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Summary: Leptin
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Leptin | |||||||||
Structure of the obese protein leptin-E100.[1] |
Identifiers | |||||||||
Symbol | Leptin | ||||||||
Pfam | PF02024 | ||||||||
Pfam clan | CL0053 | ||||||||
InterPro | IPR000065 | ||||||||
SCOP | 1ax8 | ||||||||
SUPERFAMILY | 1ax8 | ||||||||
Leptin (Greek λεπτός (leptos) meaning "thin") is a 16-kDa protein hormone that plays a key role in regulating energy intake and expenditure, including appetite/hunger, metabolism, as well as behavior. It is one of the most important adipose-derived hormones.[2] Leptin functions by binding to the leptin receptor. The Ob(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans.[3]
Contents |
[edit] Discovery
The effects of leptin were observed by studying mutant obese mice that arose at random within a mouse colony at the Jackson Laboratory in 1950.[4] These mice were morbidly obese and excessively voracious. Ultimately, several strains of laboratory mice have been found to be homozygous for single-gene mutations that cause them to become obese, and they fall into two classes: "ob/ob", those having mutations in the gene for the protein hormone leptin, and "db/db", those having mutations in the gene that encodes the receptor for leptin. When ob/ob mice are treated with injections of leptin, they lose their excess fat and return to normal body weights.
Leptin itself was co-discovered in 1994 by Jeffrey M. Friedman and Rudolph Leibel at the Rockefeller University and Douglas L. Coleman through the study of such mice.[3][5][6][7]
[edit] Biosynthesis
Human leptin is a protein of 167 amino acids. It is manufactured primarily in the adipocytes of white adipose tissue, and the level of circulating leptin is proportional to the total amount of fat in the body.
In addition to white adipose tissue—the major source of leptin—it can also be produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (the lower part of the fundic glands), mammary epithelial cells, bone marrow, pituitary, and liver.[8]
Leptin has also been discovered to be synthesized from gastric chief cells and P/D1 cells in the stomach.[9]
[edit] Function
Leptin acts on receptors in the hypothalamus of the brain, where it inhibits appetite
- counteracting the effects of neuropeptide Y (a potent feeding stimulant secreted by cells in the gut and in the hypothalamus)
- counteracting the effects of anandamide (another potent feeding stimulant that binds to the same receptors as THC)
- promoting the synthesis of α-MSH, an appetite suppressant.
This appetite inhibition is long-term, in contrast to the rapid inhibition of eating 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 food intake and resulting obesity. Several studies have shown fasting or following a very-low-calorie diet (VLCD) lowers leptin levels.[10] In the short-term, leptin might be an indicator of energy balance. This system is more sensitive to starvation than to overfeeding; leptin levels change more when food intake decreases than when it increases.[11] The dynamics of leptin due to an acute change in energy balance may be related to appetite and eventually to food intake. Although this is a new hypothesis, some data already support it.[12][13]
Controversy is ongoing regarding the regulation of leptin by melatonin during the night. One research group suggested increased levels of melatonin caused a downregulation of leptin.[14] However, in 2004, Brazilian researchers found melatonin to increase leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping.[15]
Mice with type 1 diabetes treated with leptin alone or in conjunction with insulin did better (blood sugar did not fluctuate as much; cholesterol levels decreased; less body fat formed) than those treated with insulin alone, raising the prospect of a new treatment for diabetes.[16]
[edit] Adiposity signal
To date, only leptin and insulin are known to act as adiposity signals. In general,
- Leptin circulates at levels directly proportional to body fat.
- It enters the central nervous system in proportion to its plasma concentration.
- Its receptors are found in brain neurons involved in regulating energy intake and expenditure.
- It controls food intake and energy expenditure by acting on receptors in the mediobasal hypothalamus.[17]
[edit] Interaction with amylin
Coadministration of two neurohormones known to have a role in body weight control, amylin (produced by beta cells in the pancreas) and leptin (produced by fat cells), results in sustained, fat-specific weight loss in a leptin-resistant animal model of obesity.[18]
[edit] Satiety
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 the brain that the body has had enough to eat, producing a feeling of satiety. Moreover, this fullness hormone may make it easier for people to resist the temptation of foods high in calories.[19]
Circulating leptin levels give the brain input regarding energy storage, so it can regulate appetite and metabolism. Leptin works by inhibiting the activity of neurons that contain neuropeptide Y (NPY) and agouti-related peptide (AgRP), and by increasing the activity of neurons expressing α-melanocyte-stimulating hormone (α-MSH). The NPY neurons are a key element in the regulation of appetite; 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 receptor at which α-MSH acts in the brain are linked to obesity in humans.
A very small group of humans possesses homozygous mutations for the leptin gene, leading to a constant desire for food and resulting in severe obesity. This condition can be treated somewhat successfully by the administration of recombinant human leptin.[20][21] However, extensive clinical trials using recombinant human leptin as a therapeutic agent for treating obesity in humans have been inconclusive because only the most obese subjects who were given the highest doses of exogenous leptin produced statistically significant weight loss. Large and frequent doses are needed to provide only modest benefit because of leptin's low circulating half-life, low potency, and poor solubility. Furthermore, these injections caused some participants to drop out of the study due to inflammatory responses of the skin at the injection site. Some of these problems can be alleviated by a form of leptin called Fc-leptin, which takes the Fc fragment from the immunoglobulin gamma chain as the N-terminal fusion partner and follows it with leptin. This Fc-leptin fusion has been experimentally proven to be highly soluble, more biologically potent, and contain a much longer serum half-life. As a result, this Fc-leptin was successfully shown to treat obesity in both leptin-deficient and normal mice, although studies have not been undertaken on human subjects. This makes Fc-leptin a potential treatment for obesity in humans after more extensive testing.[22][23][24]
[edit] 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, which is a predisposing factor in patients with obesity.[25]
Exogenous leptin can promote angiogenesis by increasing vascular endothelial growth factor levels.
In some epidemiological studies, hyperleptinemia is considered as a risk factor. However, a few animal experiments demonstrated systemic hyperleptinemia produced by infusion or adenoviral gene transfer decreases blood pressure in rats.[26][27]
[edit] Lung surfactant activity
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.[28]
[edit] Reproduction
In mice, leptin is also required for male and female fertility. It has a lesser effect in humans. In mammals such as humans, 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. Some studies have indicated leptin levels outside an ideal range can have a negative effect on egg quality and outcome during in vitro fertilization.[29]
The body's fat cells, under normal conditions, are responsible for the constant production and release of leptin. This can also be produced by the placenta.[30] Leptin levels rise during pregnancy and fall after parturition (childbirth). Leptin is also expressed in fetal membranes and the uterine tissue. Uterine contractions are inhibited by leptin.[31]
Leptin plays a role in hyperemesis gravidarum (severe morning sickness of pregnancy),[32] in polycystic ovary syndrome[33] and hypothalamic leptin is implicated in bone growth.[34] It has been shown that high levels of Leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche.[35] This may eventually lead to shorter stature as oestrogen secretion starts during menarche and causes early closure of epiphyses.
[edit] Effects on bone
Leptin's ability to regulate bone mass was first recognized in 2000.[36] Leptin can affect bone metabolism via direct signalling from the brain, and although leptin acts to reduce cancellous bone, it conversely increases cortical bone. A number of theories have been put forward concerning the cortical-cancellous dichotomy, including a recent theory suggesting increased leptin during obesity may represent a mechanism for enlarging bone size and thus bone resistance to cope with increased body weight.[37]
Bone metabolism is under direct control of the brain, so nerve fibres are present in bone tissue.[38] 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.[38][39] This evidence supports a direct signalling system between the brain and bone with accumulating evidence suggesting that these molecules are directly involved in the regulation of bone metabolism. Leptin, once released from fat tissue, can cross the blood–brain barrier and bind to its receptors in the brain, where it acts through the sympathetic nervous system to regulate bone metabolism.[40] In addition to its effects through the brain, leptin may act directly on cells in the bone to regulate bone metabolism. In reality, leptin probably signals to bone on multiple levels, with local and systemic checks and balances impacting the final outcome.[citation needed] As a result, the clinical utility of leptin for treatment of bone diseases remains open, but ongoing research may yet provide much-needed therapies for stimulating bone formation.
[edit] Clinical significance
Leptin has traditionally been regarded as a link between fat mass, food intake, and energy expenditure. This link originally arose from animal research findings, but its application to describing human systems has since been challenged.[41] 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 level is decreased after short-term fasting (24–72 hours), even when changes in fat mass are not observed.[42]
- In obese patients with obstructive sleep apnea, leptin level is increased, but decreased after the administration of continuous positive airway pressure.[43][44] In non-obese individuals, however, restful sleep (i.e., 8–12 hours of unbroken sleep) can increase leptin to normal levels.
- Serum level of leptin is reduced by sleep deprivation.[45][46] However, a recent study showed that sleep deprivation was linked with higher levels of leptin.
- Leptin level is increased by perceived emotional stress.[47]
- Leptin level is decreased or increased by increases in testosterone or estrogen level, respectively.[48]
- Leptin level is chronically reduced by physical exercise training.[49]
[edit] Inflammatory marker
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,[50][51][52] 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][51][53] Circulating leptin seems to affect the HPA axis, suggesting a role for leptin in stress response.[54] Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.[55]
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.[56] 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.[57]
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.[58] (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.)[59] Furthermore, plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis, concurrent hypocaloric dieting and weight loss notwithstanding.[60] 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.
[edit] Obesity and leptin resistance
Although leptin reduces appetite as a circulating signal, obese individuals generally exhibit an unusually high circulating concentration of leptin.[61] These people are said to be resistant to the effects of leptin, in much the same way that people with type 2 diabetes are resistant to the effects of insulin. The sustained high concentrations of leptin from the enlarged adipose stores result in leptin desensitization. The pathway of leptin control in obese people might be flawed at some point, so the body does not adequately receive the satiety feeling subsequent to eating.
Some researchers attempted to explain the failure of leptin to prevent obesity in modern humans as a metabolic disorder, possibly caused by a specific nutrient or a combination of nutrients not present or uncommon in the prehistoric diet. Some proposed "villain" nutrients include lectins[62] and fructose.[63]
A signal-to-noise ratio theory has been proposed to explain the phenomenon of leptin resistance.[41] In healthy individuals, baseline leptin levels are between 1 and 5 ng/dl in men and 7 and 13 ng/dl in women.[41] A large intake of calories triggers a leptin response that reduces hunger, thereby preventing an overload of the inflammatory response induced by caloric intake. In obese individuals, the leptin response to caloric intake is theorized to be blunted due to chronic, low-grade hyperleptinemia, depressing the signal-to-noise ratio such that acute leptin responses have less of a physiological effect on the body.
Although leptin resistance is sometimes described as a metabolic disorder that contributes to obesity, similar to the way insulin resistance is sometimes described as a metabolic disorder that has the potential to progress into type 2 diabetes, it is not certain that it is true in most cases. The mere fact that leptin resistance is extremely common in obese individuals suggests it may simply be an adaptation to excess body weight. The major physiological role of leptin is suggested to be not as a "satiety signal" to prevent obesity in times of energy excess, but as a "starvation signal" to maintain adequate fat stores for survival during times of energy deficit,[64][65] and leptin resistance in overweight individuals is the standard feature of mammalian physiology, which possibly confers a survival advantage.[66]
A different form of leptin resistance (in combination with insulin resistance and weight gain) easily arises in laboratory animals (such as rats), as soon as they are given unlimited (ad libitum) access to palatable, energy-dense foods,[67] and it is reversed when these animals are put back on low energy-density chow.[68] That, too, may have an evolutionary advantage: "the ability to efficiently store energy during periods of sporadic feast represented a survival advantage in ancestral societies subjected to periods of starvation."[69] The combination of two mechanisms (one, which temporarily suspends leptin action when presented with excess of high-quality food, and the other, which blunts the processes that could drive the body weight back to "normal"), could explain the current obesity epidemic without invoking any metabolic disorders or "villain" nutrients.
Although the notion of obesity as a state of 'leptin resistance' has become ingrained in the minds of many researchers, some observations do not directly support this contention. For example, the work of Rudolph Leibel at Columbia University has shown that, in both obese and lean individuals, leptin injections do not reduce body mass. Despite the lack of response in obese and lean subjects, there is little argument that lean subjects are also leptin-resistant; hence, whether obese subjects are in fact resistant to leptin remains to be empirically demonstrated. This finding also underscores the notion that the brain is not designed to respond to increased leptin by decreasing food intake; rather, as discussed above, lack of leptin acts as a signal to increase food intake. Indeed, Leibel's work has shown that the decreases in serum leptin that occur post-weight-loss constitute a state of leptin deficiency, which drives increased appetite. As such, leptin injections in weight-reduced patients can prevent the increases in appetite and thereby allow patients to maintain weight loss. These studies therefore demonstrate that leptin treatment may be a useful strategy to treat obesity in humans, if not by driving weight loss directly then by allowing weight loss (as a result of diet and exercise) to be more readily maintained.
[edit] Interactions with fructose
The consumption of high amounts of fructose is suggested to cause leptin resistance and elevated triglycerides in rats. The rats consuming the high-fructose diet subsequently ate more and gained more weight than controls when fed a high-fat, high-calorie diet.[63][70][71] These studies, however, did not control against other monosaccharides or polysaccharides, therefore leptin resistance may be a result of a diet that contains high saccharide indices (soda, candy, and other foods with easily liberated sugar).[citation needed]
[edit] Leptin and weight regain
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.[72]
A decline in levels of circulating leptin also changes brain activity in areas involved in the regulatory, emotional, and cognitive control of food intake that are reversed by administration of leptin.[72]
[edit] Mechanism of action
Leptin interacts with six types of receptors (Ob-Ra–Ob-Rf, or LepRa-LepRf), that in turn are encoded by a single gene, LEPR.[73] Ob-Rb is the only receptor isoform that can signal intracellularly via the Jak-Stat and MAPK signal transduction pathways,[74] and is present in hypothalamic nuclei.[75]
Whether leptin can cross the blood–brain barrier to access receptor neurons is unknown, because the blood–brain barrier is attenuated in the area of the median eminence, close to where the NPY neurons of the arcuate nucleus are located. 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.
Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to presumably effect changes in gene expression. One of the main effects on gene expression is the down-regulation of the expression of endocannabinoids, responsible for increasing appetite.[citation needed] Other intracellular pathways are activated by leptin, but less is known about how they function in this system. In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them.
Leptin action is recognized to be more decentralized than previously assumed. In addition to its endocrine action at a distance (from adipose tissue to brain), leptin also acts as a paracrine mediator.[8]
Recently, 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.[76]
[edit] Metreleptin
An analog of human leptin, metreleptin, is under investigation for the treatment of diabetes and/or hypertriglyceridemia, in patients with rare forms of lipodystrophy, syndromes characterized by abnormalities in adipose tissue distribution, and severe metabolic abnormalities. Amylin Pharmaceuticals, the drug's developer, has received orphan drug designation for metreleptin from the US Food and Drug Administration (FDA) Office of Orphan Products Development, as well as fast track designation for this indication. In a three-year study of metreleptin in patients with lipodystrophy organized by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health, metreleptin treatment was associated with a significant decrease in blood glucose (A1c decreased from 9.4% at baseline to 7.0% at study end) and triglyceride concentration (from 500 mg/dl at baseline to 200 mg/dl at study end).[77] The Juvenile Diabetes Research Foundation has also partnered with Amylin Pharmaceuticals and researchers at the University of Texas Southwestern Medical Center to study whether metreleptin can be used to improve the treatment of type 1 diabetes.[78]
[edit] See also
[edit] References
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- ^ Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G (January 2000). "Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass". Cell 100 (2): 197–207. doi:10.1016/S0092-8674(00)81558-5. PMID 10660043.
- ^ Hamrick MW, Ferrari SL (July 2008). "Leptin and the sympathetic connection of fat to bone". Osteoporos Int 19 (7): 905–912. doi:10.1007/s00198-007-0487-9. PMID 17924050.
- ^ a b Allison SJ, Herzog H (2006). "NPY and bone". EXS (95): 171–82. PMID 16383006.
- ^ Gordeladze JO, Reseland JE (March 2003). "A unified model for the action of leptin on bone turnover". J. Cell. Biochem. 88 (4): 706–712. doi:10.1002/jcb.10385. PMID 12577304.
- ^ Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G (November 2002). "Leptin regulates bone formation via the sympathetic nervous system". Cell 111 (3): 305–317. doi:10.1016/S0092-8674(02)01049-8. PMID 12419242.
- ^ a b c Pilon B. "Leptin and Inflammation | Inflammation Theory". Press75.com. Retrieved 2011-04-19.
- ^ Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS (May 2003). "The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men". J. Clin. Invest. 111 (9): 1409–1421. doi:10.1172/JCI17490. PMC 154448. PMID 12727933.
- ^ Zirlik S, Hauck T, Fuchs FS, Neurath MF, Konturek PC, Harsch IA (February 2011). "Leptin, Obestatin and Apelin levels in patients with obstructive sleep apnoea syndrome". Med. Sci. Monit. 17 (3): CR159–64. PMID 21358603.
- ^ Harsch IA, Konturek PC, Koebnick C, Kuehnlein PP, Fuchs FS, Pour Schahin S, Wiest GH, Hahn EG, Lohmann T, Ficker JH (August 2003). "Leptin and ghrelin levels in patients with obstructive sleep apnoea: effect of CPAP treatment". Eur. Respir. J. 22 (2): 251–257. doi:10.1183/09031936.03.00010103. PMID 12952256.
- ^ Seaborg, E (2007). "Growing evidence links too little sleep to obesity and diabetes". Endocrine News: 14–15.
- ^ Knutson KL, Spiegel K, Penev P, Van Cauter E (June 2007). "The metabolic consequences of sleep deprivation". Sleep Med Rev 11 (3): 163–178. doi:10.1016/j.smrv.2007.01.002. PMC 1991337. PMID 17442599.
- ^ Otsuka R, Yatsuya H, Tamakoshi K, Matsushita K, Wada K, Toyoshima H (October 2006). "Perceived psychological stress and serum leptin concentrations in Japanese men". Obesity (Silver Spring) 14 (10): 1832–1838. doi:10.1038/oby.2006.211. PMID 17062814.
- ^ Ahima RS, Flier JS (2000). "Leptin". Annu. Rev. Physiol. 62: 413–437. doi:10.1146/annurev.physiol.62.1.413. PMID 10845097.
- ^ de Salles BF, Simão R, Fleck SJ, Dias I, Kraemer-Aguiar LG, Bouskela E (July 2010). "Effects of resistance training on cytokines". Int J Sports Med 31 (7): 441–450. doi:10.1055/s-0030-1251994. PMID 20432196.
- ^ Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI (August 1998). "Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression". Nature 394 (6696): 897–901. doi:10.1038/29795. PMID 9732873.
- ^ a b Fantuzzi G, Faggioni R (October 2000). "Leptin in the regulation of immunity, inflammation, and hematopoiesis". J. Leukoc. Biol. 68 (4): 437–46. PMID 11037963.
- ^ Caldefie-Chezet F, Poulin A, Tridon A, Sion B, Vasson MP (March 2001). "Leptin: a potential regulator of polymorphonuclear neutrophil bactericidal action?". J. Leukoc. Biol. 69 (3): 414–8. PMID 11261788.
- ^ Madej T, Boguski MS, Bryant SH (October 1995). "Threading analysis suggests that the obese gene product may be a helical cytokine". FEBS Lett. 373 (1): 13–18. doi:10.1016/0014-5793(95)00977-H. PMID 7589424.
- ^ Heiman ML, Ahima RS, Craft LS, Schoner B, Stephens TW, Flier JS (September 1997). "Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress". Endocrinology 138 (9): 3859–3863. doi:10.1210/en.138.9.3859. PMID 9275075.
- ^ Mabuchi T, Yatsuya H, Tamakoshi K, Otsuka R, Nagasawa N, Zhang H, Murata C, Wada K, Ishikawa M, Hori Y, Kondo T, Hashimoto S, Toyoshima H (2005). "Association between serum leptin concentration and white blood cell count in middle-aged Japanese men and women". Diabetes Metab. Res. Rev. 21 (5): 441–447. doi:10.1002/dmrr.540. PMID 15724240.
- ^ Hamilton BS, Paglia D, Kwan AY, Deitel M (September 1995). "Increased obese mRNA expression in omental fat cells from massively obese humans". Nat. Med. 1 (9): 953–956. doi:10.1038/nm0995-953. PMID 7585224.
- ^ Perrier S, Caldefie-Chezet F, Vasson MP. (2009) L-1 family in breast cancer: potential interplay with leptin and other adipocytokines. FEBS Lett. 583(2):259-65>http://www.ncbi.nlm.nih.gov/pubmed/19111549
- ^ Wabitsch M, Jensen PB, Blum WF, Christoffersen CT, Englaro P, Heinze E, Rascher W, Teller W, Tornqvist H, Hauner H (October 1996). "Insulin and cortisol promote leptin production in cultured human fat cells". Diabetes 45 (10): 1435–1438. doi:10.2337/diabetes.45.10.1435. PMID 8826983.
- ^ LaPensee CR, Hugo ER, Ben-Jonathan N (November 2008). "Insulin stimulates interleukin-6 expression and release in LS14 human adipocytes through multiple signaling pathways". Endocrinology 149 (11): 5415–5422. doi:10.1210/en.2008-0549. PMC 2584585. PMID 18617614.
- ^ Worm D, Vinten J, Vaag A, Henriksen JE, Beck-Nielsen H (September 2000). "The nicotinic acid analogue acipimox increases plasma leptin and decreases free fatty acids in type 2 diabetic patients". Eur. J. Endocrinol. 143 (3): 389–395. doi:10.1530/eje.0.1430389. PMID 11022182.
- ^ Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL (February 1996). "Serum immunoreactive-leptin concentrations in normal-weight and obese humans". N. Engl. J. Med. 334 (5): 292–295. doi:10.1056/NEJM199602013340503. PMID 8532024.
- ^ Jönsson T, Olsson S, Ahrén B, Bøg-Hansen TC, Dole A, Lindeberg S (2005). "Agrarian diet and diseases of affluence--do evolutionary novel dietary lectins cause leptin resistance?". BMC Endocr Disord 5: 10. doi:10.1186/1472-6823-5-10. PMC 1326203. PMID 16336696.
- ^ a b Shapiro A, Mu W, Roncal C, Cheng KY, Johnson RJ, Scarpace PJ (November 2008). "Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding". Am. J. Physiol. Regul. Integr. Comp. Physiol. 295 (5): R1370–5. doi:10.1152/ajpregu.00195.2008. PMC 2584858. PMID 18703413.
- ^ Oswal A, Yeo G (February 2010). "Leptin and the control of body weight: a review of its diverse central targets, signaling mechanisms, and role in the pathogenesis of obesity". Obesity (Silver Spring) 18 (2): 221–9. doi:10.1038/oby.2009.228. PMID 19644451.
- ^ Banks WA, Farr SA, Morley JE (June 2006). "The effects of high fat diets on the blood-brain barrier transport of leptin: failure or adaptation?". Physiol. Behav. 88 (3): 244–8. doi:10.1016/j.physbeh.2006.05.037. PMID 16781741.
- ^ Myers MG, Cowley MA, Münzberg H (2008). "Mechanisms of leptin action and leptin resistance". Annu. Rev. Physiol. 70: 537–556. doi:10.1146/annurev.physiol.70.113006.100707. PMID 17937601.
- ^ Wang J, Obici S, Morgan K, Barzilai N, Feng Z, Rossetti L (December 2001). "Overfeeding rapidly induces leptin and insulin resistance". Diabetes 50 (12): 2786–2791. doi:10.2337/diabetes.50.12.2786. PMID 11723062.
- ^ Enriori PJ, Evans AE, Sinnayah P, Jobst EE, Tonelli-Lemos L, Billes SK, Glavas MM, Grayson BE, Perello M, Nillni EA, Grove KL, Cowley MA (March 2007). "Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons". Cell Metab. 5 (3): 181–194. doi:10.1016/j.cmet.2007.02.004. PMID 17339026.
- ^ Obici S, Rossetti L (December 2003). "Minireview: nutrient sensing and the regulation of insulin action and energy balance". Endocrinology 144 (12): 5172–8. doi:10.1210/en.2003-0999. PMID 12970158.
- ^ "Fructose Sets Table For Weight Gain Without Warning". Science News. Science Daily. 2008-10-19. Retrieved 2008-11-15.
- ^ Vasselli JR (November 2008). "Fructose-induced leptin resistance: discovery of an unsuspected form of the phenomenon and its significance. Focus on "Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding," by Shapiro et al". Am. J. Physiol. Regul. Integr. Comp. Physiol. 295 (5): R1365–R1369. doi:10.1152/ajpregu.90674.2008. PMID 18784330.
- ^ a b Ahima RS (July 2008). "Revisiting leptin's role in obesity and weight loss". J. Clin. Invest. 118 (7): 2380–3. doi:10.1172/JCI36284. PMC 2430504. PMID 18568083.
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- ^ Malendowicz W, Rucinski M, Macchi C, Spinazzi R, Ziolkowska A, Nussdorfer GG, Kwias Z (October 2006). "Leptin and leptin receptors in the prostate and seminal vesicles of the adult rat". Int. J. Mol. Med. 18 (4): 615–8. PMID 16964413.
- ^ "LepRb antibody (commercial site)".
- ^ Ciriello J, Moreau JM (November 2012). "Systemic administration of leptin potentiates the response of neurons in the nucleus of the solitary tract to chemoreceptor activation in the rat". J. Neuroscience 229: 88–99. doi:10.1016/j.neuroscience.2012.10.065.
- ^ "Amylin to Present Data Showing Investigational Metreleptin Treatment Led to Long-Term Improvements in Diabetes and Lipid Control in Patients with Lipodystrophy". Press Release. Amylin Pharmaceuticals. 2011-04-15. Retrieved 2011-10-27.
- ^ "JDRF & Amylin Partner to Investigate Therapy to Improve Blood Glucose Control". Press Release. JDRF.
[edit] Further reading
- Torday JS, Sun H, Wang L, Torres E, Sunday ME, Rubin LP (March 2002). "Leptin mediates the parathyroid hormone-related protein paracrine stimulation of fetal lung maturation". Am. J. Physiol. Lung Cell Mol. Physiol. 282 (3): L405–10. PMC 2942763. PMID 11839533.
- Torday JS, Rehan VK (July 2002). "Stretch-stimulated surfactant synthesis is coordinated by the paracrine actions of PTHrP and leptin". Am. J. Physiol. Lung Cell Mol. Physiol. 283 (1): L130–5. doi:10.1152/ajplung.00380.2001 (inactive 2010-08-06). PMID 12060569.
- Dubey L, Hesong Z (2006). "Role of leptin in atherogenesis". Exp Clin Cardiol 11 (4): 269–75. PMC 2274849. PMID 18651016.
- Friedman JM, Halaas JL (1998). "Leptin and the regulation of body weight in mammals". Nature 395 (6704): 763–770. doi:10.1038/27376. PMID 9796811.
- Prolo P, Wong ML, Licinio J (1999). "Leptin". Int. J. Biochem. Cell Biol. 30 (12): 1285–1290. doi:10.1016/S1357-2725(98)00094-6. PMID 9924798.
- Heshka JT, Jones PJ (2001). "A role for dietary fat in leptin receptor, OB-Rb, function". Life Sci. 69 (9): 987–1003. doi:10.1016/S0024-3205(01)01201-2. PMID 11508653.
- Janeckova R (2002). "The role of leptin in human physiology and pathophysiology". Physiological research / Academia Scientiarum Bohemoslovaca 50 (5): 443–59. PMID 11702849.
- Lee DW, Leinung MC, Rozhavskaya-Arena M, Grasso P (2002). "Leptin and the treatment of obesity: its current status". Eur. J. Pharmacol. 440 (2–3): 129–139. doi:10.1016/S0014-2999(02)01424-3. PMID 12007531.
- Al-Daghri N, Bartlett WA, Jones AF, Kumar S (2002). "Role of leptin in glucose metabolism in type 2 diabetes". Diabetes, obesity & metabolism 4 (3): 147–155. doi:10.1046/j.1463-1326.2002.00194.x. PMID 12047393.
- Sabath Silva EF (2002). "[Leptin]". Rev. Invest. Clin. 54 (2): 161–5. PMID 12053815.
- Thomas T, Burguera B (2003). "Is leptin the link between fat and bone mass?". J. Bone Miner. Res. 17 (9): 1563–1569. doi:10.1359/jbmr.2002.17.9.1563. PMID 12211425.
- Kraemer RR, Chu H, Castracane VD (2002). "Leptin and exercise". Exp. Biol. Med. (Maywood) 227 (9): 701–8. PMID 12324651.
- Waelput W, Brouckaert P, Broekaert D, Tavernier J (2003). "A role for leptin in the systemic inflammatory response syndrome (SIRS) and in immune response". Current drug targets. Inflammation and allergy 1 (3): 277–289. doi:10.2174/1568010023344634. PMID 14561193.
- Stenvinkel P, Pecoits-Filho R, Lindholm B (2004). "Leptin, ghrelin, and proinflammatory cytokines: compounds with nutritional impact in chronic kidney disease?". Advances in renal replacement therapy 10 (4): 332–345. doi:10.1053/j.arrt.2003.08.009. PMID 14681862.
- Cohen P, Ntambi JM, Friedman JM (2004). "Stearoyl-CoA desaturase-1 and the metabolic syndrome". Curr. Drug Targets Immune Endocr. Metabol. Disord. 3 (4): 271–280. doi:10.2174/1568008033340117. PMID 14683458.
- Sahu A (2004). "Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance". Frontiers in neuroendocrinology 24 (4): 225–253. doi:10.1016/j.yfrne.2003.10.001. PMID 14726256.
- Elefteriou F, Karsenty G (2004). "[Bone mass regulation by leptin: a hypothalamic control of bone formation]". Pathol. Biol. 52 (3): 148–153. doi:10.1016/j.patbio.2003.05.006. PMID 15063934.
- Blüher S, Mantzoros CS (2004). "The role of leptin in regulating neuroendocrine function in humans". J. Nutr. 134 (9): 2469S–2474S. PMID 15333744.
- Farooqi S, O'Rahilly S (2007). "Genetics of obesity in humans". Endocr. Rev. 27 (7): 710–18. doi:10.1210/er.2006-0040. PMID 17122358.
- Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL (February 1996). "Serum immunoreactive-leptin concentrations in normal-weight and obese humans". N. Engl. J. Med. 334 (5): 292–5. doi:10.1056/NEJM199602013340503. PMID 8532024.
[edit] External links
- Leptin in a bulletin by the Howard Hughes Medical Institute (HHMI)
- Leptin: Your brain, appetite and obesity by the British Society of Neuroendocrinology
- Leptin/ghrelin and their role in obesity from hungerhormones.com, a weight control website
- Leptin by Colorado State University
- Leptin at 3Dchem.com, description and structure diagrams
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This is the Wikipedia entry entitled "Teleost leptins". More...
Teleost leptins Edit Wikipedia article
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.
Contents |
[edit] Examples
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.
[edit] 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]
[edit] 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]
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 to 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]
[edit] Tissue distribution
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).
[edit] 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.
[edit] 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.
[edit] References
- ^ Zhang F, Basinski MB, Beals JM, et al. (May 1997). "Crystal structure of the obese protein leptin-E100". Nature 387 (6629): 206–9. doi:10.1038/387206a0. PMID 9144295.
- ^ Boswell T, Dunn IC, Wilson PW, Joseph N, Burt DW, Sharp PJ (April 2006). "Identification of a non-mammalian leptin-like gene: characterization and expression in the tiger salamander (Ambystoma tigrinum)". Gen. Comp. Endocrinol. 146 (2): 157–66. doi:10.1016/j.ygcen.2005.08.001. PMID 16480984.
- ^ a b c Crespi EJ, Denver RJ (June 2006). "Leptin (ob gene) of the South African clawed frog Xenopus laevis". Proc. Natl. Acad. Sci. U.S.A. 103 (26): 10092–7. doi:10.1073/pnas.0507519103. PMC 1502511. PMID 16782821. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1502511.
- ^ a b c d e f g h i j k Kurokawa T, Uji S, Suzuki T (May 2005). "Identification of cDNA coding for a homologue to mammalian leptin from pufferfish, Takifugu rubripes". Peptides 26 (5): 745–50. doi:10.1016/j.peptides.2004.12.017. PMID 15808904.
- ^ a b c d e f g h i j k l m n Rønnestad I, Nilsen TO, Murashita K, Angotzi AR, Moen A-GG, Stefansson SO, Kling P, Björnsson BTh, Kurokawa T (in press). "Leptin and leptin receptor genes in Atlantic salmon: cloning, phylogeny, tissue distribution and expression correlated to long-term feeding status". General and Comparative Endocrinology.
- ^ a b c d e Murashita K, Uji S, Yamamoto T, Rønnestad I, Kurokawa T (August 2008). "Production of recombinant leptin and its effects on food intake in rainbow trout (Oncorhynchus mykiss)". Comp. Biochem. Physiol. B, Biochem. Mol. Biol. 150 (4): 377–84. doi:10.1016/j.cbpb.2008.04.007. PMID 18539064.
- ^ Frøiland E, Murashita K, Jørgensen EH, Kurokawa T (January 2010). "Leptin and ghrelin in anadromous Arctic charr: cloning and change in expressions during a seasonal feeding cycle". Gen. Comp. Endocrinol. 165 (1): 136–43. doi:10.1016/j.ygcen.2009.06.010. PMID 19539626.
- ^ a b Li X, He J, Hu W, Yin Z (June 2009). "The essential role of endogenous ghrelin in growth hormone expression during zebrafish adenohypophysis development". Endocrinology 150 (6): 2767–74. doi:10.1210/en.2008-1398. PMID 19264876.
- ^ a b c d e f g h i Huising MO, Geven EJ, Kruiswijk CP, Nabuurs SB, Stolte EH, Spanings FA, Verburg-van Kemenade BM, Flik G (December 2006). "Increased leptin expression in common Carp (Cyprinus carpio) after food intake but not after fasting or feeding to satiation". Endocrinology 147 (12): 5786–97. doi:10.1210/en.2006-0824. PMID 16935838.
- ^ a b c d e f g h i Kurokawa T, Murashita K (April 2009). "Genomic characterization of multiple leptin genes and a leptin receptor gene in the Japanese medaka, Oryzias latipes". Gen. Comp. Endocrinol. 161 (2): 229–37. doi:10.1016/j.ygcen.2009.01.008. PMID 19523397.
- ^ a b c d e f g h Gorissen M, Bernier NJ, Nabuurs SB, Flik G, Huising MO (June 2009). "Two divergent leptin paralogues in zebrafish (Danio rerio) that originate early in teleostean evolution". J. Endocrinol. 201 (3): 329–39. doi:10.1677/JOE-09-0034. PMID 19293295.
- ^ Jaillon O, Aury JM, Brunet F, Petit JL, Stange-Thomann N, Mauceli E, Bouneau L, Fischer C, Ozouf-Costaz C, Bernot A, Nicaud S, Jaffe D, Fisher S, Lutfalla G, Dossat C, Segurens B, Dasilva C, Salanoubat M, Levy M, Boudet N, Castellano S, Anthouard V, Jubin C, Castelli V, Katinka M, Vacherie B, Biémont C, Skalli Z, Cattolico L, Poulain J, De Berardinis V, Cruaud C, Duprat S, Brottier P, Coutanceau JP, Gouzy J, Parra G, Lardier G, Chapple C, McKernan KJ, McEwan P, Bosak S, Kellis M, Volff JN, Guigó R, Zody MC, Mesirov J, Lindblad-Toh K, Birren B, Nusbaum C, Kahn D, Robinson-Rechavi M, Laudet V, Schachter V, Quétier F, Saurin W, Scarpelli C, Wincker P, Lander ES, Weissenbach J, Roest Crollius H (October 2004). "Genome duplication in the teleost fish Tetraodon nigroviridis reveals the early vertebrate proto-karyotype". Nature 431 (7011): 946–57. doi:10.1038/nature03025. PMID 15496914.
- ^ Allendorf FW, Thorgaard G (1984). "Tetraploidy and the evolution of salmonid fishes". In Turner BJ. Evolutionary genetics of fishes. New York: Plenum Press. pp. 1–45. ISBN 0-306-41520-8.
- ^ a b Kurokawa T, Murashita K, Suzuki T, Uji S (August 2008). "Genomic characterization and tissue distribution of leptin receptor and leptin receptor overlapping transcript genes in the pufferfish, Takifugu rubripes". Gen. Comp. Endocrinol. 158 (1): 108–14. doi:10.1016/j.ygcen.2008.06.003. PMID 18582469.
- ^ a b Li GG, Liang XF, Xie Q, Li G, Yu Y, Lai K (March 2010). "Gene structure, recombinant expression and functional characterization of grass carp leptin". Gen. Comp. Endocrinol. 166 (1): 117–27. doi:10.1016/j.ygcen.2009.10.009. PMID 19857495.
- ^ Guex N, Peitsch MC, Schwede T (June 2009). "Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: a historical perspective". Electrophoresis 30 Suppl 1: S162–73. doi:10.1002/elps.200900140. PMID 19517507.
- ^ a b c d e f Moen A-GG, Rønnestad I, Stefansson SO, Kling P, Björnsson BT, Taranger GL, Finn RN (submitted). "Short-term, but not long-term feed restriction causes differential expression of leptins in Atlantic salmon". General and Comparative Endocrinology.
- ^ York IA, Rock KL (1996). "Antigen processing and presentation by the class I major histocompatibility complex". Annu. Rev. Immunol. 14: 369–96. doi:10.1146/annurev.immunol.14.1.369. PMID 8717519.
- ^ Zhang Y, Olbort M, Schwarzer K, Nuesslein-Hildesheim B, Nicolson M, Murphy E, Kowalski TJ, Schmidt I, Leibel RL (November 1997). "The leptin receptor mediates apparent autocrine regulation of leptin gene expression". Biochem. Biophys. Res. Commun. 240 (2): 492–5. doi:10.1006/bbrc.1997.7622. PMID 9388507.
- ^ de Pedro N, Martínez-Alvarez R, Delgado MJ (March 2006). "Acute and chronic leptin reduces food intake and body weight in goldfish (Carassius auratus)". J. Endocrinol. 188 (3): 513–20. doi:10.1677/joe.1.06349. PMID 16522731.
- ^ Volkoff H, Eykelbosh AJ, Peter RE (May 2003). "Role of leptin in the control of feeding of goldfish Carassius auratus: interactions with cholecystokinin, neuropeptide Y and orexin A, and modulation by fasting". Brain Res. 972 (1-2): 90–109. doi:10.1016/S0006-8993(03)02507-1. PMID 12711082.
- ^ Johnson RM, Johnson TM, Londraville RL (June 2000). "Evidence for leptin expression in fishes". J. Exp. Zool. 286 (7): 718–24. PMID 10797324.
- ^ Baker DM, Larsen DA, Swanson P, Dickhoff WW (April 2000). "Long-term peripheral treatment of immature coho salmon (Oncorhynchus kisutch) with human leptin has no clear physiologic effect". Gen. Comp. Endocrinol. 118 (1): 134–8. doi:10.1006/gcen.1999.7450. PMID 10753575.
- ^ Silverstein JT, Plisetskaya EM (2000). "The effects of NPY and insulin on food intake regulation in fish". American Zoologist 40 (2): 296–308. doi:10.1093/icb/40.2.296.
- ^ Londraville RL, Duvall CS (October 2002). "Murine leptin injections increase intracellular fatty acid-binding protein in green sunfish (Lepomis cyanellus)". Gen. Comp. Endocrinol. 129 (1): 56–62. PMID 12409096.
- ^ Baumann H, Morella KK, White DW, Dembski M, Bailon PS, Kim H, Lai CF, Tartaglia LA (August 1996). "The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors". Proc. Natl. Acad. Sci. U.S.A. 93 (16): 8374–8. doi:10.1073/pnas.93.16.8374. PMC 38678. PMID 8710878. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=38678.
- ^ Tartaglia LA (March 1997). "The leptin receptor". J. Biol. Chem. 272 (10): 6093–6. doi:10.1074/jbc.272.10.6093. PMID 9102398.
- ^ Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW, Myers MG (February 2003). "STAT3 signalling is required for leptin regulation of energy balance but not reproduction". Nature 421 (6925): 856–9. doi:10.1038/nature01388. PMID 12594516.
- ^ Liu Q, Chen Y, Copeland D, Ball H, Duff RJ, Rockich B, Londraville RL (April 2010). "Expression of leptin receptor gene in developing and adult zebrafish". Gen. Comp. Endocrinol. 166 (2): 346–55. doi:10.1016/j.ygcen.2009.11.015. PMID 19941865.
- ^ Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O'Rahilly S (June 1997). "Congenital leptin deficiency is associated with severe early-onset obesity in humans". Nature 387 (6636): 903–8. doi:10.1038/43185. PMID 9202122.
- ^ Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (December 1994). "Positional cloning of the mouse obese gene and its human homologue". Nature 372 (6505): 425–32. doi:10.1038/372425a0. PMID 7984236.
- ^ a b Kling P, Rønnestad I, Stefansson SO, Murashita K, Kurokawa T, Björnsson BT (July 2009). "A homologous salmonid leptin radioimmunoassay indicates elevated plasma leptin levels during fasting of rainbow trout". Gen. Comp. Endocrinol. 162 (3): 307–12. doi:10.1016/j.ygcen.2009.04.003. PMID 19362558.
- ^ Aursand M, Bleivik B, Rainuzzo JR, Jørgensen L, Mohr V (1994). "Lipid distribution and composition of commercially farmed Atlantic salmon (Salmo salar)". J. Sci. Food Agric. 64 (2): 239–248. doi:10.1002/jsfa.2740640214.
- ^ 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.
- ^ 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
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
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
Pseudofam: | PF02024 |
SCOP: | 1ax8 |
SYSTERS: | Leptin |
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.
Cellular component | extracellular region (GO:0005576) |
Molecular function | hormone activity (GO:0005179) |
Biological process | signal transduction (GO:0007165) |
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
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...
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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) |
Jalview | ||||||||
PP/heatmap | 1 | |||||||
Pfam viewer |
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
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) |
Raw Stockholm | ||||||||
Gzipped |
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...
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.
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
HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details: |
Model length: | 146 | ||||||||||||
Family (HMM) version: | 10 | ||||||||||||
Download: | download the raw HMM for this family |
Species distribution
Sunburst controls
ShowThis 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...
Tree controls
HideThe tree shows the occurrence of this domain across different species. More...
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.
There is 1 interaction for this family. More...
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.
Loading structure mapping...


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Autumn Barber with the twins, Anson Timothy (left) and Ayla James (right), who were born in January. Autumn's husband, Tempe police Detective Tim Barber lost his battle with prostate cancer on Aug. 27, 2011. Autumn and Tim's family and friends, carry on Tim's message of fighting against prostate cancer and the importance for men to get checked for it. (Photo courtesy of Steponme Photo)
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Brittany Barber (holding babies), older daughter of Tempe police Detective Tim Barber with her sister, Ayla James (left) and brother, Anson Timothy (right), twins born in January. Brittany returned home from attending Northern Arizona University in Flagstaff to help take care of her father who lost his battle against prostate cancer on Aug. 27, 2011. (Photo courtesy of Autumn Barber)
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Echo Press hires new graphic designer
Hometown girl Kendall Brickweg is the newest addition to the Echo Press team. Brickweg joins the local newspaper as a graphic designer.
Hometown girl Kendall Brickweg is the newest addition to the Echo Press team. Brickweg joins the local newspaper as a graphic designer.
Born and raised in Alexandria, Brickweg graduated from Jefferson High School in 2008 and went on to study fine arts at the University of Minnesota Duluth before earning her Associate degree in Communication Art and Design at Alexandria Technical and Community College.
"I decided that what I would really like to do is become a graphic designer and wanted to focus on getting my degree and a fast track education for graphics instead of liberal education," Brickweg said.
Brickweg has worked as a graphic designer locally for American Solutions for Business, Lakes Area Graphix and PhotoMagic. She interned with Johnson Group Marketing in St. Cloud.
Brickweg enjoys creating typography and looks forward to working on all the extra publications and projects the Echo Press publishes. She sees the wide variety of work and being directly involved with the community as added bonuses to her position.
Newlywed this fall, Brickweg lives with her husband, Bryce, on Lake Blackwell in Farwell with their two dogs, Willa and Kiana. In her spare time she likes to spend time with family, friends and dogs. Hobbies include crafting, running, Pilates, shopping and watching movies.
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'The "door of faith" (Acts 14:27) is always open for us, ushering us into the life of communion with God and offering entry into his Church. It is possible to cross that threshold when the word of God is proclaimed and the heart allows itself to be shaped by transforming grace. To enter through that door is to set out on a journey that lasts a lifetime.' (par1)
These are the opening words of Pope Benedict's Apostolic Letter, Porta Fidei, introducing the Year of Faith which began on 11th October 2012 and which will run through until the Feast of Christ the King on 24th November 2013. From conversations with other people it would appear that the Year of Faith has captured the minds and imagination of many Catholics. It was certainly heartening at the meeting of our own Diocesan Council of Laity in November 2012 to see that parishes across the diocese have drawn up plans for a whole variety of celebrations, events, pilgrimages and discussions during this coming year. There was also the wish expressed that at least some of our special events should be done together with other Christian Churches.
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Staff Writer
CHARLESTON - On Nov. 21, a memorandum decision was handed down by the West Virginia Supreme Court in the matter of Case No. 11-1206; Lonnie Hannah, Sheriff of Mingo County, West Virginia, Petitioner vs. Max Jeremy Mounts, Respondent.
The decision rendered stated that Mounts, a deputy sheriff, would serve in his original position until the Civil Service Commission determined whether his resignation was accepted before it was rescinded.
Mounts allegedly resigned from his position as a deputy sheriff in November 2010. However, the next day, he claims to have visited Mingo County Sheriff Lonnie Hannah's house, withdrawing that resignation, according to the information provided by court documents.
Court documents stated that Hannah told him to come in Monday to talk more about his decision, but Mounts said that when he went to the sheriff's office, Hannah reportedly told him he already had accepted the resignation and that he was no longer employed as a deputy.
Mounts filed a motion for reinstatement before the Civil Service Commission but the commission ruled that the resignation became effective the day he resigned, agreeing with Sheriff Hannah. The commission did not rule to reinstate Mounts, but said his name would be placed at the top of the roster for those applying for the position in the future.
Following the ruling, the Mingo County Circuit Court found the record was unclear whether his resignation was accepted before it was rescinded. The circuit court said there were only two options available to the commission and that was to either reinstate or not reinstate Mounts, the ruling to have him placed on the potential hire list was not acceptable.
In its Nov. 21 memorandum decision, the state Supreme Court referenced a similar case, West Virginia Department of Environmental Protection vs. Falquero, which ruled a public employee could rescind a resignation before an effective date as long as the employer has not yet accepted it.
In addition, justices said the acceptance of a resignation occurs when an employer "clearly indicates acceptance through communication with the employee, or acts in good faith reliance on the tender," which counsel for the respondent, C. Christopher Younger, claims did not occur in this case. The memorandum decision stated that it is the sole responsibility of the Civil Service Commission to determine if Hannah accepted the resignation before Mounts rescinded it.
The case will once again be presented to the Civil Service Commission on Jan. 10, 2013, which will be after Sheriff Hannah's term as sheriff concludes and the sheriff-elect, Eugene Crum assumes the position. More information regarding this matter will be released as it becomes available.


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The fog was less than 100 feet from our balcony when Louis took this photo. He normally points the lens over both of the freeways below (I-80; I-580), but if you look across the bottom of the image, you'll see that Louis didn't do that this time and cars on I-580 are visible.


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Welcome all new and old members of the Bremen HospEx community
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Skipper has become somewhat chubby, so in the interest of exercise, meet Prissy! She's a Pom/Chi mix from the shelter. He's about 75% ok and 25% PO'd. I see a beautiful future together. Meet Prissy! | |||
Her she is! | ||||
Prissy is the name the shelter gave her and I'm not liking it. I had a dog named Prissy about 30 years ago and the memory of her is painful. so I'm open to suggestions! | ||||
Look at that smile! Very sweet - everyone getting along? Try Cissy - it will sound familiar enough to her and won't be too much the same for you. | ||||
Hold on! I had a clever thought - Skipper and MaryAnn??? OK - that was for giggles but it is cute! | ||||
yep, that's a giggle. DH likes Foxy. I don't. Men are so simple minded. she reminds me of something, but I can't quite get it. she has light brown eyes, her coat is all white with a dusting of cream. Skipper is ready for the play date to be over. I'm keeping her separated from Aslan until she's spayed and recovered. | ||||
DH suggested an alteration in her name from Prissy to Little Miss Priss. Emphasis on Priss. I can do that. | ||||
What a couple of cuties! Whether You Think You Can Or You Think You Can't..... You're Right - Henry Ford | ||||
I think little Priss is a sweetheart; so glad you had room in your heart and home for her! Skipper is going to be so excited once he gets to play with her (after her surgery) and Aslan will be in high heaven ~ another member of his "pack" to look after. Great job, Sandra, someone needed a friend and you found her! Happy here... | ||||
We are truly blessed with our pack. Skipper is being all male protective, but hopefully when Prissy is healed properly, she can stand up for herself. Aslan is very gentle with her. Miss Priss was feeling poorly after surgery last night. Had to have her supper brought to her, carried down the steps to pee, just a baby. She perked up today, but is still being careful. Our pack is complete now. 2 big, 2 little. Everyone has a playmate. And I'm sworn off Petfinder. Rescues are like potato chips. | ||||
Awwww, she's a little beauty. It sounds like you have a very happy house hold. G*d bless you and dh for taking in these sweet babies and giving them a happy home and much love! | ||||
The white one is Prissy. for those who's memory is about like mine. | ||||
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WASHINGTON (AP) — Federal Reserve Chairman Ben Bernanke said Monday that it's important that Congress raise the nation's borrowing limit before the Treasury runs out of maneuvering room to avoid a potential default on U.S. debt.
Bernanke, speaking at the University of Michigan, said the approaching debt limit is one of the "critical fiscal watersheds" for the government in coming weeks.
President Barack Obama also spoke Monday about the urgency of raising the limit. Obama said he wouldn't let congressional Republicans use the debt limit as leverage in negotiations over spending cuts.
Bernanke noted that an impasse over the debt ceiling in 2011 led to a rating downgrade of long-term U.S. debt, the first time that's occurred. He said Congress should raise the ceiling to "avoid a situation where our government doesn't pay its bills."
The Fed decided last month to keep buying $85 billion a month in Treasurys and mortgage bonds to try to keep borrowing costs low and encourage more spending. The bond-buying program was left open-ended.
But it turned out that Fed officials differed about how long the bond purchases should continue. When the minutes of the meeting were released Jan. 3, they revealed that "several" committee members thought the purchases should slow or end well before year's end. These officials fear the bond buying is keeping rates so low for so long that it could ignite inflation or encourage speculative buying of risky assets.
Still, many economists have said they think the Fed will maintain its bond purchases at their current level through 2013.
On Monday, Bernanke didn't address the divisions within the Fed. But he said he thought the new round of bond buying was providing key support. He said the Fed will continue to assess the benefits of the bond buying against any risks of continuing the purchases.
Bernanke said the purchases have shown that the Fed still has "ammunition" to aid the economy even after having cut short-term interest rates to near zero.
Last month, the Fed also said it planned to keep its key short-term interest rate at a record low even after unemployment falls close to a normal level — which it said might take three more years. Unemployment remains high at 7.8 percent because the economy is growing too slowly and not creating jobs fast enough. Continued...
In December, employers added 155,000 jobs, roughly matching the monthly average in 2011 and 2012. That's just been enough to slowly reduce the unemployment rate, which fell 0.7 percentage point during 2012.
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