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Wikipedia

Leptin

February 15, 2024

Not to be confused with Lectin, Lecithin, or Lepton.

Leptin (from Greek λεπτός leptos, "thin" or "light" or "small") is a protein hormone predominantly made by adipocytes (cells of adipose tissue) and its primary role is likely to regulate long-term energy balance.[6]

LEP
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesLEP, LEPD, OB, OBS, leptin
External IDsOMIM: 164160 MGI: 104663 HomoloGene: 193 GeneCards: LEP
Orthologs
SpeciesHumanMouse
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 MbChr 6: 29.06 – 29.07 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Leptin
Structure of the obese protein leptin-E100[5]
Identifiers
SymbolLeptin
PfamPF02024
Pfam clanCL0053
InterProIPR000065
SCOP21ax8 / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1ax8​

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.[7]

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.[8][9]

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.[10][11][12][13][14][15]

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.[16] A synonym for LEP is OB (for obese).[17]

Effects edit

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, 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.[18]

Location 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.[19]
Mode 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,[20] 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.[19]
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 edit

 
Classic leptin–melanocortin model

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.[21]
  • Leptin receptor signaling in the hippocampus enhances learning and memory.[22] Treatment with leptin has been shown to enhance learning and memory in animal models.[22]
  • In humans, low circulating plasma leptin has been associated with cognitive changes associated with anorexia,[23] depression, and Alzheimer's Disease.[24]
  • Studies in transgenic mouse models of Alzheimer's disease have shown that chronic administration of leptin can ameliorate brain pathology and improve cognitive performance,[25] by reducing b-amyloid and hyperphosphorylated Tau,[26][27] 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.[28]

Increased levels of melatonin causes a downregulation of leptin,[29] however, melatonin also appears to increase leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping.[30] Partial sleep deprivation has also been associated with decreased leptin levels.[31]

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.[32]

Hypothalamus edit

 
Summary of the different ways leptin can indirectly affect POMC neurons

Leptin acts on receptors in the lateral hypothalamus to inhibit hunger and the medial hypothalamus to stimulate satiety.[33]

  • In the lateral hypothalamus, leptin inhibits hunger[34] 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[35] 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).[33] 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.[36][37][38][39] Leptin levels change more when food intake decreases than when it increases.[40] 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.[41][42]

  • It controls food intake and energy expenditure by acting on receptors in the mediobasal hypothalamus.[43]

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.[44]

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.[45] Ob-Rb is the only receptor isoform that can signal intracellularly via the JAK-STAT and MAPK signal transduction pathways,[46] and is present in hypothalamic nuclei.[47]

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.[48] 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 edit

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.[49][50]

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.[51][52]

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.[53]

Fetal lung edit

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.[54]

Reproductive system edit

Ovulatory cycle edit

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.[55] Leptin is involved in reproduction by stimulating gonadotropin-releasing hormone from the hypothalamus.[56]

Pregnancy edit

The placenta produces leptin.[57] 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.[58] Leptin plays a role in hyperemesis gravidarum (severe morning sickness of pregnancy),[59] in polycystic ovary syndrome[60] and hypothalamic leptin is implicated in bone growth in mice.[61]

Lactation edit

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.[62]

Puberty edit

Leptin along with kisspeptin controls the onset of puberty.[63] High levels of leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche.[64] This may eventually lead to shorter stature as oestrogen secretion starts during menarche and causes early closure of epiphyses.

Bone edit

Leptin's role in regulating bone mass was identified in 2000.[65][66] 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.[67]

Bone metabolism can be regulated by central sympathetic outflow, since sympathetic pathways innervate bone tissue.[68] 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.[68][69] Leptin binds to its receptors in the hypothalamus, where it acts through the sympathetic nervous system to regulate bone metabolism.[70] Leptin may also act directly on bone metabolism via a balance between energy intake and the IGF-I pathway.[67][71] There is a potential for treatment of diseases of bone formation - such as impaired fracture healing - with leptin.[72]

Immune system edit

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,[73][74][75] 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.[5][74][76] Circulating leptin seems to affect the HPA axis, suggesting a role for leptin in stress response.[77] Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.[78]

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, the size of individual fat cells, and overeating, 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.[79] 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.[80] High leptin levels have been also demonstrated in patients with COVID-19 pneumonia.[81]

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.[82] (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.)[83] Furthermore, plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis, concurrent hypocaloric dieting and weight loss notwithstanding.[84] 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.[85]

Leptin increases the production of leukocytes via actions on the hematopoietic niche, a pathway that is more active in sedentary mice and humans when compared to individuals which are physically active.[50]

Location of gene and structure of hormone edit

The Ob(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans.[86] Human leptin is a 16-kDa protein of 167 amino acids.

Mutations edit

A human mutant leptin was first described in 1997,[87] 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.[88] These eight mutations all cause extreme obesity in infancy, with hyperphagia.[88]

Nonsense edit

A nonsense mutation in the leptin gene that results in a stop codon and lack of leptin production was first observed in mice. 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.[14]

Frameshift edit

A recessive frameshift mutation resulting in a reduction of leptin has been observed in two consanguineous children with juvenile obesity. A 2001 study of 13 people with a heterozygous frameshift mutation known as delta-G133 found that they had lower blood leptin levels than controls. There was an increased rate of obesity in these individuals, with 76% having a BMI of over 30 compared to 26% in the control group.[89]

Polymorphisms edit

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.[90]

A 2006 study found a link between the common LEP-2548 G/A genotype and morbid obesity in Taiwanese aborigines,[91][92] but a 2014 meta-analysis did not,[92] however, this polymorphism has been associated with weight gain in patients taking antipsychotics.[93][94][95]

The LEP-2548 G/A polymorphism has been linked with an increased risk of prostate cancer,[96] gestational diabetes,[97] and osteoporosis.[98]

Other rare polymorphisms have been found but their association with obesity are not consistent.[90]

Transversion edit

A single case of a homozygous transversion mutation of the gene encoding for leptin was reported in January 2015.[88] 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."[88]

Sites of synthesis edit

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,[19] gastric chief cells and P/D1 cells.[99]

 
Diagram representing where leptin is produced in the human body, where it goes, and what it causes

Blood levels edit

Leptin circulates in blood in free form and bound to proteins.[100]

Physiologic variation edit

Leptin levels vary exponentially, not linearly, with fat mass.[101][102] Leptin levels in blood are higher between midnight and early morning, perhaps suppressing appetite during the night.[103] The diurnal rhythm of blood leptin levels may be modified by meal-timing.[104]

In specific conditions edit

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:

In mutations edit

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.[88]

Role in disease edit

Obesity edit

 
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.[15] 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. Triglycerides crossing the blood brain barrier (BBB) can induce leptin and insulin resistance in the hypothalamus.[22] Triglycerides can also impair leptin transport across the BBB.[22]

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.[121] 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.[122] 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.[121] 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.[122] 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),[123] 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.[124]

When leptin binds with the leptin receptor, it activates a number of pathways. Leptin resistance may be caused by defects in one or more parts 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.[125]

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.[126]

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.[125][127] This would mean that leptin resistance in obese people is a normal part of mammalian physiology and possibly, could confer a survival advantage.[128] 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.[129] This effect is reversed when the animals are put back on a low-energy diet.[130] 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.[131]

A fad diet, the Rosedale diet is based on ideas about how leptin might affect weight. It is based on unsound science and marketed with unevidenced claims of health benefits.[132]

Role in osteoarthritis with obesity edit

Obesity and osteoarthritis edit

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).[133] Consequently, it has been shown that decreasing body fat lessens osteoarthritis to a greater extent than weight loss per se.[134] 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.[135][136][137][138][139]

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 edit

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.[15] 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.[140][141][142][143] 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.[144][145][146][147] 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.[144][145][148][149][150][151] 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 [151][152][153][154]

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.[citation needed]

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.[citation needed]

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.[citation needed]

There are nutritional supplements and pharmacological agents capable of directing these factors and improving both conditions.[citation needed]

Therapeutic use edit

Leptin edit

Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalized lipodystrophy.[155]

Analog metreleptin edit

Main article: Metreleptin

An analog of human leptin metreleptin (trade names Myalept, Myalepta) was first approved in Japan in 2013, and in the United States in February 2014 and in Europe in 2018. 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.[156][157] In Europe based on EMA, metreleptin should be used in addition to diet to treat lipodystrophy, where patients have loss of fatty tissue under the skin and build-up of fat elsewhere in the body such as in the liver and muscles. The medicine is used in adults and children above the age of 2 years with generalised lipodystrophy (Berardinelli-Seip syndrome and Lawrence syndrome); and in adults and children above the age of 12 years with partial lipodystrophy (including Barraquer-Simons syndrome), when standard treatments have failed.[158]

The National Health Service in England will commission metreleptin treatment for all with congenital leptin deficiency regardless of age beginning on April 1, 2019.[159]

Research edit

Leptin is currently being evaluated as a potential target for the treatment of anorexia nervosa.[160] It is hypothesized that the gradual loss of body fat mass, and more specifically the ensuing low leptin levels, escalate the preexisting drive for thinness into an obsessive-compulsive-like and addictive-like state. It was shown that short-term metreleptin treatment of patients with anorexia nervosa had rapid on-set of beneficial cognitive, emotional, and behavioral effects. Among other things, depression, drive for activity, repetitive thoughts of food, inner restlessness, and weight phobia decreased rapidly. Whether metreleptin (or another leptin analogue) is a suitable treatment for anorexia nervosa is currently unknown. Potential side effects are weight loss and the development of anti-metreleptin antibodies.[161]

History edit

The leptin was discovered by Jeffrey Friedman in 1994 after several decades of research conducted by others institutions since 1950 on obese mouse models [162]

Identification of the encoding gene edit

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.[163] 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.[164][165][166] In 1990 Rudolph Leibel and Jeffrey M. Friedman reported mapping of the db gene.[167][168][169]

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.[10][11][12][13]

In 1994, Friedman's laboratory reported the identification of the gene.[166] 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.[14] At the suggestion of Roger Guillemin, Friedman named this new hormone "leptin" from the Greek lepto meaning thin.[10][170] Leptin was the first fat cell-derived hormone (adipokine) to be discovered.[171]

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.[172][173][174][175]

Recognition of scientific advances edit

Coleman and Friedman have been awarded numerous prizes acknowledging their roles in discovery of leptin, including the Gairdner Foundation International Award (2005),[176] the Shaw Prize (2009),[177] the Lasker Award,[178] the BBVA Foundation Frontiers of Knowledge Award[179] and the King Faisal International Prize,[180] 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.[181][182]

The discovery of leptin also is documented in a series of books including Fat: Fighting the Obesity Epidemic by Robert Pool,[183] 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.[184][185] 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.[citation needed]

See also edit

References edit

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External links edit

  • – last updated 1998
  • Leptin at 3Dchem.com, description and structure diagrams
  • Overview of all the structural information available in the PDB for UniProt: P41159 (Leptin) at the PDBe-KB.
 
Wikimedia Commons has media related to Leptin.

February 15, 2024
leptin, confused, with, lectin, lecithin, lepton, this, article, needs, more, reliable, medical, references, verification, relies, heavily, primary, sources, please, review, contents, article, appropriate, references, unsourced, poorly, sourced, material, chal. Not to be confused with Lectin Lecithin or Lepton This article needs more reliable medical references for verification or relies too heavily on primary sources Please review the contents of the article and add the appropriate references if you can Unsourced or poorly sourced material may be challenged and removed Find sources Leptin news newspapers books scholar JSTOR July 2020 Leptin from Greek leptos leptos thin or light or small is a protein hormone predominantly made by adipocytes cells of adipose tissue and its primary role is likely to regulate long term energy balance 6 LEPAvailable structuresPDBOrtholog search PDBe RCSBList of PDB id codes1AX8IdentifiersAliasesLEP LEPD OB OBS leptinExternal IDsOMIM 164160 MGI 104663 HomoloGene 193 GeneCards LEPGene location Human Chr Chromosome 7 human 1 Band7q32 1Start128 241 278 bp 1 End128 257 629 bp 1 Gene location Mouse Chr Chromosome 6 mouse 2 Band6 A3 3 6 12 3 cMStart29 060 219 bp 2 End29 073 876 bp 2 RNA 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 functionhormone activity peptide hormone receptor binding signaling receptor bindingCellular componentcytoplasm extracellular region extracellular spaceBiological processregulation 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 processSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez395216846EnsemblENSG00000174697ENSMUSG00000059201UniProtP41159P41160RefSeq mRNA NM 000230NM 008493RefSeq protein NP 000221NP 032519Location UCSC Chr 7 128 24 128 26 MbChr 6 29 06 29 07 MbPubMed search 3 4 WikidataView Edit HumanView Edit MouseLeptinStructure of the obese protein leptin E100 5 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 7 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 8 9 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 10 11 12 13 14 15 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 16 A synonym for LEP is OB for obese 17 Contents 1 Effects 1 1 Central nervous system 1 1 1 Hypothalamus 1 2 Circulatory system 1 3 Fetal lung 1 4 Reproductive system 1 4 1 Ovulatory cycle 1 4 2 Pregnancy 1 4 3 Lactation 1 4 4 Puberty 1 5 Bone 1 6 Immune system 2 Location of gene and structure of hormone 3 Mutations 3 1 Nonsense 3 2 Frameshift 3 3 Polymorphisms 3 4 Transversion 4 Sites of synthesis 5 Blood levels 5 1 Physiologic variation 5 2 In specific conditions 5 3 In mutations 6 Role in disease 6 1 Obesity 6 2 Role in osteoarthritis with obesity 6 2 1 Obesity and osteoarthritis 6 2 2 Leptin and osteoarthritis 7 Therapeutic use 7 1 Leptin 7 2 Analog metreleptin 8 Research 9 History 9 1 Identification of the encoding gene 9 2 Recognition of scientific advances 10 See also 11 References 12 External linksEffects editMain articles Leptin receptor and Energy expenditure nbsp 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 18 Location 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 19 Mode 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 20 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 19 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 edit nbsp Classic leptin melanocortin modelIn 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 21 Leptin receptor signaling in the hippocampus enhances learning and memory 22 Treatment with leptin has been shown to enhance learning and memory in animal models 22 In humans low circulating plasma leptin has been associated with cognitive changes associated with anorexia 23 depression and Alzheimer s Disease 24 Studies in transgenic mouse models of Alzheimer s disease have shown that chronic administration of leptin can ameliorate brain pathology and improve cognitive performance 25 by reducing b amyloid and hyperphosphorylated Tau 26 27 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 28 Increased levels of melatonin causes a downregulation of leptin 29 however melatonin also appears to increase leptin levels in the presence of insulin therefore causing a decrease in appetite during sleeping 30 Partial sleep deprivation has also been associated with decreased leptin levels 31 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 32 Hypothalamus edit nbsp Summary of the different ways leptin can indirectly affect POMC neuronsLeptin acts on receptors in the lateral hypothalamus to inhibit hunger and the medial hypothalamus to stimulate satiety 33 In the lateral hypothalamus leptin inhibits hunger 34 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 35 by promoting the synthesis of a MSH a hunger suppressantThus 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 33 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 36 37 38 39 Leptin levels change more when food intake decreases than when it increases 40 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 41 42 It controls food intake and energy expenditure by acting on receptors in the mediobasal hypothalamus 43 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 44 Leptin receptor activation inhibits neuropeptide Y and agouti related peptide AgRP and activates a melanocyte stimulating hormone a 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 a MSH is an important mediator of satiety and differences in the gene for the a 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 45 Ob Rb is the only receptor isoform that can signal intracellularly via the JAK STAT and MAPK signal transduction pathways 46 and is present in hypothalamic nuclei 47 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 48 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 edit 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 49 50 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 51 52 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 53 Fetal lung edit 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 54 Reproductive system edit Ovulatory cycle edit 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 55 Leptin is involved in reproduction by stimulating gonadotropin releasing hormone from the hypothalamus 56 Pregnancy edit The placenta produces leptin 57 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 58 Leptin plays a role in hyperemesis gravidarum severe morning sickness of pregnancy 59 in polycystic ovary syndrome 60 and hypothalamic leptin is implicated in bone growth in mice 61 Lactation edit 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 62 Puberty edit Leptin along with kisspeptin controls the onset of puberty 63 High levels of leptin as usually observed in obese females can trigger neuroendocrine cascade resulting in early menarche 64 This may eventually lead to shorter stature as oestrogen secretion starts during menarche and causes early closure of epiphyses Bone edit Leptin s role in regulating bone mass was identified in 2000 65 66 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 67 Bone metabolism can be regulated by central sympathetic outflow since sympathetic pathways innervate bone tissue 68 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 68 69 Leptin binds to its receptors in the hypothalamus where it acts through the sympathetic nervous system to regulate bone metabolism 70 Leptin may also act directly on bone metabolism via a balance between energy intake and the IGF I pathway 67 71 There is a potential for treatment of diseases of bone formation such as impaired fracture healing with leptin 72 Immune system edit 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 73 74 75 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 5 74 76 Circulating leptin seems to affect the HPA axis suggesting a role for leptin in stress response 77 Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women 78 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 the size of individual fat cells and overeating 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 79 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 80 High leptin levels have been also demonstrated in patients with COVID 19 pneumonia 81 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 82 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 83 Furthermore plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis concurrent hypocaloric dieting and weight loss notwithstanding 84 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 85 Leptin increases the production of leukocytes via actions on the hematopoietic niche a pathway that is more active in sedentary mice and humans when compared to individuals which are physically active 50 Location of gene and structure of hormone editThe Ob Lep gene Ob for obese Lep for leptin is located on chromosome 7 in humans 86 Human leptin is a 16 kDa protein of 167 amino acids Mutations editA human mutant leptin was first described in 1997 87 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 88 These eight mutations all cause extreme obesity in infancy with hyperphagia 88 Nonsense edit A nonsense mutation in the leptin gene that results in a stop codon and lack of leptin production was first observed in mice 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 14 Frameshift edit A recessive frameshift mutation resulting in a reduction of leptin has been observed in two consanguineous children with juvenile obesity A 2001 study of 13 people with a heterozygous frameshift mutation known as delta G133 found that they had lower blood leptin levels than controls There was an increased rate of obesity in these individuals with 76 having a BMI of over 30 compared to 26 in the control group 89 Polymorphisms edit 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 90 A 2006 study found a link between the common LEP 2548 G A genotype and morbid obesity in Taiwanese aborigines 91 92 but a 2014 meta analysis did not 92 however this polymorphism has been associated with weight gain in patients taking antipsychotics 93 94 95 The LEP 2548 G A polymorphism has been linked with an increased risk of prostate cancer 96 gestational diabetes 97 and osteoporosis 98 Other rare polymorphisms have been found but their association with obesity are not consistent 90 Transversion edit A single case of a homozygous transversion mutation of the gene encoding for leptin was reported in January 2015 88 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 88 Sites of synthesis editLeptin 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 19 gastric chief cells and P D1 cells 99 nbsp Diagram representing where leptin is produced in the human body where it goes and what it causesBlood levels editLeptin circulates in blood in free form and bound to proteins 100 Physiologic variation edit Leptin levels vary exponentially not linearly with fat mass 101 102 Leptin levels in blood are higher between midnight and early morning perhaps suppressing appetite during the night 103 The diurnal rhythm of blood leptin levels may be modified by meal timing 104 In specific conditions edit 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 105 106 Leptin level is decreased after short term fasting 24 72 hours even when changes in fat mass are not observed 107 108 109 Serum level of leptin is reduced by sleep deprivation 110 111 Leptin levels are paradoxically increased in obesity 85 Leptin level is increased by emotional stress 112 Leptin level is chronically reduced by physical exercise training 113 114 115 Leptin level is decreased by increases in testosterone levels and increased by increases in estrogen levels 116 Leptin level is increased by insulin 117 Leptin release is increased by dexamethasone 118 In obese patients with obstructive sleep apnea leptin level is increased but decreased after the administration of continuous positive airway pressure 119 120 In non obese individuals however restful sleep i e 8 12 hours of unbroken sleep can increase leptin to normal levels In mutations edit 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 88 Role in disease editObesity edit nbsp Leptin and Ghrelin on the metabolism controlAlthough 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 15 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 Triglycerides crossing the blood brain barrier BBB can induce leptin and insulin resistance in the hypothalamus 22 Triglycerides can also impair leptin transport across the BBB 22 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 121 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 122 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 121 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 122 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 123 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 124 When leptin binds with the leptin receptor it activates a number of pathways Leptin resistance may be caused by defects in one or more parts 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 125 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 126 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 125 127 This would mean that leptin resistance in obese people is a normal part of mammalian physiology and possibly could confer a survival advantage 128 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 129 This effect is reversed when the animals are put back on a low energy diet 130 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 131 A fad diet the Rosedale diet is based on ideas about how leptin might affect weight It is based on unsound science and marketed with unevidenced claims of health benefits 132 Role in osteoarthritis with obesity edit Obesity and osteoarthritis edit 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 133 Consequently it has been shown that decreasing body fat lessens osteoarthritis to a greater extent than weight loss per se 134 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 135 136 137 138 139 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 edit 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 15 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 140 141 142 143 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 144 145 146 147 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 144 145 148 149 150 151 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 151 152 153 154 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 citation needed 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 citation needed 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 citation needed There are nutritional supplements and pharmacological agents capable of directing these factors and improving both conditions citation needed Therapeutic use editLeptin edit Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalized lipodystrophy 155 Analog metreleptin edit Main article Metreleptin An analog of human leptin metreleptin trade names Myalept Myalepta was first approved in Japan in 2013 and in the United States in February 2014 and in Europe in 2018 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 156 157 In Europe based on EMA metreleptin should be used in addition to diet to treat lipodystrophy where patients have loss of fatty tissue under the skin and build up of fat elsewhere in the body such as in the liver and muscles The medicine is used in adults and children above the age of 2 years with generalised lipodystrophy Berardinelli Seip syndrome and Lawrence syndrome and in adults and children above the age of 12 years with partial lipodystrophy including Barraquer Simons syndrome when standard treatments have failed 158 The National Health Service in England will commission metreleptin treatment for all with congenital leptin deficiency regardless of age beginning on April 1 2019 159 Research editLeptin is currently being evaluated as a potential target for the treatment of anorexia nervosa 160 It is hypothesized that the gradual loss of body fat mass and more specifically the ensuing low leptin levels escalate the preexisting drive for thinness into an obsessive compulsive like and addictive like state It was shown that short term metreleptin treatment of patients with anorexia nervosa had rapid on set of beneficial cognitive emotional and behavioral effects Among other things depression drive for activity repetitive thoughts of food inner restlessness and weight phobia decreased rapidly Whether metreleptin or another leptin analogue is a suitable treatment for anorexia nervosa is currently unknown Potential side effects are weight loss and the development of anti metreleptin antibodies 161 History editThe leptin was discovered by Jeffrey Friedman in 1994 after several decades of research conducted by others institutions since 1950 on obese mouse models 162 Identification of the encoding gene edit 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 163 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 164 165 166 In 1990 Rudolph Leibel and Jeffrey M Friedman reported mapping of the db gene 167 168 169 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 10 11 12 13 In 1994 Friedman s laboratory reported the identification of the gene 166 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 14 At the suggestion of Roger Guillemin Friedman named this new hormone leptin from the Greek lepto meaning thin 10 170 Leptin was the first fat cell derived hormone adipokine to be discovered 171 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 172 173 174 175 Recognition of scientific advances edit Coleman and Friedman have been awarded numerous prizes acknowledging their roles in discovery of leptin including the Gairdner Foundation International Award 2005 176 the Shaw Prize 2009 177 the Lasker Award 178 the BBVA Foundation Frontiers of Knowledge Award 179 and the King Faisal International Prize 180 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 181 182 The discovery of leptin also is documented in a series of books including Fat Fighting the Obesity Epidemic by Robert Pool 183 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 184 185 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 citation needed See also editGhrelin NAPEs Teleost leptinsReferences edit a b c GRCh38 Ensembl release 89 ENSG00000174697 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000059201 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine a b Zhang F Basinski MB Beals JM Briggs 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October 2022 The role of hypoleptinemia in the psychological and behavioral adaptation to starvation Implications for anorexia nervosa Neuroscience and Biobehavioral Reviews 141 104807 doi 10 1016 j neubiorev 2022 104807 PMID 35931221 S2CID 251259742 Milos G Antel J Kaufmann LK Barth N Koller A Tan S et al August 2020 Short term metreleptin treatment of patients with anorexia nervosa rapid on set of beneficial cognitive emotional and behavioral effects Translational Psychiatry 10 1 303 doi 10 1038 s41398 020 00977 1 PMC 7453199 PMID 32855384 The Rockefeller University Hospital Centennial centennial rucares org Retrieved 2018 10 11 Dickie MM Lane PW 1957 Plus letter to Roy Robinson 7 7 70 Mouse News Lett 17 52 Bahary N Siegel DA Walsh J Zhang Y Leopold L Leibel R et al September 1993 Microdissection of proximal mouse chromosome 6 identification of RFLPs tightly linked to the ob mutation Mammalian Genome 4 9 511 515 doi 10 1007 BF00364786 PMID 7906968 S2CID 2130385 Friedman JM Leibel RL 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University Archived from the original on 2013 08 29 Retrieved 2013 08 08 Jeffrey Friedman receives Shaw Prize for discovery of leptin News Medical net 2009 The Lasker Foundation 2010 Awards Lasker Foundation 2010 Archived from the original on 2016 02 24 Retrieved 2013 08 08 BBVA Foundation Frontiers of Knowledge Awards BBVA Foundation 2012 Archived from the original on 2016 10 06 Retrieved 2013 08 08 KFF KFIP Winners 2013 Medicine King Faisal Foundation 2013 Archived from the original on 2013 12 02 Retrieved 2013 08 08 Shell E 2002 On the Cutting Edge The Hungry Gene The Inside Story of the Obesity Industry Atlantic Monthly Press ISBN 978 1 4223 5243 4 page needed Shell E 2002 Hunger The Hungry Gene The Inside Story of the Obesity Industry Atlantic Monthly Press ISBN 978 1 4223 5243 4 page needed Pool R 2001 Fat fighting the obesity epidemic New York Oxford University Press ISBN 978 0 19 511853 7 page needed Kolata GB 2007 Rethinking thin the new science of weight loss and the myths and realities of dietin New York Farrar ISBN 978 0 374 10398 9 page needed Castracane VD Henson MC 2006 The Obese Ob Ob Mouse and the Discovery of Leptin In Castracane VD Henson MC eds Leptin Endocrine Updates Vol 25 pp 1 9 doi 10 1007 978 0 387 31416 7 1 ISBN 978 0 387 31415 0 External links editLeptin Your brain appetite and obesity by the British Society of Neuroendocrinology Leptin by Colorado State University last updated 1998 Leptin at 3Dchem com description and structure diagrams Overview of all the structural information available in the PDB for UniProt P41159 Leptin at the PDBe KB nbsp Wikimedia Commons has media related to Leptin Retrieved from https en wikipedia org w index php title Leptin amp oldid 1193725494, wikipedia, wiki, book, books, library,

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