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1  structure 124  species 1  interaction 218  sequences 1  architecture

Family: Leptin (PF02024)

Summary: Leptin

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Not to be confused with Lectin or Lecithin.
Leptin
Leptin.png
PDB rendering based on 1ax8.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols LEP ; LEPD; OB; OBS
External IDs OMIM164160 MGI104663 HomoloGene193 GeneCards: LEP Gene
RNA expression pattern
PBB GE LEP 207092 at tn.png
More reference expression data
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:
127.88 – 127.9 Mb
Chr 6:
29.06 – 29.07 Mb
PubMed search [1] [2]
Leptin
PDB 1ax8 EBI.jpg
Structure of the obese protein leptin-E100.[1]
Identifiers
Symbol Leptin
Pfam PF02024
Pfam clan CL0053
InterPro IPR000065
SCOP 1ax8
SUPERFAMILY 1ax8

Leptin (from Greek λεπτός leptos, "thin"), the "satiety hormone", is a hormone made by fat cells which regulates the amount of fat stored in the body. It does this by adjusting both the sensation of hunger, and adjusting energy expenditures. Hunger is inhibited (satiety) when the amount of fat stored reaches a certain level. Leptin is then secreted and circulates through the body, eventually activating leptin receptors in the arcuate nucleus of the hypothalamus. Energy expenditure is increased both by the signal to the brain, and directly via leptin receptors on peripheral targets. The effect of leptin is opposite to that of ghrelin, the "hunger hormone". Ghrelin receptors are on the same brain cells as leptin receptors, so these cells receive competing satiety and hunger signals.[2] Leptin and ghrelin, along with many other hormones, participate in the complex process of energy homeostasis.

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 multiple sites of synthesis other than fat cells, and the multiple cell types beside hypothalamic cells which have leptin receptors. Many of these additional functions are yet to be defined.[3][4][5][6][7][8]

Discovery of the gene

The existence of a hormone regulating hunger and energy expenditure was hypothesized based on studies of mutant obese mice that arose at random within a mouse colony at the Jackson Laboratory in 1950. Mice homozygous for the ob mutation (ob/ob) ate voraciously and were massively obese.[9] 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.[10][11][12] Rudolph Leibel and Jeffrey M. Friedman reported the mapping of the ob gene in 1990.[13][14][15] 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.[3][4][5][6] In 1994, with the ob gene isolated, Friedman reported the discovery of the gene.[12] In 1995, Caro’s laboratory provided evidence that the mutations present in the mouse ob gene did not occur in humans. Furthermore the ob gene expresion was increased in human obesity, which led to postulate the concept of leptin resistance.[7] At the suggestion of Roger Guillemin, Friedman named this new hormone "leptin" from the Greek lepto meaning thin.[3][16] Leptin was the first fat cell-derived hormone to be discovered. Subsequent studies 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.[17][18][19][20]

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),[21] the Shaw Prize (2009),[22] the Lasker Award,[23] the BBVA Prize[24] and the King Faisal International Prize,[25] 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.[26][27]

The discovery of leptin is also documented in a series of books including Fat: Fighting the Obesity Epidemic by Robert Pool,[28] 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.[29][30] 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.[31] Human leptin is a 16 kDa protein of 167 amino acids.

Sites of synthesis

Leptin is produced primarily in the adipocytes of white adipose tissue. It is also produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (the lower part of the fundic glands), mammary epithelial cells, bone marrow, pituitary, liver,[32]gastric chief cells and P/D1 cells.[33]

Blood levels

Physiologic variation

Leptin circulates in blood in free form and bound to proteins.[34] Leptin levels vary exponentially, not linearly, with fat mass.[35][36][full citation needed] Leptin levels in blood are higher between midnight and early morning, perhaps suppressing appetite during the night.[37] The diurnal rhythm of blood leptin levels can be modified by meal-timing.[38]

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:

Effects

Central (hypothalamic)

Two white mice both with similar sized ears, black eyes, and pink noses: The body of the mouse on the left, however, is about three times the width of the normal-sized mouse on the right.
A comparison of a mouse unable to produce leptin, resulting in obesity (left), and a normal mouse (right)

It is important to recognize that the terms central, primary, and direct are not used interchangeably: Central vs peripheral refers to hypothalamic 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.[56]

Leptin acts on receptors in the hypothalamus, where it inhibits hunger by

  1. counteracting the effects of neuropeptide Y, a potent hunger promoter secreted by cells in the gut and in the hypothalamus.
  2. counteracting the effects of anandamide, another potent hunger promoter that binds to the same receptors as THC.
  3. promoting the synthesis of α-MSH, a hunger suppressant.

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.[57][58][59][60] Leptin levels change more when food intake decreases than when it increases.[61] 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.[62][63]

  • It controls food intake and energy expenditure by acting on receptors in the mediobasal hypothalamus.[64]

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.[65]

Leptin receptor activation inhibits neuropeptide Y (NPY) 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.[66] Ob-Rb is the only receptor isoform that can signal intracellularly via the Jak-Stat and MAPK signal transduction pathways,[67] and is present in hypothalamic nuclei.[68]

Leptin is generally 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.[69]

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.[70] In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them.

Increased levels of melatonin causes a downregulation of leptin.[71] However melatonin also appears to increase leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping.[72] Partial sleep deprivation has also been associated with decreased leptin levels.[73]

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 as much; cholesterol levels decreased; less body fat formed.[74]

Peripheral

Non-hypothalamic targets of leptin are referred to as peripheral targets, in contrast to the hypothalamic target which is the central target. Leptin receptors are found on a wide range of cell types. There is a different relative importance of central and peripheral leptin interactions under different physiologic states, and variations between species.[32] In the periphery leptin is a modulator of energy expenditure, modulator between fetal and maternal metabolism, permissive factor in puberty, activator of immune cells, activator of beta islet cells,and a growth factor. Further, it interacts with other hormones and energy regulators: insulin, glucagon, insulin-like growth factor, growth hormone, glucocorticoids, cytokines, and metabolites.[32]

Circulatory system

The role of leptin/leptin receptors in modulation of T cell activity in immune system was shown in experimentation with mice. It modulates the immune response to atherosclerosis, of which obesity is a predisposing factor.[75]

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.[76][77]

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.[78]

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.[79]

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 can have a negative effect on egg quality and outcome during in vitro fertilization.[80] Leptin is involved in reproduction by stimulating gonadotropin-releasing hormone from the hypothalamus.[81]

Pregnancy

The placenta produces leptin.[82] 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.[83] Leptin plays a role in hyperemesis gravidarum (severe morning sickness of pregnancy),[84] in polycystic ovary syndrome[85] and hypothalamic leptin is implicated in bone growth in mice.[86]

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.[87]

Puberty

Leptin along with kisspeptin controls the onset of puberty.[88] High levels of leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche.[89] 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.[90] 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.[91]

Bone metabolism can be regulated by central sympathetic outflow, since sympathetic pathways innervate bone tissue.[92] 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.[92][93] Leptin binds to its receptors in the hypothalamus, where it acts through the sympathetic nervous system to regulate bone metabolism.[94] Leptin may also act directly on bone metabolism via a balance between energy intake and the IGF-I pathway.[91][95] There is a potential for treatment of diseases of bone formation - such as impaired fracture healing - with leptin.[96]

Brain

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).

  • Deficiency of leptin has been shown to alter brain proteins and neuronal functions of obese mice which can be restored by leptin injection.[97]
  • In humans, low circulating plasma leptin has been associated with cognitive changes associated with anorexia,[98] depression, and HIV.[99]
  • Studies in transgenic mouse models of Alzheimer's disease have shown that chronic administration of leptin can ameliorate brain pathology and improve cognitive performance[100] by reducing b-amyloid and hyperphosphorylated Tau,[101][102] two hallmarks of Alzheimer's pathology.

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,[103][104][105] 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.[1][104][106] Circulating leptin seems to affect the HPA axis, suggesting a role for leptin in stress response.[107] Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.[108]

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. However, while leptin is associated with body fat mass, 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.[109] 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.[110]

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 fat cells' ability 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.[111] (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.)[112] Furthermore, plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis, concurrent hypocaloric dieting and weight loss notwithstanding.[113] Such findings appear to demonstrate high caloric loads in excess of fat cells' storage rate capacities 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.[55]

Role in obesity and weight loss

Obesity

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.[8] 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 or alterations occurring during development.[114]

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[115] In humans it has been observed that the ratio of leptin in the blood compared to the CSF is lower in obese people than in people of a normal weight.[116] 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.[115] 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.[116] 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),[117] 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.[118]

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 which prevents the activation of STAT3 are obese and exhibit hyperphagia. The PI3K pathway may also be involved in leptin resistance, as has been demonstarated in mice by artificial blocking of PI3K signalling. The PI3K pathway is also 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.[119]

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.[120][121] 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 is uncertain if leptin resistance is caused by high levels of carbohydrates or fats, or if an increase or both is needed.[122]

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 reisistance, amylin has been suggested as possible therapy for obesity.[123]

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.[119][124] This would mean that leptin resistance in obese people is a normal part of mammalian physiology and could possibly confer a survival advantage.[114] 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.[125] This effect is reversed when the animals are put back on a low-energy diet.[126] This may also have an evolutionary advantage: allowing energy to be stored efficiently when food is plentiful would be advantageous in populations where food can frequently be scarce.[127]

Mutations

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. No homologous mutation has been found in humans. 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 in order to produce a stop codon, which is much less likely to happen.[7]


Leptin over-expression in adipose tissue has been observed in a number of individuals with morbid obesity. However, the association between leptin mutations and obesity in humans is less clear than in mice. A Human Genome Equivalent (HuGE) review of previous studies looking at the connection between genetic mutations affecting leptin regulation and obesity was published in 2004. As well as looking at a common polymorphism in the leptin gene (A19G; frequency 0.46), they also reviewed 3 mutations in the leptin receptor gene (Q223R, K109R and K656N) and 2 mutations in the PPARG gene (P12A and C161T). They found no association between any of the polymorphisms and obesity.[128]


A meta-analysis found no association between the common LEP-2548 G/A mutation and obesity in the overall results but did find a significant link between obesity and the GG phenotype in the American population.[129] A previous study has found a similar link between the GG phenotype and morbid obesity in Taiwanese aborigines.[130] The -2548A/G polymorphism has been associated with weight gain patients taking antipsychotics.[131][132][133] This polymorphism has also been linked with an increased risk of prostate cancer,[134] gestational diabetes[135] and osteoporosis.[136]

A recessive frameshift mutation resulting in a reduction of leptin has been observed in two consanguineous children with juvenile obesity. Other rare polymorphisms have been found but their association with obesity are not consistent. This may be due to the fact that obesity is a complex problem involving multiple genes as well as environmental influences.[128]

Weight loss

Dieters who lose weight 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. The result is that a person who has lost weight has a lower basal metabolic rate than an individual at the same weight who has never lost weight; these changes are leptin-mediated, homeostatic responses meant to reduce energy expenditure and promote weight regain. Many of these changes are reversed by peripheral administration of recombinant leptin to restore pre-diet levels.[137]

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.[137]

Therapeutic use

Leptin

Leptin has not been approved for any therapeutic use.

Analog

Main article: Metreleptin

An analog of human leptin, metreleptin (trade name Myalept), has been approved in Japan for metabolic disorders including lipodystrophy. In the United States it is approved as a treatment for complications of leptin deficiency, including diabetes and hypertriglyceridemia, in people with congenital generalized or acquired generalized lipodystrophy.[138][139]

See also

References

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This is the Wikipedia entry entitled "Teleost leptins". More...

Teleost leptins Edit Wikipedia article

Leptin
PDB 1ax8 EBI.jpg
Structure of the obese protein leptin-E100.[1]
Identifiers
Symbol Leptin
Pfam PF02024
Pfam clan CL0053
InterPro IPR000065
SCOP 1ax8
SUPERFAMILY 1ax8

Teleost leptins are a family of peptide hormones found in fish (teleostei) that are orthologs of the mammalian hormone leptin. The teleost and mammalian leptins appear to have similar functions, namely, regulation of energy intake and expenditure.

The leptin (LEP) hormone was long thought to be specific to mammals, but in recent years the gene (lep) has been found in amphibia such as the tiger salamander (Ambystoma tigrinum),[2] and the African clawed frog (Xenopus laevi).[3] The discovery of lep in puffer fish (Takifugu rubripes)[4] demonstrates the ancient ancestry of this hormone.

Examples

Figure 1. Phylogenetic tree of vertebrate leptins

There are two closely related lep paralogues in Atlantic salmon (Salmo salar).[5] A single lep gene has been documented for green-spotted pufferfish (Tetraodon nigroviridis),[4] rainbow trout (Oncorhynchus mykiss),[6] Arctic charr (Salvelinus alpinus),[7] silver carp (Hypophthalmichthys molitrix), and grass carp (Ctenopharyngodon idellus).[8] In other species there are reports of two closely related lep paralogues, including common carp (Cyprinus carpio)[9] and Atlantic salmon.[5] More distantly related lep genes have been found in medaka (Oryzias latipes)[10] and zebrafish (Danio rerio).[11] At least 2 leptin genes (lepa and lepb) exist in the crown-clade (Fig. 1).[4][9][10][11] Early findings have shown that lepa and lepb share low interspecies aa identity, and are argued to have arisen through whole genome duplication,[4] which occurred early in the teleost lineage.[12] The duplicity of genes has been described for Atlantic salmon, Japanese medaka, common carp and zebrafish.[5][9][10][11] Both lep paralogues[5] cluster with lepa, and therefore suggest that at least one or more form (lepb) may exist in this species, since it is tetraploid.[13] However, previous attempts using genomic synteny have only found the putative genomic duplicates in medaka and zebrafish paralogue.[10][11] Currently it remains unclear, whether lepb exists in other teleosts due to the degenerative nature of this paralogue.

Comparison with mammalian leptin

The large differences among endothermic (warm-blooded) mammalian and ectothermic (cold-blooded) teleost leptins raised the question of whether the energy homeostatic functions of the teleost leptins are conserved. Initial phylogenetic analysis has revealed that amino acid conservation with other vertebrate Lep orthologues is low, with only 13.2% sequence identity between torafugu and human LEP.[4] Subsequent investigations have confirmed the low amino acid identity of teleost leps compared to mammalian LEP.[4][9][14][15]

Structure

The three-dimensional homology modeling predicts strong conservation of the tertiary structure between Atlantic salmon and other teleost Leps compared to their mammalian orthologues (Fig. 2).[4][5][6][10][11]

Figure 2. Homology models (created using the SwissProt ProModII homology modeling server[16]) of Atlantic salmon leptins (lepa1, lepa2) compared to the crystallographic structure (PDB 1AX8) of human leptin (LEP). The human leptin structure shows the four anti-parallel α-helices (1, 2, 4, 5) with corresponding domains in the Atlantic salmon proteins. The C-terminal cysteine is depicted as ball and stick diagram.[17]

Both lepa1 and lepa2 have two characteristic cysteine residues which predict the formation of a disulfide bond in Lep, which is a pre-equisite for this 3D configuration and bioactivity of human LEP.[18][19] The models suggest that the bonding of lepa2 might be different from lepa1. There are several differences between the 3D structures of lepa1 and lepa2; e.g. α-helix 5 is considerable shorter in lepa1 than lepa2. Furthermore α-helix 1 for lepa2 appears to be split by a short-disordered region, and may therefore have a poorer affinity. However, considering that it is a predicted model based upon the structure mask of human LEP, the significance of these putative conformational adjustments remains to be tested.

The importance of the conserved tertiary structure of Lep is most likely explained by requirements for specific LepR-binding affinity and is constrained by the structure of the receptor-binding pocket.[3] This might also explain some of the results from studies on teleost using heterologous mammalian Lep. E.g. treatment with the mammalian hormone caused an anorexic effect in goldfish (Carassius auratus)[20][21] and green sunfish (Lepomis cyanellus),[22] but not in Coho salmon (Oncorhynchus kisutch),[23] channel catfish (Ictalurus punctatus) [24] and green sunfish.[25] These contradicting results have been explained by the relatively large differences in amino acid sequences observed between mammals and fish.[3][4][9]

Rønnestad and colleagues[5] recently detected five isoforms of the leptin receptor (lepr) that have differences in 3'-end of the mRNA sequence. Of these, only the longest form conserved all functionally important domains (such as three fibronectin type III domains, the Ig C2-like domain, a pair of WSXWS motifs, two JAK2-binding motif boxes, and a STAT-binding domain),[5] while the other four forms have only the intra-cellular region. The long form of mammalian LepR has a function for full signal transduction through the JAK/STAT pathways, whereas the shorter forms exhibit partial or no signaling capabilities.[26][27] The biological importance of long form LepR via the JAK/STAT pathway in maintaining body weight and energy homeostasis has been demonstrated.[28] Previous studies in teleosts have only identified a single lepr.[10][14][29] Rønnestad et al.,[5] is the first to report that plural LepR transcripts in any ectotherm species. When looking at the available motif for lepr, the model suggests that it would bind easily to lepa1 and not lepa2 (Fig. 2). Furthermore the relatively ubiquitous expression of lepr in salmon tissues supports diverse roles of lep in teleosts.[5]

Tissue distribution

Fig. 3. Summary of the tissue distribution of the distantly related lep genes and more closely related lep paralogues in teleost.

The study on torafugu[4] indicated that lep is mainly expressed in the liver in contrasts to the adipose secretion in mammals.[30][31] However recent studies have shown that lep is expressed in several peripheral tissues, including intestine, kidney, ovary, muscle and adipose tissue.[5][6][10] The multiplicity of lep genes and their low conservation in Teleostei.[9][10][11] suggest that their physiological roles may be more divergent than reported for mammals.

The tissue expression pattern for the Atlantic salmon lep paralogues differs substantially (Fig.3)[5] and hence indicates a possible difference in function. With the exception of the results presented here, and those for zebrafish and Japanese medaka.[5][10][11] Few studies have investigated the broad tissue distribution of lep in teleost fishes. The more distantly related lep genes (lepa and lepb) showed distinct differences in tissue distribution, as shown in e.g. medaka, where lepa is being expressed in liver and muscle, while lepb is more highly expressed in the brain and eye. However, these differences are also observed for more closely related lep paralogues, such as lepa1 in Atlantic salmon, being more highly expressed in brain, liver and white muscle, while lepa2 is mainly expressed in the stomach and midgut. (Fig. 3).

Effects of nutritional status

The observations that long-term feed restriction does not significantly affect lep expression in Atlantic salmon[5] has also been noted in other teleosts. However it is likely that prolonged feed restriction can influence several endocrine parameters to adapt to the nutritional condition. For example in common carp, a rapid response in ob gene expression in hepatic tissue of common carp shortly after feeding, but no changes in expression in response to different long-term feeding regime was observed.[9] These authors suggested that this effect could be explained by the fact that starved fish do not lose weight as rapidly as mammals, a consequence of being ectothermic and possessing a much lower standard metabolic rate, and therefore can withstand longer periods of starvation. A similar study on grass carp showed that chronic injection of species-specific Lep did not affect long-term food intake and body weight, while acute injection decreased food intake.[8] Conversely, Murashita et al., (unpublished results) observed increased proopiomelanocortin a1(pomca1) levels following chronic injection of Lep in Atlantic salmon, which suggests that chronic exposure to elevated Lep levels can decrease food intake through the Pomc pathway in this species. Recent studies in Atlantic salmon did not observe any difference of feed restriction in circulating plasma levels,[17] which contrasts recent results in rainbow trout[32] and suggest that the relation between circulating lep levels and energy status differs from that in mammals. However, salmon RIA appears to allow interspecies assessment of plasma lep levels.[32] This only confirms that more comprehensive studies are needed for conclusive data interpretation. Studies on rainbow trout also implicated Lep as an anorectic hormone as in mammals. Injection of rainbow trout with recombinant trout leptin (rt-leptin) resulted in a significantly reduced appetite over two days that coincided with a decrease in hypothalamic mRNA expression of neuropeptide Y (npy) and increase of pomc mRNAs, respectively.[6] Whether these observations are due to species-specific differences in long-term leptin regulation of appetite or growth is not known, however, consensus data indicate that the effects of Lep on appetite regulation may be short-term in teleosts.

Short-term feed restriction

Recent studies on short-term effects of a meal or the absence of a meal[17] has revealed that lepa1 expression specifically peaks in the peripheral tissues after 6 – 9 hr in the unfed fish. This suggests that the transcript specific response could be associated with the absence of food. Conversely, since the unfed fish had not received food for 33 hr (24 + 9 hr), the peaks could represent an unrelated effect. Each lepa1 peak occurred during a phase of falling plasma Lep, and since this occurred in both fed and unfed fish, the temporal upregulation of lepa1 does not in fact appear to be specifically related to the absence of food.

The earliest peak of lepa1 occurred in the white muscle, which represents an important lipid reservoir in Atlantic salmon.[33] Unlike pufferfish, which utilizes the liver as a major lipid repository,[4] Atlantic salmon shows that despite a high visceral lipid content, hepatocytes contain few lipid droplets compared to other fish species,[34] yet are an important site for leptin expression.[4][5][6][9][11][17] Moen and colleagues[17] reported that both lepa1 and lepa2 peaked at 9 hr in the liver of unfed fish. By contrast, however, studies in common carp demonstrated a peak in leptin-I(lepa1) and leptin–II (lepa2) in liver at 3 and 6 hr post feeding respectively.[9] The earlier expression response of leptins in common carp likely reflects the higher temperature under which the experiments were conducted, but contrasts the findings of upregulation of lepa1 due to the absence of food.[17] Similarly, in mice, a postprandial increase in hepatic leptin expression has also been reported.[35] However, in grass carp, intraperitoneal injection of recombinant leptin only alters the appetite on the first day, and does not influence food intake during the ensuing 12 days.[15] At present, the data for Atlantic salmon are therefore quite different and suggest that leptin expression in this species may have a complex lipostatic function.

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  34. ^ Bruslé J., Gonzàlez i Anadon G (1996). "The structure and function of fish liver". In Datta-Munshi JS, Dutta HM. Fish Morphology. Boca Raton: CRC. pp. 77–93. ISBN 90-5410-289-6. 
  35. ^ Saladin R, De Vos P, Guerre-Millo M, Leturque A, Girard J, Staels B, Auwerx J (October 1995). "Transient increase in obese gene expression after food intake or insulin administration". Nature 377 (6549): 527–9. doi:10.1038/377527a0. PMID 7566150. 

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Leptin Provide feedback

No Pfam abstract.

Literature references

  1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM; , Nature 1994;372:425-432.: Positional cloning of the mouse obese gene and its human homologue PUBMED:7984236 EPMC:7984236

  2. Zhang F, Basinski MB, Beals JM, Briggs SL, Churgay LM, Clawson DK, DiMarchi RD, Furman TC, Hale JE, Hsiung HM, Schoner BE, Smith DP, Zhang XY, Wery JP, Schevitz RW; , Nature 1997;387:206-209.: Crystal structure of the obese protein leptin-E100. PUBMED:9144295 EPMC:9144295


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000065

Leptin, a metabolic monitor of food intake and energy need, is expressed by the ob obesity gene. The protein may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot [PUBMED:7984236], the hormone effectively turning the brain's appetite message off when it senses that the body is satiated. Obese humans have high levels of the protein, suggesting a similarity to type II (adult onset) diabetes, in which sufferers over-produce insulin, but can't respond to it metabolically - they have become insulin resistant. Similarly, it is thought that obese individuals may be leptin resistant.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan 4H_Cytokine (CL0053), which has the following description:

Cytokines are regulatory peptides that can be produced by various cells for communicating and orchestrating the large multicellular system. Cytokines are key mediators of hematopoiesis, immunity, allergy, inflammation, tissue remodeling, angiogenesis, and embryonic development [2]. This superfamily includes both the long and short chain helical cytokines.

The clan contains the following 22 members:

CNTF EPO_TPO Flt3_lig GM_CSF Hormone_1 IFN-gamma IL10 IL11 IL12 IL13 IL2 IL22 IL3 IL34 IL4 IL5 IL6 Interferon Leptin LIF_OSM PRF SCF

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(7)
Full
(218)
Representative proteomes NCBI
(189)
Meta
(0)
RP15
(1)
RP35
(3)
RP55
(6)
RP75
(24)
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(7)
Full
(218)
Representative proteomes NCBI
(189)
Meta
(0)
RP15
(1)
RP35
(3)
RP55
(6)
RP75
(24)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(7)
Full
(218)
Representative proteomes NCBI
(189)
Meta
(0)
RP15
(1)
RP35
(3)
RP55
(6)
RP75
(24)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download    
Gzipped Download   Download   Download   Download   Download   Download   Download    

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: PSI-blast P41159
Previous IDs: none
Type: Domain
Author: Bateman A
Number in seed: 7
Number in full: 218
Average length of the domain: 120.30 aa
Average identity of full alignment: 70 %
Average coverage of the sequence by the domain: 91.48 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 25.4 25.0
Noise cut-off 24.9 23.9
Model length: 146
Family (HMM) version: 10
Download: download the raw HMM for this family

Species distribution

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Tree controls

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The tree shows the occurrence of this domain across different species. More...

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Interactions

There is 1 interaction for this family. More...

Leptin

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Leptin domain has been found. There are 1 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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