, and as a potential biomarker in the progression of the disease, which suggests that leptin, as well as regulation and signalling mechanisms, can be a new and promising target in the treatment of osteoarthritis, especially in obese patients. Obese individuals are predisposed to developing osteoarthritis, not only due to the excess mechanical load, but also due to the excess expression of soluble factors, that is, leptin and pro-inflammatory cytokines, which contribute to joint inflammation and cartilage destruction. As such, obese individuals are in an altered state, due to a metabolic insufficiency, which requires specific nutritional treatment capable of normalising the leptin production and reducing the systematic low - level inflammation, in order to reduce the harmful impact of these systematic mediators on the joint health. There are nutritional supplements and pharmacological agents capable of directing these factors and improving both conditions. Therapeutic use Leptin Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalized lipodystrophy. Analog metreleptin Main article : Metreleptin An analog of human leptin metreleptin ( trade name Myalept ) was first approved in Japan in 2013, and in the United States in February 2014. In the US it is indicated as a treatment for complications of leptin deficiency, and for the diabetes and hypertriglyceridemia associated with congenital or acquired generalized lipodystrophy. See also NAPEs Teleost leptins Notes Jump up ^ Leptin controls the satiety indirectly by saying that we do or not have enough energy on board. Bearing in mind that other hormones such as ghrelin operate in a faster - time scale, it would be misleading to define it as `` the satiety hormone ''. References ^ Jump up to : GRCh38 : Ensembl release 89 : ENSG00000174697 - Ensembl, May 2017 ^ Jump up to : GRCm38 : Ensembl release 89 : ENSMUSG00000059201 - Ensembl, May 2017 Jump up ^ `` Human PubMed Reference : ''. 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External links Leptin : Your brain, appetite and obesity by the British Society of Neuroendocrinology Leptin by Colorado State University -- nice illustrations, but last updated 1998 Leptin at 3Dchem.com, description and structure diagrams Hormones Endocrine glands Hypothalamic - pituitary Hypothalamus GnRH TRH Dopamine CRH GHRH Somatostatin ( GHIH ) MCH Posterior pituitary Oxytocin Vasopressin Anterior pituitary FSH LH TSH Prolactin POMC CLIP ACTH MSH Endorphins Lipotropin GH Adrenal axis Adrenal cortex Aldosterone Cortisol Cortisone DHEA DHEA - S Androstenedione Adrenal medulla Epinephrine Norepinephrine Thyroid Thyroid hormones Calcitonin Thyroid axis Parathyroid PTH Gonadal axis Testis Testosterone AMH Inhibin Ovary Estradiol Progesterone Activin Inhibin Relaxin GnSAF Placenta hCG HPL Estrogen Progesterone Pancreas Glucagon Insulin Amylin Somatostatin Pancreatic polypeptide Pineal gland Melatonin N, N - Dimethyltryptamine 5 - Methoxy - N, N - dimethyltryptamine Other Thymus Thymosins Thymosin α1 Beta thymosins Thymopoietin Thymulin Digestive system Stomach Gastrin Ghrelin Duodenum CCK Incretins GIP GLP - 1 Secretin Motilin VIP Ileum Enteroglucagon Peptide YY Liver / other Insulin - like growth factor IGF - 1 IGF - 2 Adipose tissue Leptin Adiponectin Resistin Skeleton Osteocalcin Kidney Renin EPO Calcitriol Prostaglandin Heart Natriuretic peptide ANP BNP Signaling peptide / protein receptor modulators Adiponectin AdipoR Agonists : Peptide : Adiponectin ADP - 355 ADP - 399 ; Non-peptide : AdipoRon ( -- ) - Arctigenin Arctiin Gramine Matairesinol Antagonists : Peptide : ADP - 400 AdipoR Agonists : Peptide : Adiponectin ADP - 355 ADP - 399 ; Non-peptide : AdipoRon Deoxyschizandrin Parthenolide Syringing Taxifoliol Antagonists : Peptide : ADP - 400 Angiotensin See here instead. Bradykinin Agonists : Bradykinin Kallidin Antagonists : FR - 173657 Icatibant LF22 - 0542 CGRP Agonists : Amylin CGRP Pramlintide Antagonists : Atogepant BI 44370 TA CGRP ( 8 - 37 ) MK - 3207 Olcegepant Rimegepant SB - 268262 Telcagepant Ubrogepant Antibodies : Eptinezumab Erenumab Fremanezumab Galcanezumab Cholecystokinin CCK Agonists : Cholecystokinin Antagonists : Amiglumide Asperlicin Devazepide Dexloxiglumide Lintitript Lorglumide Loxiglumide Pranazepide Proglumide Tarazepide Tomoglumide CCK Agonists : Cholecystokinin CCK - 4 Gastrin Pentagastrin ( CCK - 5 ) Antagonists : Ceclazepide CI - 988 ( PD - 134308 ) Itriglumide L - 365,360 Netazepide Proglumide Spiroglumide Unsorted Antagonists : Nastorazepide CRH CRF Agonists : Cortagine Corticorelin Corticotropin releasing hormone Sauvagine Stressin I Urocortin Antagonists : Antalarmin Astressin - B CP - 154,526 Emicerfont Hypericin LWH - 234 NBI - 27914 NBI - 74788 Pexacerfont R - 121919 TS - 041 Verucerfont CRF Agonists : Corticorelin Corticotropin releasing hormone Sauvagine Urocortin Antagonists : Astressin - B Cytokine See here instead. Endothelin Agonists : Endothelin 1 Endothelin 2 Endothelin 3 IRL - 1620 Antagonists : A-192621 ACT - 132577 Ambrisentan Aprocitentan Atrasentan Avosentan Bosentan BQ - 123 BQ - 788 Clazosentan Darusentan Edonentan Enrasentan Fandosentan Feloprentan Macitentan Nebentan Sitaxentan Sparsentan Tezosentan Zibotentan Galanin GAL Agonists : Galanin Galanin ( 1 - 15 ) Galanin - like peptide Galmic Galnon NAX 810 - 2 Antagonists : C7 Dithiepine - 1, 1, 4, 4 - tetroxide Galantide ( M15 ) M32 M35 M40 SCH - 202596 GAL Agonists : Galanin Galanin ( 1 - 15 ) Galanin ( 2 - 11 ) Galanin - like peptide Galmic Galnon J18 NAX 810 - 2 Antagonists : C7 Galantide ( M15 ) M32 M35 M40 M871 GAL Agonists : Galanin Galanin ( 1 - 15 ) Galmic Galnon Antagonists : C7 Galantide ( M15 ) GalR3ant HT - 2157 M32 M35 M40 SNAP - 37889 SNAP - 398299 Ghrelin / GHS See here instead. GH See here instead. GHRH See here instead. GLP GLP - 1 Agonists : Albiglutide Beinaglutide Dulaglutide Efpeglenatide Exenatide GLP - 1 Langlenatide Liraglutide Lixisenatide Oxyntomodulin Pegapamodutide Semaglutide Taspoglutide GLP - 2 Agonists : Apraglutide Elsiglutide Glepaglutide GLP - 2 Teduglutide Others Propeptides : Preproglucagon Proglucagon Glucagon Agonists : Dasiglucagon Glucagon Oxyntomodulin Antagonists : Adomeglivant L - 168,049 LGD - 6972 Propeptides : Preproglucagon Proglucagon GnRH See here instead. Gonadotropin See here instead. Growth factor See here instead. Insulin Agonists : Chaetochromin ( 4548 - G05 ) Insulin - like growth factor 1 Insulin - like growth factor 2 Insulin Insulin aspart Insulin degludec Insulin detemir Insulin glargine Insulin glulisine Insulin lispro Mecasermin Mecasermin rinfabate Antagonists : BMS - 754807 S661 S961 Kinase inhibitors : Linsitinib Antibodies : Xentuzumab ( against IGF - 1 and IGF - 2 ) Kisspeptin Agonists : Kisspeptin Kisspeptin - 10 Antagonists : Kisspeptin - 234 Leptin Agonists : Leptin Metreleptin MCH MCH Agonists : Melanin concentrating hormone Antagonists : ATC - 0065 ATC - 0175 GW - 803430 NGD - 4715 SNAP - 7941 SNAP - 94847 MCH Agonists : Melanin concentrating hormone Melanocortin See here instead. Neuropeptide FF Agonists : Neuropeptide AF Neuropeptide FF Neuropeptide SF ( RFRP - 1 ) Neuropeptide VF ( RFRP - 3 ) Antagonists : BIBP - 3226 RF9 Neuropeptide S Agonists : Neuropeptide S Antagonists : ML - 154 SHA - 68 Neuropeptide Y Y Agonists : Neuropeptide Y Peptide YY Antagonists : BIBO - 3304 BIBP - 3226 BVD - 10 GR - 231118 PD - 160170 Y Agonists : 2 - Thiouridine 5 ' - triphosphate Neuropeptide Y Neuropeptide Y ( 13 - 36 ) Peptide YY Peptide YY ( 3 - 36 ) Antagonists : BIIE - 0246 JNJ - 5207787 SF - 11 Y Agonists : GR - 231118 Neuropeptide Y Pancreatic polypeptide Peptide YY Antagonists : UR - AK49 Y Agonists : BWX - 46 Neuropeptide Y Peptide YY Antagonists : CGP - 71683 FMS - 586 L - 152,804 Lu AA - 33810 MK - 0557 NTNCB Velneperit ( S - 2367 ) Neurotensin NTS Agonists : Neurotensin Neuromedin N Antagonists : Meclinertant SR - 142948 NTS Agonists : Neurotensin Antagonists : Levocabastine SR - 142948 Opioid See here instead. Orexin OX Agonists : Orexin ( A, B) Antagonists : ACT - 335827 ACT - 462206 Almorexant Filorexant Lemborexant Nemorexant RTIOX - 276 SB - 334867 SB - 408124 SB - 649868 Suvorexant TCS - 1102 OX Agonists : Orexin ( A, B) SB - 668875 Antagonists : ACT - 335827 ACT - 462206 Almorexant EMPA Filorexant JNJ - 10397049 Lemborexant MK - 1064 SB - 649868 Seltorexant Suvorexant TCS - 1102 TCS - OX2 - 29 Oxytocin See here instead. Prolactin Agonists : Growth hormone Human placental lactogen Placental growth hormone ( growth hormone variant ) Prolactin S179D - hPRL Somatotropin Antagonists : Δ1 -- 9 - G129R - hPRL Δ1 -- 14 - G129R - hPRL G120K - hGH G129R - hPRL Prolactin modulators : Prolactin inhibitors : D receptor agonists ( e.g., bromocriptine, cabergoline ) ; Prolactin releasers : D receptor antagonists ( e.g., domperidone, metoclopramide, risperidone ) Estrogens ( e.g., estradiol ) Progestogens ( e.g., progesterone ) PTH Agonists : Abaloparatide Parathyroid hormone Parathyroid hormone - related protein ( PTHrP ) Semparatide Teriparatide Relaxin Agonists : Insulin - like factor 3 Relaxin ( 1, 2, 3 ) Serelaxin Somatostatin See here instead. Tachykinin See here instead. TRH Agonists : Azetirelin Fertirelin Montirelin Orotirelin Posatirelin Protirelin Rovatirelin Taltirelin TRH ( TRF ) TSH Agonists : Thyrotropin alfa TSH ( thyrotropin ) Vasopressin See here instead. VIP / PACAP VIPR Agonists : Peptide : Bay 55 - 9837 LBT - 3393 PACAP VIP VIPR Agonists : Peptide : LBT - 3627 PACAP VIP PAC Agonists : PACAP PACAP ( 1 - 27 ) PACAP ( 1 - 38 ) Antagonists : PACAP ( 6 - 38 ) Unsorted PHI PHM PHV Others Endogenous : Adrenomedullin Apelin Asprosin Bombesin Calcitonin Carnosine CART CLIP DSIP Enteroglucagon Formyl peptide GALP GIP GRP Integrin ligands ( collagens, fibrinogen, fibronectin, laminins, ICAM - 1, ICAM - 2, osteopontin, VCAM - 1, vitronectin ) Kininogens Motilin Natriuretic peptides ( ANP, BNP, CNP, urodilatin ) Nesfatin - 1 Neuromedin B Neuromedin N Neuromedin S Neuromedin U Obestatin Osteocalcin Resistin Secretin Thymopoietin Thymosins Thymulin Urotensin - II VGF Exogenous : Lifitegrast ( LFA - 1 antagonist ) See also Receptor / signaling modulators Human diets Main articles Cuisine Dietitian Hunger Leptin Meal Nutrition Obesity Staple food Diet Basic types Omnivore Entomophagy Pescetarian Plant - based Religious diets Buddhist Christian Hindu Islamic Jain Jewish Rastafari Sikh Vegetarianism and veganism Dried fruit Fruitarianism Meat analogue Milk substitute Raw vegan Tofu Semi-vegetarianism Supplement diets Bodybuilding supplements Meal replacement Therapeutic food Non-solid diets Liquid diets Very low calorie Specific restrictions Calorie restrictions Gluten - free Gluten - free and casein - free Low - carbohydrate No - carbohydrate Specific carbohydrate Low - FODMAP Low - fat Low - glycemic Low - sodium Other diets Cotton ball Pica DASH Inuit MIND Raw foodist U.S. military Food faddism Atkins Cambridge Macrobiotic Junk food Superfood Slow - Carb Paleolithic Ketogenic List of diets Diet food Dieting Nutrition Amino acids Alanine Arginine Asparagine Aspartic acid Cysteine Glutamic acid Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Proline Selenocysteine Serine Threonine Tryptophan Tyrosine Valine Vitamins Vitamin A Vitamin B Vitamin B Vitamin B Vitamin B Vitamin B Vitamin B Vitamin B Vitamin B Vitamin C Vitamin D Vitamin E Vitamin K Minerals Calcium Chlorine Chromium Cobalt Copper Iodine Iron Magnesium Manganese Molybdenum Nickel Phosphorus Potassium Selenium Sodium Vanadium Zinc Nutritional advice 5 A Day Dairy Council of California Food circle Food pyramid Fruits & Veggies -- More Matters Healthy eating pyramid Latin American Diet Pyramid French paradox Mediterranean Diet Pyramid MyPlate MyPyramid Vegetarian Diet Pyramid Commons Cookbook Food portal, Health and fitness portal Wikimedia Commons has media related to Leptin. Retrieved from `` https://en.wikipedia.org/w/index.php?title=Leptin&oldid=851259029 '' Categories : Genes on human chromosome 7 Leptin receptor agonists Peptide hormones Mutated genes Obesity Hidden categories : Wikipedia articles needing page number citations from November 2013 CS1 Chinese - language sources ( zh ) All articles with unsourced statements Articles with unsourced statements from August 2016 Talk Contents About Wikipedia Български Bosanski Català Čeština Cymraeg Dansk Deutsch Ελληνικά Español Euskara فارسی Français Galego 한국어 Հայերեն हिन्दी Hrvatski Bahasa Indonesia Íslenska Italiano עברית Latina Nederlands 日本 語 Polski Português Română Русский Simple English Slovenščina Српски / srpski Srpskohrvatski / српскохрватски Suomi Svenska தமிழ் Türkçe Українська Tiếng Việt 中文 31 more Edit links This page was last edited on 21 July 2018, at 03 : 19 ( UTC ). Text is available under the Creative Commons Attribution - ShareAlike License ; additional terms may apply. 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Question: ​on which organ or tissue does leptin primarily act
Answer: adipose tissue