Leptin Explained

Symbol:Leptin
Leptin
Pfam:PF02024
Pfam Clan:CL0053
Interpro:IPR000065
Scop:1ax8

Leptin (from Greek λεπτός leptos, "thin" or "light" or "small"), also known as obese protein[1], is a protein hormone predominantly made by adipocytes (cells of adipose tissue). Its primary role is likely to regulate long-term energy balance.[2]

As one of the major signals of energy status, leptin levels influence appetite, satiety, and motivated behaviors oriented towards the maintenance of energy reserves (e.g., feeding, foraging behaviors).

The amount of circulating leptin correlates with the amount of energy reserves, mainly triglycerides stored in adipose tissue. High leptin levels are interpreted by the brain that energy reserves are high, whereas low leptin levels indicate that energy reserves are low, in the process adapting the organism to starvation through a variety of metabolic, endocrine, neurobiochemical, and behavioral changes.[3]

Leptin is coded for by the LEP gene. Leptin receptors are expressed by a variety of brain and peripheral cell types. These include cell receptors in the arcuate and ventromedial nuclei, as well as other parts of the hypothalamus and dopaminergic neurons of the ventral tegmental area, consequently mediating feeding.[4] [5]

Although regulation of fat stores is deemed to be the primary function of leptin, it also plays a role in other physiological processes, as evidenced by its many sites of synthesis other than fat cells, and the many cell types beyond hypothalamic cells that have leptin receptors. Many of these additional functions are yet to be fully defined.[6] [7]

In obesity, a decreased sensitivity to leptin occurs (similar to insulin resistance in type 2 diabetes), resulting in an inability to detect satiety despite high energy stores and high levels of leptin.[8]

Effects

See main article: Leptin receptor and Energy expenditure. Predominantly, the "energy expenditure hormone" leptin is made by adipose cells, and is thus labeled fat cell-specific. In the context of its effects, the short describing words central, direct and primary are not used interchangeably. In regard to the hormone leptin, central vs peripheral refers to the hypothalamic portion of the brain vs non-hypothalamic location of action of leptin; direct vs indirect refers to whether there is no intermediary, or there is an intermediary in the mode of action of leptin; and primary vs secondary is an arbitrary description of a particular function of leptin.[9]

Location of action: The central location of action (effect) of the fat cell-specific hormone leptin is the hypothalamus, a part of the brain, which is a part of the central nervous system. Non-hypothalamic targets of leptin are referred to as peripheral targets. There is a different relative importance of central and peripheral leptin interactions under different physiologic states, and variations between species.
Mode of action: Leptin acts directly on leptin receptors in the cell membrane of different types of cells in the human body in particular, and in vertebrates in general. The leptin receptor is found on a wide range of cell types. It is a single-transmembrane-domain type I cytokine receptor,[10] a special class of cytokine receptors. Further, leptin interacts with other hormones and energy regulators, indirectly mediating the effects of: insulin, glucagon, insulin-like growth factor, growth hormone, glucocorticoids, cytokines, and metabolites.
Function: The primary function of the hormone leptin is the regulation of adipose tissue mass through central hypothalamus mediated effects on hunger, food energy use, physical exercise and energy balance. Outside the brain, in the periphery of the body, leptin's secondary functions are: modulation of energy expenditure, modulation between fetal and maternal metabolism, and that of a permissive factor in puberty, activator of immune cells, activator of beta islet cells, and growth factor.

Central nervous system

In vertebrates, the nervous system consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The primary effect of leptins is in the hypothalamus, a part of the central nervous system. Leptin receptors are expressed not only in the hypothalamus but also in other brain regions, particularly in the hippocampus. Thus some leptin receptors in the brain are classified as central (hypothalamic) and some as peripheral (non-hypothalamic).

As scientifically known so far, the general effects of leptin in the central nervous system are:

Generally, leptin is thought to enter the brain at the choroid plexus, where the intense expression of a form of leptin receptor molecule could act as a transport mechanism.[17]

Increased levels of melatonin causes a downregulation of leptin,[18] however, melatonin also appears to increase leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping.[19] Partial sleep deprivation has also been associated with decreased leptin levels.[20]

Mice with type 1 diabetes treated with leptin or leptin plus insulin, compared to insulin alone had better metabolic profiles: blood sugar did not fluctuate so much; cholesterol levels decreased; less body fat formed.[21]

Hypothalamus

Leptin acts on receptors in the lateral hypothalamus to inhibit hunger and the medial hypothalamus to stimulate satiety.[22]

Thus, a lesion in the lateral hypothalamus causes anorexia (due to a lack of hunger signals) and a lesion in the medial hypothalamus causes excessive hunger (due to a lack of satiety signals).[22] 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.[25] [26] [27] [28] Leptin levels change more when food intake decreases than when it increases.[29] 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.[30] [31]

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.[33]

Leptin receptor activation inhibits neuropeptide Y and agouti-related peptide (AgRP), and activates α-melanocyte-stimulating hormone (α-MSH). The NPY neurons are a key element in the regulation of hunger; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic. Conversely, α-MSH is an important mediator of satiety, and differences in the gene for the α-MSH receptor are linked to obesity in humans.

Leptin interacts with six types of receptors (Ob-Ra–Ob-Rf, or LepRa-LepRf), which in turn are encoded by a single gene, LEPR.[34] Ob-Rb is the only receptor isoform that can signal intracellularly via the JAK-STAT and MAPK signal transduction pathways,[35] and is present in hypothalamic nuclei.[36]

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

Circulatory system

The role of leptin/leptin receptors in modulation of T cell activity and the innate immune system was shown in experimentation with mice. It modulates the immune response to atherosclerosis, of which obesity is a predisposing and exercise a mitigating factor.[38] [39]

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.[40] [41]

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.[42]

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.[43]

Reproductive system

Ovulatory cycle

In mice, and to a lesser extent in humans, leptin is required for male and female fertility. Ovulatory cycles in females are linked to energy balance (positive or negative depending on whether a female is losing or gaining weight) and energy flux (how much energy is consumed and expended) much more than energy status (fat levels). When energy balance is highly negative (meaning the woman is starving) or energy flux is very high (meaning the woman is exercising at extreme levels, but still consuming enough calories), the ovarian cycle stops and females stop menstruating. Only if a female has an extremely low body fat percentage does energy status affect menstruation. Leptin levels outside an ideal range may have a negative effect on egg quality and outcome during in vitro fertilization.[44] Leptin is involved in reproduction by stimulating gonadotropin-releasing hormone from the hypothalamus.[45]

Pregnancy

The placenta produces leptin.[46] 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.[47] Leptin plays a role in hyperemesis gravidarum (severe morning sickness of pregnancy),[48] in polycystic ovary syndrome[49] and hypothalamic leptin is implicated in bone growth in mice.[50]

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.[51]

Puberty

Leptin along with kisspeptin controls the onset of puberty.[52] High levels of leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche.[53] This may eventually lead to shorter stature as oestrogen secretion starts during menarche and causes early closure of epiphyses.

Bone

Leptin's role in regulating bone mass was identified in 2000.[54] [55] 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.[56]

Bone metabolism can be regulated by central sympathetic outflow, since sympathetic pathways innervate bone tissue.[57] 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.[57] [58] Leptin binds to its receptors in the hypothalamus, where it acts through the sympathetic nervous system to regulate bone metabolism.[59] Leptin may also act directly on bone metabolism via a balance between energy intake and the IGF-I pathway.[56] [60] There is a potential for treatment of diseases of bone formation - such as impaired fracture healing - with leptin.[61]

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,[62] [63] [64] 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.[63] [65] Circulating leptin seems to affect the HPA axis, suggesting a role for leptin in stress response.[66] Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.[67]

Similar to what is observed in chronic inflammation, chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including hypertension, metabolic syndrome, and cardiovascular disease. While leptin is associated with body fat mass, the size of individual fat cells, and overeating, it is not affected by exercise (for comparison, IL-6 is released in response to muscular contractions). Thus, it is speculated that leptin responds specifically to adipose-derived inflammation.[68] 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.[69] High leptin levels have been also demonstrated in patients with COVID-19 pneumonia.[70]

Taken as such, increases in leptin levels (in response to caloric intake) function as an acute pro-inflammatory response mechanism to prevent excessive cellular stress induced by overeating. When high caloric intake overtaxes the ability of fat cells to grow larger or increase in number in step with caloric intake, the ensuing stress response leads to inflammation at the cellular level and ectopic fat storage, i.e., the unhealthy storage of body fat within internal organs, arteries, and/or muscle. The insulin increase in response to the caloric load provokes a dose-dependent rise in leptin, an effect potentiated by high cortisol levels.[71] (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.)[72] Furthermore, plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis, concurrent hypocaloric dieting and weight loss notwithstanding.[73] Such findings appear to demonstrate high caloric loads in excess of storage rate capacities of fat cells lead to stress responses that induce an increase in leptin, which then operates as an adipose-derived inflammation stopgap signaling for the cessation of food intake so as to prevent adipose-derived inflammation from reaching elevated levels. This response may then protect against the harmful process of ectopic fat storage, which perhaps explains the connection between chronically elevated leptin levels and ectopic fat storage in obese individuals.

Leptin increases the production of leukocytes via actions on the hematopoietic niche, a pathway that is more active in sedentary mice and humans when compared to individuals which are physically active.[39]

Location of gene and structure of hormone

The Ob(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans.[74] Human leptin is a 16-kDa protein of 167 amino acids.

Mutations

A human mutant leptin was first described in 1997,[75] and subsequently six additional mutations were described. All of those affected were from Eastern countries; and all had variants of leptin not detected by the standard immunoreactive technique, so leptin levels were low or undetectable. The most recently described eighth mutation reported in January 2015, in a child with Turkish parents, is unique in that it is detected by the standard immunoreactive technique, where leptin levels are elevated; but the leptin does not turn on the leptin receptor, hence the patient has functional leptin deficiency.[76] These eight mutations all cause extreme obesity in infancy, with hyperphagia.[76]

Nonsense

A nonsense mutation in the leptin gene that results in a stop codon and lack of leptin production was first observed in mice. In the mouse gene, arginine-105 is encoded by CGA and only requires one nucleotide change to create the stop codon TGA. The corresponding amino acid in humans is encoded by the sequence CGG and would require two nucleotides to be changed to produce a stop codon, which is much less likely to happen.

Frameshift

A recessive frameshift mutation resulting in a reduction of leptin has been observed in two consanguineous children with juvenile obesity. A 2001 study of 13 people with a heterozygous frameshift mutation known as delta-G133 found that they had lower blood leptin levels than controls. There was an increased rate of obesity in these individuals, with 76% having a BMI of over 30 compared to 26% in the control group.[77]

Polymorphisms

A Human Genome Equivalent (HuGE) review in 2004 looked at studies of the connection between genetic mutations affecting leptin regulation and obesity. They reviewed a common polymorphism in the leptin gene (A19G; frequency 0.46), three mutations in the leptin receptor gene (Q223R, K109R and K656N) and two mutations in the PPARG gene (P12A and C161T). They found no association between any of the polymorphisms and obesity.[78]

A 2006 study found a link between the common LEP-2548 G/A genotype and morbid obesity in Taiwanese aborigines,[79] [80] but a 2014 meta-analysis did not,[80] however, this polymorphism has been associated with weight gain in patients taking antipsychotics.[81] [82] [83]

The LEP-2548 G/A polymorphism has been linked with an increased risk of prostate cancer,[84] gestational diabetes,[85] and osteoporosis.[86]

Other rare polymorphisms have been found but their association with obesity are not consistent.[78]

Transversion

A single case of a homozygous transversion mutation of the gene encoding for leptin was reported in January 2015.[76] It leads to functional leptin deficiency with high leptin levels in circulation. The transversion of (c.298G → T) changed aspartic acid to tyrosine at position 100 (p.D100Y). The mutant leptin could neither bind to nor activate the leptin receptor in vitro, nor in leptin-deficient mice in vivo. It was found in a two-year-old boy with extreme obesity with recurrent ear and pulmonary infections. Treatment with metreleptin led to "rapid change in eating behavior, a reduction in daily energy intake, and substantial weight loss."[76]

Sites of synthesis

Leptin is produced primarily in the adipocytes of white adipose tissue. It also is produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (the lower part of the fundic glands), mammary epithelial cells, bone marrow,[87] gastric chief cells and P/D1 cells.[88]

Blood levels

Leptin circulates in blood in free form and bound to proteins.[89]

Physiologic variation

Leptin levels vary exponentially, not linearly, with fat mass.[90] [91] Leptin levels in blood are higher between midnight and early morning, perhaps suppressing appetite during the night.[92] The diurnal rhythm of blood leptin levels may be modified by meal-timing.[93]

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:

In mutations

All known leptin mutations except one are associated with low to undetectable immunoreactive leptin blood levels. The exception is a mutant leptin reported in January 2015 which is not functional, but is detected with standard immunoreactive methods. It was found in a massively obese -year-old boy who had high levels of circulating leptin which had no effect on leptin receptors, so he was functionally leptin-deficient.[76]

Role in disease

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. These people show resistance to leptin, similar to resistance of insulin in type 2 diabetes, with the elevated levels failing to control hunger and modulate their weight. A number of explanations have been proposed to explain this. An important contributor to leptin resistance is changes to leptin receptor signalling, particularly in the arcuate nucleus, however, deficiency of, or major changes to, the leptin receptor itself are not thought to be a major cause. Triglycerides crossing the blood brain barrier (BBB) can induce leptin and insulin resistance in the hypothalamus.[111] Triglycerides can also impair leptin transport across the BBB.

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.[112] In humans it has been observed that the ratio of leptin in the CSF compared to the blood is lower in obese people than in people of a normal weight.[113] 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.[112] 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.[113] 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),[114] 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.[115]

When leptin binds with the leptin receptor, it activates a number of pathways. Leptin resistance may be caused by defects in one or more parts of this process, particularly the JAK/STAT pathway. Mice with a mutation in the leptin receptor gene that prevents the activation of STAT3 are obese and exhibit hyperphagia. The PI3K pathway may also be involved in leptin resistance, as has been demonstrated in mice by artificial blocking of PI3K signalling. The PI3K pathway also is activated by the insulin receptor and is therefore an important area where leptin and insulin act together as part of energy homeostasis. The insulin-pI3K pathway can cause POMC neurons to become insensitive to leptin through hyperpolarization. Leptin is known to interact with amylin, a hormone involved in gastric emptying and creating a feeling of fullness. When both leptin and amylin were given to obese, leptin-resistant rats, sustained weight loss was seen. Due to its apparent ability to reverse leptin resistance, amylin has been suggested as possible therapy for obesity.[116]

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.[117] [118] This would mean that leptin resistance in obese people is a normal part of mammalian physiology and possibly, could confer a survival advantage.[119] 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.[120] This effect is reversed when the animals are put back on a low-energy diet.[121] This also may have an evolutionary advantage: allowing energy to be stored efficiently when food is plentiful would be advantageous in populations where food frequently may be scarce.[122]

A fad diet, the Rosedale diet is based on ideas about how leptin might affect weight. It is based on unsound science and marketed with unevidenced claims of health benefits.[123]

Role in osteoarthritis with obesity

Obesity and osteoarthritis

Osteoarthritis and obesity are closely linked. Obesity is one of the most important preventable factors for the development of osteoarthritis.

Originally, the relationship between osteoarthritis and obesity was considered to be exclusively biomechanically based, according to which the excess weight caused the joint to become worn down more quickly. However, today we recognise that there is also a metabolic component which explains why obesity is a risk factor for osteoarthritis, not only for weight-bearing joints (for example, the knees), but also for joints that do not bear weight (for example, the hands).[124] Consequently, it has been shown that decreasing body fat lessens osteoarthritis to a greater extent than weight loss per se.[125] This metabolic component related with the release of systemic factors, of a pro-inflammatory nature, by the adipose tissues, which frequently are critically associated with the development of osteoarthritis.[126] [127] [128] [129] [130]

Thus, the deregulated production of adipokines and inflammatory mediators, hyperlipidaemia, and the increase of systemic oxidative stress are conditions frequently associated with obesity which can favour joint degeneration. Furthermore, many regulation factors have been implicated in the development, maintenance and function, both of adipose tissues, as well as of the cartilage and other joint tissues. Alterations in these factors can be the additional link between obesity and osteoarthritis.

Leptin and osteoarthritis

Adipocytes interact with other cells through producing and secreting a variety of signalling molecules, including the cell signalling proteins known as adipokines. Certain adipokines can be considered as hormones, as they regulate the functions of organs at a distance, and several of them have been specifically involved in the physiopathology of joint diseases. In particular, there is one, leptin, which has been the focus of attention for research in recent years.

The circulating leptin levels are positively correlated with the Body Mass Index (BMI), more specifically with fatty mass, and obese individuals have higher leptin levels in their blood circulation, compared with non-obese individuals. In obese individuals, the increased circulating leptin levels induce unwanted responses, that is, reduced food intake or losing body weight does not occur as there is a resistance to leptin (ref 9). In addition to the function of regulating energy homeostasis, leptin carries out a role in other physiological functions such as neuroendocrine communication, reproduction, angiogenesis and bone formation. More recently, leptin has been recognised as a cytokine factor as well as with pleiotropic actions also in the immune response and inflammation.[131] [132] [133] [134] For example, leptin can be found in the synovial fluid in correlation with the body mass index, and the leptin receptors are expressed in the cartilage, where leptin mediates and modulates many inflammatory responses that can damage cartilage and other joint tissues. Leptin has thus emerged as a candidate to link obesity and osteoarthritis and serves as an apparent objective as a nutritional treatment for osteoarthritis.

As in the plasma, the leptin levels in the synovial fluid are positively correlated with BMI.[135] [136] [137] [138] The leptin of the synovial fluid is synthesised at least partially in the joint and may originate in part in the circulation. Leptin has been shown to be produced by chondrocytes, as well as by other tissues in the joints, including the synovial tissue, osteophytes, the meniscus and bone.[139] [140] [141] [142] An infrapatellar fat pad located extrasynovially within the knee joint is also adjacent to the synovial membrane and cartilage, and has recently been highly appreciated as an important source of leptin, as well as other adipokines and mediators which contribute to the pathogenesis of osteoarthritis [143] [144] [145]

The risk of suffering osteoarthritis can be decreased with weight loss. This reduction of risk is related in part with the decrease of the load on the joint, but also in the decrease of fatty mass, the central adipose tissue and the low-level inflammation associated with obesity and systemic factors.

This growing evidence points to leptin as a cartilage degradation factor in the pathogenesis of osteoarthritis, and as a potential biomarker in the progression of the disease, which suggests that leptin, as well as regulation and signalling mechanisms, can be a new and promising target in the treatment of osteoarthritis, especially in obese patients.

Obese individuals are predisposed to developing osteoarthritis, not only due to the excess mechanical load, but also due to the excess expression of soluble factors, that is, leptin and pro-inflammatory cytokines, which contribute to joint inflammation and cartilage destruction. As such, obese individuals are in an altered state, due to a metabolic insufficiency, which requires specific nutritional treatment capable of normalising the leptin production and reducing the systematic low-level inflammation, in order to reduce the harmful impact of these systematic mediators on the joint health.

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

Therapeutic use

Leptin

Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalized lipodystrophy.[146]

Analog metreleptin

See main article: Metreleptin.

An analog of human leptin metreleptin (trade names Myalept, Myalepta) was first approved in Japan in 2013, and in the United States in February 2014 and in Europe in 2018. In the US it is indicated as a treatment for complications of leptin deficiency, and for the diabetes and hypertriglyceridemia associated with congenital or acquired generalized lipodystrophy.[147] [148] In Europe based on EMA, metreleptin should be used in addition to diet to treat lipodystrophy, where patients have loss of fatty tissue under the skin and build-up of fat elsewhere in the body such as in the liver and muscles. The medicine is used in adults and children above the age of 2 years with generalised lipodystrophy (Berardinelli-Seip syndrome and Lawrence syndrome); and in adults and children above the age of 12 years with partial lipodystrophy (including Barraquer-Simons syndrome), when standard treatments have failed.[149]

The National Health Service in England will commission metreleptin treatment for all with congenital leptin deficiency regardless of age beginning on April 1, 2019.[150]

Research

Leptin is currently being evaluated as a potential target for the treatment of anorexia nervosa.[151] It is hypothesized that the gradual loss of body fat mass, and more specifically the ensuing low leptin levels, escalate the preexisting drive for thinness into an obsessive-compulsive-like and addictive-like state. It was shown that short-term metreleptin treatment of patients with anorexia nervosa had rapid on-set of beneficial cognitive, emotional, and behavioral effects. Among other things, depression, drive for activity, repetitive thoughts of food, inner restlessness, and weight phobia decreased rapidly. Whether metreleptin (or another leptin analogue) is a suitable treatment for anorexia nervosa is currently unknown. Potential side effects are weight loss and the development of anti-metreleptin antibodies.[152]

History

The leptin was discovered by Jeffrey Friedman in 1994 after several decades of research conducted by others institutions since 1950 on obese mouse models [153]

Identification of the encoding gene

In 1949, a non-obese mouse colony being studied at the Jackson Laboratory produced a strain of obese offspring, suggesting that a mutation had occurred in a hormone regulating hunger and energy expenditure. Mice homozygous for the so-called ob mutation (ob/ob) ate voraciously and were massively obese.[154] 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.[155] [156] [157] In 1990 Rudolph Leibel and Jeffrey M. Friedman reported mapping of the db gene.[158] [159] [160]

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.[161] [162] [163] [164]

In 1994, Friedman's laboratory reported the identification of the gene.[157] In 1995, Jose F. Caro's laboratory provided evidence that the mutations in the mouse ob gene did not occur in humans. Furthermore, since ob gene expression was increased, not decreased, in human obesity, it suggested resistance to leptin to be a possibility. At the suggestion of Roger Guillemin, Friedman named this new hormone "leptin" from the Greek lepto meaning thin.[165] Leptin was the first fat cell-derived hormone (adipokine) to be discovered.[166]

Subsequent studies in 1995 confirmed that the db gene encodes the leptin receptor, and that it is expressed in the hypothalamus, a region of the brain known to regulate the sensation of hunger and body weight.[167] [168] [169] [170]

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),[171] the Shaw Prize (2009),[172] the Lasker Award,[173] the BBVA Foundation Frontiers of Knowledge Award[174] and the King Faisal International Prize,[175] 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.[176] [177]

The discovery of leptin also is documented in a series of books including Fat: Fighting the Obesity Epidemic by Robert Pool,[178] 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.[179] [180] 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.

See also

External links

Notes and References

  1. Web site: LEP - Leptin precursor - Homo sapiens (Human) - LEP gene & protein . www.uniprot.org . 8 May 2022 . en.
  2. Al-Hussaniy HA, Alburghaif AH, Naji MA . 2021 . Leptin hormone and its effectiveness in reproduction, metabolism, immunity, diabetes, hopes and ambitions . Journal of Medicine and Life . 14 . 5 . 600–605 . 10.25122/jml-2021-0153 . 8742898 . 35027962.
  3. Hebebrand J, Hildebrandt T, Schlögl H, Seitz J, Denecke S, Vieira D, Gradl-Dietsch G, Peters T, Antel J, Lau D, Fulton S . 6 . The role of hypoleptinemia in the psychological and behavioral adaptation to starvation: Implications for anorexia nervosa . Neuroscience and Biobehavioral Reviews . 141 . 104807 . October 2022 . 35931221 . 10.1016/j.neubiorev.2022.104807 . 251259742 .
  4. Brennan AM, Mantzoros CS . Drug Insight: the role of leptin in human physiology and pathophysiology--emerging clinical applications . Nature Clinical Practice. Endocrinology & Metabolism . 2 . 6 . 318–327 . June 2006 . 16932309 . 10.1038/ncpendmet0196 . 13118779 .
  5. Bouret S, Levin BE, Ozanne SE . Gene-environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity . Physiological Reviews . 95 . 1 . 47–82 . January 2015 . 25540138 . 4281588 . 10.1152/physrev.00007.2014 .
  6. Considine RV, Considine EL, Williams CJ, Nyce MR, Magosin SA, Bauer TL, Rosato EL, Colberg J, Caro JF . 6 . Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity . The Journal of Clinical Investigation . 95 . 6 . 2986–2988 . June 1995 . 7769141 . 295988 . 10.1172/JCI118007 .
  7. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL . 6 . Serum immunoreactive-leptin concentrations in normal-weight and obese humans . The New England Journal of Medicine . 334 . 5 . 292–295 . February 1996 . 8532024 . 10.1056/NEJM199602013340503 . free .
  8. Pan H, Guo J, Su Z . Advances in understanding the interrelations between leptin resistance and obesity . Physiology & Behavior . 130 . 157–169 . May 2014 . 24726399 . 10.1016/j.physbeh.2014.04.003 . 12502104 .
  9. Mantzoros CS . The role of leptin in human obesity and disease: a review of current evidence . Annals of Internal Medicine . 130 . 8 . 671–680 . April 1999 . 10215564 . 10.7326/0003-4819-130-8-199904200-00014 . 12488741 .
  10. Cirillo D, Rachiglio AM, la Montagna R, Giordano A, Normanno N . Leptin signaling in breast cancer: an overview . Journal of Cellular Biochemistry . 105 . 4 . 956–964 . November 2008 . 18821585 . 10.1002/jcb.21911 . 25572220 .
  11. Farr SA, Banks WA, Morley JE . Effects of leptin on memory processing . Peptides . 27 . 6 . 1420–1425 . June 2006 . 16293343 . 10.1016/j.peptides.2005.10.006 . 42496027 .
  12. Casanueva FF, Dieguez C, Popovic V, Peino R, Considine RV, Caro JF . Serum immunoreactive leptin concentrations in patients with anorexia nervosa before and after partial weight recovery . Biochemical and Molecular Medicine . 60 . 2 . 116–120 . April 1997 . 9169091 . 10.1006/bmme.1996.2564 .
  13. Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, DeCarli C, Wolf PA, Seshadri S . 6 . Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging . JAMA . 302 . 23 . 2565–2572 . December 2009 . 20009056 . 2838501 . 10.1001/jama.2009.1836 .
  14. Greco SJ, Bryan KJ, Sarkar S, Zhu X, Smith MA, Ashford JW, Johnston JM, Tezapsidis N, Casadesus G . 6 . Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer's disease . Journal of Alzheimer's Disease . 19 . 4 . 1155–1167 . 2010 . 20308782 . 2862270 . 10.3233/JAD-2010-1308 .
  15. Doherty GH, Beccano-Kelly D, Yan SD, Gunn-Moore FJ, Harvey J . Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β . Neurobiology of Aging . 34 . 1 . 226–237 . January 2013 . 22921154 . 10.1016/j.neurobiolaging.2012.08.003 . 24676545 .
  16. Greco SJ, Sarkar S, Johnston JM, Tezapsidis N . Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells . Biochemical and Biophysical Research Communications . 380 . 1 . 98–104 . February 2009 . 19166821 . 2657956 . 10.1016/j.bbrc.2009.01.041 .
  17. Lynn RB, Cao GY, Considine RV, Hyde TM, Caro JF . Autoradiographic localization of leptin binding in the choroid plexus of ob/ob and db/db mice . Biochemical and Biophysical Research Communications . 219 . 3 . 884–889 . February 1996 . 8645274 . 10.1006/bbrc.1996.0328 .
  18. Kus I, Sarsilmaz M, Colakoglu N, Kukne A, Ozen OA, Yilmaz B, Kelestimur H . Pinealectomy increases and exogenous melatonin decreases leptin production in rat anterior pituitary cells: an immunohistochemical study . Physiological Research . 53 . 4 . 403–408 . 2004 . 10.33549/physiolres.930478 . 15311999 . 1664461 . free .
  19. Alonso-Vale MI, Andreotti S, Peres SB, Anhê GF, das Neves Borges-Silva C, Neto JC, Lima FB . Melatonin enhances leptin expression by rat adipocytes in the presence of insulin . American Journal of Physiology. Endocrinology and Metabolism . 288 . 4 . E805–812 . April 2005 . 15572654 . 10.1152/ajpendo.00478.2004 . 187830 .
  20. Copinschi G . Metabolic and endocrine effects of sleep deprivation . Essential Psychopharmacology . 6 . 6 . 341–347 . 2005 . 16459757 .
  21. Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, Wenner BR, Bain JR, Charron MJ, Newgard CB, Unger RH . 6 . Leptin therapy in insulin-deficient type I diabetes . Proceedings of the National Academy of Sciences of the United States of America . 107 . 11 . 4813–4819 . March 2010 . 20194735 . 2841945 . 10.1073/pnas.0909422107. free . 2010PNAS..107.4813W .
  22. Elmquist JK, Elias CF, Saper CB . From lesions to leptin: hypothalamic control of food intake and body weight . Neuron . 22 . 2 . 221–232 . February 1999 . 10069329 . 10.1016/S0896-6273(00)81084-3 . 1712670 . free .
  23. Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C, Flier JS, Saper CB, Elmquist JK . 6 . Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area . Neuron . 23 . 4 . 775–786 . August 1999 . 10482243 . 10.1016/S0896-6273(01)80035-0 . 18748215 . free .
  24. Fekete C, Légrádi G, Mihály E, Huang QH, Tatro JB, Rand WM, Emerson CH, Lechan RM . 6 . alpha-Melanocyte-stimulating hormone is contained in nerve terminals innervating thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and prevents fasting-induced suppression of prothyrotropin-releasing hormone gene expression . The Journal of Neuroscience . 20 . 4 . 1550–1558 . February 2000 . 10662844 . 6772359 . 10.1523/JNEUROSCI.20-04-01550.2000 .
  25. Dubuc GR, Phinney SD, Stern JS, Havel PJ . Changes of serum leptin and endocrine and metabolic parameters after 7 days of energy restriction in men and women . Metabolism . 47 . 4 . 429–434 . April 1998 . 9550541 . 10.1016/S0026-0495(98)90055-5 .
  26. Pratley RE, Nicolson M, Bogardus C, Ravussin E . Plasma leptin responses to fasting in Pima Indians . The American Journal of Physiology . 273 . 3 Pt 1 . E644–649 . September 1997 . 9316457 . 10.1152/ajpendo.1997.273.3.E644 .
  27. Weigle DS, Duell PB, Connor WE, Steiner RA, Soules MR, Kuijper JL . Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels . The Journal of Clinical Endocrinology and Metabolism . 82 . 2 . 561–535 . February 1997 . 10.1210/jcem.82.2.3757 . 9024254 . 1773/4373 . 7959485 .
  28. Wadden TA, Considine RV, Foster GD, Anderson DA, Sarwer DB, Caro JS . Short- and long-term changes in serum leptin dieting obese women: effects of caloric restriction and weight loss . The Journal of Clinical Endocrinology and Metabolism . 83 . 1 . 214–218 . January 1998 . 9435444 . 10.1210/jcem.83.1.4494 . 7592234 . free .
  29. Chin-Chance C, Polonsky KS, Schoeller DA . Twenty-four-hour leptin levels respond to cumulative short-term energy imbalance and predict subsequent intake . The Journal of Clinical Endocrinology and Metabolism . 85 . 8 . 2685–2691 . August 2000 . 10.1210/jcem.85.8.6755 . 10946866 . free .
  30. Keim NL, Stern JS, Havel PJ . Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women . The American Journal of Clinical Nutrition . 68 . 4 . 794–801 . October 1998 . 9771856 . 10.1093/ajcn/68.4.794 . free .
  31. Mars M, de Graaf C, de Groot CP, van Rossum CT, Kok FJ . Fasting leptin and appetite responses induced by a 4-day 65%-energy-restricted diet . International Journal of Obesity . 30 . 1 . 122–128 . January 2006 . 16158086 . 10.1038/sj.ijo.0803070 . 10029/4914 . 6769226 . free .
  32. Williams KW, Scott MM, Elmquist JK . From observation to experimentation: leptin action in the mediobasal hypothalamus . The American Journal of Clinical Nutrition . 89 . 3 . 985S–990S . March 2009 . 19176744 . 2667659 . 10.3945/ajcn.2008.26788D .
  33. Baicy K, London ED, Monterosso J, Wong ML, Delibasi T, Sharma A, Licinio J . Leptin replacement alters brain response to food cues in genetically leptin-deficient adults . Proceedings of the National Academy of Sciences of the United States of America . 104 . 46 . 18276–18279 . November 2007 . 17986612 . 2084333 . 10.1073/pnas.0706481104 . free . 2007PNAS..10418276B .
  34. Wang MY, Zhou YT, Newgard CB, Unger RH . A novel leptin receptor isoform in rat . FEBS Letters . 392 . 2 . 87–90 . August 1996 . 8772180 . 10.1016/0014-5793(96)00790-9 . 1996FEBSL.392...87W . 28037249 .
  35. Malendowicz W, Rucinski M, Macchi C, Spinazzi R, Ziolkowska A, Nussdorfer GG, Kwias Z . Leptin and leptin receptors in the prostate and seminal vesicles of the adult rat . International Journal of Molecular Medicine . 18 . 4 . 615–618 . October 2006 . 16964413 . 10.3892/ijmm.18.4.615 . free .
  36. Web site: LepRb antibody (commercial site). 2009-01-07. https://web.archive.org/web/20110714165932/http://www.neuromics.com/ittrium/visit?path=A1x66x1y1x9fx1y1x246x1y1x372x1x82y1x35d4x1x7f. 2011-07-14. dead.
  37. Di Marzo V . The endocannabinoid system in obesity and type 2 diabetes . Diabetologia . 51 . 8 . 1356–1367 . August 2008 . 18563385 . 10.1007/s00125-008-1048-2 . 21487407 . free .
  38. Taleb S, Herbin O, Ait-Oufella H, Verreth W, Gourdy P, Barateau V, Merval R, Esposito B, Clément K, Holvoet P, Tedgui A, Mallat Z . 6 . Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis . Arteriosclerosis, Thrombosis, and Vascular Biology . 27 . 12 . 2691–2698 . December 2007 . 17690315 . 10.1161/ATVBAHA.107.149567 . 17955869 . free .
  39. Frodermann V, Rohde D, Courties G, Severe N, Schloss MJ, Amatullah H, McAlpine CS, Cremer S, Hoyer FF, Ji F, van Koeverden ID, Herisson F, Honold L, Masson GS, Zhang S, Grune J, Iwamoto Y, Schmidt SP, Wojtkiewicz GR, Lee IH, Gustafsson K, Pasterkamp G, de Jager SC, Sadreyev RI, MacFadyen J, Libby P, Ridker P, Scadden DT, Naxerova K, Jeffrey KL, Swirski FK, Nahrendorf M . 6 . Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells . Nature Medicine . 25 . 11 . 1761–1771 . November 2019 . 31700184 . 6858591 . 10.1038/s41591-019-0633-x .
  40. Zhang W, Telemaque S, Augustyniak RA, Anderson P, Thomas GD, An J, Wang Z, Newgard CB, Victor RG . 6 . Adenovirus-mediated leptin expression normalises hypertension associated with diet-induced obesity . Journal of Neuroendocrinology . 22 . 3 . 175–180 . March 2010 . 20059648 . 10.1111/j.1365-2826.2010.01953.x . 25716300 .
  41. Knight WD, Seth R, Boron J, Overton JM . Short-term physiological hyperleptinemia decreases arterial blood pressure . Regulatory Peptides . 154 . 1–3 . 60–68 . April 2009 . 19323984 . 10.1016/j.regpep.2009.02.001 . 3221720 .
  42. Ciriello J, Moreau JM . Systemic administration of leptin potentiates the response of neurons in the nucleus of the solitary tract to chemoreceptor activation in the rat . Neuroscience . 229 . 88–99 . January 2013 . 23159310 . 10.1016/j.neuroscience.2012.10.065 . 22852202 .
  43. Torday JS, Rehan VK . Up-regulation of fetal rat lung parathyroid hormone-related protein gene regulatory network down-regulates the Sonic Hedgehog/Wnt/betacatenin gene regulatory network . Pediatric Research . 60 . 4 . 382–388 . October 2006 . 16940239 . 10.1203/01.pdr.0000238326.42590.03 . 21101408 . free .
  44. Anifandis G, Koutselini E, Louridas K, Liakopoulos V, Leivaditis K, Mantzavinos T, Sioutopoulou D, Vamvakopoulos N . 6 . Estradiol and leptin as conditional prognostic IVF markers . Reproduction . 129 . 4 . 531–534 . April 2005 . 15798029 . 10.1530/rep.1.00567 . 11398376 . free .
  45. Comninos AN, Jayasena CN, Dhillo WS . The relationship between gut and adipose hormones, and reproduction . Human Reproduction Update . 20 . 2 . 153–174 . 2014 . 24173881 . 10.1093/humupd/dmt033 . 18645125 . free .
  46. Zhao J, Townsend KL, Schulz LC, Kunz TH, Li C, Widmaier EP . Leptin receptor expression increases in placenta, but not hypothalamus, during gestation in Mus musculus and Myotis lucifugus . Placenta . 25 . 8–9 . 712–722 . 2004 . 15450389 . 10.1016/j.placenta.2004.01.017 .
  47. Moynihan AT, Hehir MP, Glavey SV, Smith TJ, Morrison JJ . Inhibitory effect of leptin on human uterine contractility in vitro . American Journal of Obstetrics and Gynecology . 195 . 2 . 504–509 . August 2006 . 16647683 . 10.1016/j.ajog.2006.01.106 .
  48. Aka N, Atalay S, Sayharman S, Kiliç D, Köse G, Küçüközkan T . Leptin and leptin receptor levels in pregnant women with hyperemesis gravidarum . The Australian & New Zealand Journal of Obstetrics & Gynaecology . 46 . 4 . 274–277 . August 2006 . 16866785 . 10.1111/j.1479-828X.2006.00590.x . 72562308 .
  49. Cervero A, Domínguez F, Horcajadas JA, Quiñonero A, Pellicer A, Simón C . The role of the leptin in reproduction . Current Opinion in Obstetrics & Gynecology . 18 . 3 . 297–303 . June 2006 . 16735830 . 10.1097/01.gco.0000193004.35287.89 . 7681765 .
  50. Iwaniec UT, Boghossian S, Lapke PD, Turner RT, Kalra SP . Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice . Peptides . 28 . 5 . 1012–1019 . May 2007 . 17346852 . 1986832 . 10.1016/j.peptides.2007.02.001 .
  51. Casabiell X, Piñeiro V, Tomé MA, Peinó R, Diéguez C, Casanueva FF . Presence of leptin in colostrum and/or breast milk from lactating mothers: a potential role in the regulation of neonatal food intake . The Journal of Clinical Endocrinology and Metabolism . 82 . 12 . 4270–4273 . December 1997 . 9398752 . 10.1210/jcem.82.12.4590 . free .
  52. Sanchez-Garrido MA, Tena-Sempere M . Metabolic control of puberty: roles of leptin and kisspeptins . Hormones and Behavior . 64 . 2 . 187–194 . July 2013 . 23998663 . 10.1016/j.yhbeh.2013.01.014 . 27078496 .
  53. Matkovic V, Ilich JZ, Skugor M, Badenhop NE, Goel P, Clairmont A, Klisovic D, Nahhas RW, Landoll JD . 6 . Leptin is inversely related to age at menarche in human females . The Journal of Clinical Endocrinology and Metabolism . 82 . 10 . 3239–3345 . October 1997 . 10.1210/jcem.82.10.4280 . 9329346 . 24926542 . free .
  54. Dance A . Fun facts about bones: More than just scaffolding . Knowable Magazine . 23 February 2022 . 10.1146/knowable-022222-1. free . 8 March 2022.
  55. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G . 6 . Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass . Cell . 100 . 2 . 197–207 . January 2000 . 10660043 . 10.1016/S0092-8674(00)81558-5 . 17873790 . free .
  56. Hamrick MW, Ferrari SL . Leptin and the sympathetic connection of fat to bone . Osteoporosis International . 19 . 7 . 905–912 . July 2008 . 17924050 . 10.1007/s00198-007-0487-9 . 8825233 .
  57. Book: Allison SJ, Herzog H . NPY Family of Peptides in Neurobiology, Cardiovascular and Metabolic Disorders: From Genes to Therapeutics . NPY and bone . Exs . 95 . 95 . 171–182 . 2006 . 16383006 . 10.1007/3-7643-7417-9_13 . 3-7643-7155-2 . Experientia Supplementum .
  58. Gordeladze JO, Reseland JE . A unified model for the action of leptin on bone turnover . Journal of Cellular Biochemistry . 88 . 4 . 706–712 . March 2003 . 12577304 . 10.1002/jcb.10385 . 35669344 .
  59. Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G . 6 . Leptin regulates bone formation via the sympathetic nervous system . Cell . 111 . 3 . 305–317 . November 2002 . 12419242 . 10.1016/S0092-8674(02)01049-8 . 11171580 . free .
  60. Martin A, David V, Malaval L, Lafage-Proust MH, Vico L, Thomas T . Opposite effects of leptin on bone metabolism: a dose-dependent balance related to energy intake and insulin-like growth factor-I pathway . Endocrinology . 148 . 7 . 3419–3425 . July 2007 . 17431002 . 10.1210/en.2006-1541 . free .
  61. Rőszer T, Józsa T, Kiss-Tóth ED, De Clerck N, Balogh L . Leptin receptor deficient diabetic (db/db) mice are compromised in postnatal bone regeneration . Cell and Tissue Research . 356 . 1 . 195–206 . April 2014 . 24343796 . 10.1007/s00441-013-1768-6 . 2422805 .
  62. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI . Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression . Nature . 394 . 6696 . 897–901 . August 1998 . 9732873 . 10.1038/29795 . 4431600 . 1998Natur.394..897L .
  63. Fantuzzi G, Faggioni R . Leptin in the regulation of immunity, inflammation, and hematopoiesis . Journal of Leukocyte Biology . 68 . 4 . 437–446 . October 2000 . 10.1189/jlb.68.4.437 . 11037963 . 8680598 . free .
  64. Caldefie-Chezet F, Poulin A, Tridon A, Sion B, Vasson MP . Leptin: a potential regulator of polymorphonuclear neutrophil bactericidal action? . Journal of Leukocyte Biology . 69 . 3 . 414–418 . March 2001 . 10.1189/jlb.69.3.414 . 11261788 . 15787413 .
  65. Madej T. Boguski MS. Mark Boguski. Bryant SH . Threading analysis suggests that the obese gene product may be a helical cytokine . FEBS Letters . 373 . 1 . 13–18 . October 1995 . 7589424 . 10.1016/0014-5793(95)00977-H . 1995FEBSL.373...13M. 25961554 . 10.1.1.467.3817 .
  66. Heiman ML, Ahima RS, Craft LS, Schoner B, Stephens TW, Flier JS . Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress . Endocrinology . 138 . 9 . 3859–3863 . September 1997 . 9275075 . 10.1210/endo.138.9.5366 . 7601046 . free .
  67. 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 . 6 . Association between serum leptin concentration and white blood cell count in middle-aged Japanese men and women . Diabetes/Metabolism Research and Reviews . 21 . 5 . 441–447 . 2005 . 15724240 . 10.1002/dmrr.540 . 10320501 .
  68. Hamilton BS, Paglia D, Kwan AY, Deitel M . Increased obese mRNA expression in omental fat cells from massively obese humans . Nature Medicine . 1 . 9 . 953–956 . September 1995 . 7585224 . 10.1038/nm0995-953 . 24211050 .
  69. Perrier S, Caldefie-Chézet F, Vasson MP . IL-1 family in breast cancer: potential interplay with leptin and other adipocytokines . FEBS Letters . 583 . 2 . 259–265 . January 2009 . 19111549 . 10.1016/j.febslet.2008.12.030 . 30801028 . free . 2009FEBSL.583..259P .
  70. Tonon F, Di Bella S, Giudici F, Zerbato V, Segat L, Koncan R, Misin A, Toffoli B, D'Agaro P, Luzzati R, Fabris B, Bernardi S . 6 . Discriminatory Value of Adiponectin to Leptin Ratio for COVID-19 Pneumonia . International Journal of Endocrinology . 2022 . 9908450 . 2022-04-26 . 35529082 . 9072020 . 10.1155/2022/9908450 . Salvador J . free .
  71. Wabitsch M, Jensen PB, Blum WF, Christoffersen CT, Englaro P, Heinze E, Rascher W, Teller W, Tornqvist H, Hauner H . 6 . Insulin and cortisol promote leptin production in cultured human fat cells . Diabetes . 45 . 10 . 1435–1438 . October 1996 . 8826983 . 10.2337/diabetes.45.10.1435 .
  72. LaPensee CR, Hugo ER, Ben-Jonathan N . Insulin stimulates interleukin-6 expression and release in LS14 human adipocytes through multiple signaling pathways . Endocrinology . 149 . 11 . 5415–5422 . November 2008 . 18617614 . 2584585 . 10.1210/en.2008-0549 .
  73. Worm D, Vinten J, Vaag A, Henriksen JE, Beck-Nielsen H . The nicotinic acid analogue acipimox increases plasma leptin and decreases free fatty acids in type 2 diabetic patients . European Journal of Endocrinology . 143 . 3 . 389–395 . September 2000 . 11022182 . 10.1530/eje.0.1430389 . free .
  74. Green ED, Maffei M, Braden VV, Proenca R, DeSilva U, Zhang Y, Chua SC, Leibel RL, Weissenbach J, Friedman JM . 6 . The human obese (OB) gene: RNA expression pattern and mapping on the physical, cytogenetic, and genetic maps of chromosome 7 . Genome Research . 5 . 1 . 5–12 . August 1995 . 8717050 . 10.1101/gr.5.1.5 . free .
  75. 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 . 6 . Congenital leptin deficiency is associated with severe early-onset obesity in humans . Nature . 387 . 6636 . 903–908 . June 1997 . 9202122 . 10.1038/43185 . 205032762 . 1997Natur.387..903M . free .
  76. Wabitsch M, Funcke JB, Lennerz B, Kuhnle-Krahl U, Lahr G, Debatin KM, Vatter P, Gierschik P, Moepps B, Fischer-Posovszky P . 6 . Biologically inactive leptin and early-onset extreme obesity . The New England Journal of Medicine . 372 . 1 . 48–54 . January 2015 . 25551525 . 10.1056/NEJMoa1406653 . free .
  77. Farooqi IS, Keogh JM, Kamath S, Jones S, Gibson WT, Trussell R, Jebb SA, Lip GY, O'Rahilly S . 6 . Partial leptin deficiency and human adiposity . Nature . 414 . 6859 . 34–35 . November 2001 . 11689931 . 10.1038/35102112 . 4344492 . 2001Natur.414...34F .
  78. Paracchini V, Pedotti P, Taioli E . Genetics of leptin and obesity: a HuGE review . American Journal of Epidemiology . 162 . 2 . 101–114 . July 2005 . 15972940 . 10.1093/aje/kwi174 . free .
  79. Wang TN, Huang MC, Chang WT, Ko AM, Tsai EM, Liu CS, Lee CH, Ko YC . 6 . G-2548A polymorphism of the leptin gene is correlated with extreme obesity in Taiwanese aborigines . Obesity . 14 . 2 . 183–187 . February 2006 . 16571841 . 10.1038/oby.2006.23 . 24231672 .
  80. Zhang L, Lu M, Yuan L, Lai W, Wang Y . [Association of leptin gene-2548 G/A polymorphism with obesity: a meta-analysis] . zh . Wei Sheng Yan Jiu = Journal of Hygiene Research . 43 . 1 . 128–132 . January 2014 . 24564125 .
  81. Templeman LA, Reynolds GP, Arranz B, San L . Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis . Pharmacogenetics and Genomics . 15 . 4 . 195–200 . April 2005 . 15864111 . 10.1097/01213011-200504000-00002 . 10584758 .
  82. Kang SG, Lee HJ, Park YM, Choi JE, Han C, Kim YK, Kim SH, Lee MS, Joe SH, Jung IK, Kim L . 6 . Possible association between the -2548A/G polymorphism of the leptin gene and olanzapine-induced weight gain . Progress in Neuro-Psychopharmacology & Biological Psychiatry . 32 . 1 . 160–163 . January 2008 . 17804136 . 10.1016/j.pnpbp.2007.08.002 . 53181942 .
  83. Wu R, Zhao J, Shao P, Ou J, Chang M . Genetic predictors of antipsychotic-induced weight gain: a case-matched multi-gene study . Zhong Nan da Xue Xue Bao. Yi Xue Ban = Journal of Central South University. Medical Sciences . 36 . 8 . 720–723 . August 2011 . 21937795 . 10.3969/j.issn.1672-7347.2011.08.003 .
  84. Ribeiro R, Vasconcelos A, Costa S, Pinto D, Morais A, Oliveira J, Lobo F, Lopes C, Medeiros R . 6 . Overexpressing leptin genetic polymorphism (-2548 G/A) is associated with susceptibility to prostate cancer and risk of advanced disease . The Prostate . 59 . 3 . 268–274 . May 2004 . 15042602 . 10.1002/pros.20004 . 22787605 .
  85. Vaskú JA, Vaskú A, Dostálová Z, Bienert P . Association of leptin genetic polymorphism -2548 G/A with gestational diabetes mellitus . Genes & Nutrition . 1 . 2 . 117–123 . June 2006 . 18850205 . 3454683 . 10.1007/BF02829953 .
  86. Ye XL, Lu CF . Association of polymorphisms in the leptin and leptin receptor genes with inflammatory mediators in patients with osteoporosis . Endocrine . 44 . 2 . 481–488 . October 2013 . 23460508 . 10.1007/s12020-013-9899-9 . 19769251 .
  87. Margetic S, Gazzola C, Pegg GG, Hill RA . Leptin: a review of its peripheral actions and interactions . International Journal of Obesity and Related Metabolic Disorders . 26 . 11 . 1407–1433 . November 2002 . 12439643 . 10.1038/sj.ijo.0802142 . 6611022 .
  88. Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, Moizo L, Lehy T, Guerre-Millo M, Le Marchand-Brustel Y, Lewin MJ . 6 . The stomach is a source of leptin . Nature . 394 . 6695 . 790–793 . August 1998 . 9723619 . 10.1038/29547 . 4367948 . 1998Natur.394..790B .
  89. Sinha MK, Opentanova I, Ohannesian JP, Kolaczynski JW, Heiman ML, Hale J, Becker GW, Bowsher RR, Stephens TW, Caro JF . 6 . Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting . The Journal of Clinical Investigation . 98 . 6 . 1277–1282 . September 1996 . 8823291 . 507552 . 10.1172/JCI118913 .
  90. Lönnqvist F, Arner P, Nordfors L, Schalling M . Overexpression of the obese (ob) gene in adipose tissue of human obese subjects . Nature Medicine . 1 . 9 . 950–953 . September 1995 . 7585223 . 10.1038/nm0995-950 . 2661056 .
  91. Madej T . Considerations in the use of lipid-based drug products . Journal of Intravenous Nursing . 21 . 6 . 326 . 1998 . 10392096 .
  92. Sinha MK, Ohannesian JP, Heiman ML, Kriauciunas A, Stephens TW, Magosin S, Marco C, Caro JF . 6 . Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects . The Journal of Clinical Investigation . 97 . 5 . 1344–1347 . March 1996 . 8636448 . 507189 . 10.1172/JCI118551 .
  93. Schoeller DA, Cella LK, Sinha MK, Caro JF . Entrainment of the diurnal rhythm of plasma leptin to meal timing . The Journal of Clinical Investigation . 100 . 7 . 1882–1887 . October 1997 . 9312190 . 508375 . 10.1172/JCI119717 .
  94. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS . Role of leptin in the neuroendocrine response to fasting . Nature . 382 . 6588 . 250–252 . July 1996 . 8717038 . 10.1038/382250a0 . 4331304 . 1996Natur.382..250A .
  95. Friedman JM . Leptin at 14 y of age: an ongoing story . The American Journal of Clinical Nutrition . 89 . 3 . 973S–979S . March 2009 . 19190071 . 2667654 . 10.3945/ajcn.2008.26788B .
  96. Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS . The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men . The Journal of Clinical Investigation . 111 . 9 . 1409–1421 . May 2003 . 12727933 . 154448 . 10.1172/JCI17490 .
  97. Kolaczynski JW, Considine RV, Ohannesian J, Marco C, Opentanova I, Nyce MR, Myint M, Caro JF . 6 . Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves . Diabetes . 45 . 11 . 1511–1515 . November 1996 . 8866554 . 10.2337/diab.45.11.1511 . 27173749 .
  98. Kolaczynski JW, Ohannesian JP, Considine RV, Marco CC, Caro JF . Response of leptin to short-term and prolonged overfeeding in humans . The Journal of Clinical Endocrinology and Metabolism . 81 . 11 . 4162–41625 . November 1996 . 8923877 . 10.1210/jcem.81.11.8923877 . 25314527 . free .
  99. Book: Copinschi G, Leproult R, Spiegel K . How Gut and Brain Control Metabolism . The Important Role of Sleep in Metabolism . Frontiers of Hormone Research . 42 . 59–72 . 2014 . 24732925 . 10.1159/000358858 . 978-3-318-02638-2 .
  100. Knutson KL, Spiegel K, Penev P, Van Cauter E . The metabolic consequences of sleep deprivation . Sleep Medicine Reviews . 11 . 3 . 163–178 . June 2007 . 17442599 . 1991337 . 10.1016/j.smrv.2007.01.002 .
  101. Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV . Leptin: the tale of an obesity gene . Diabetes . 45 . 11 . 1455–1462 . November 1996 . 8866547 . 10.2337/diab.45.11.1455 . 5142768 .
  102. Otsuka R, Yatsuya H, Tamakoshi K, Matsushita K, Wada K, Toyoshima H . Perceived psychological stress and serum leptin concentrations in Japanese men . Obesity . 14 . 10 . 1832–1838 . October 2006 . 17062814 . 10.1038/oby.2006.211 . 6208047 . free .
  103. de Salles BF, Simão R, Fleck SJ, Dias I, Kraemer-Aguiar LG, Bouskela E . Effects of resistance training on cytokines . International Journal of Sports Medicine . 31 . 7 . 441–450 . July 2010 . 20432196 . 10.1055/s-0030-1251994 . 11273036 . free .
  104. Hickey MS, Considine RV, Israel RG, Mahar TL, McCammon MR, Tyndall GL, Houmard JA, Caro JF . 6 . Leptin is related to body fat content in male distance runners . The American Journal of Physiology . 271 . 5 Pt 1 . E938-940 . November 1996 . 8944684 . 10.1152/ajpendo.1996.271.5.E938 .
  105. Hickey MS, Houmard JA, Considine RV, Tyndall GL, Midgette JB, Gavigan KE, Weidner ML, McCammon MR, Israel RG, Caro JF . 6 . Gender-dependent effects of exercise training on serum leptin levels in humans . The American Journal of Physiology . 272 . 4 Pt 1 . E562–566 . April 1997 . 9142875 . 10.1152/ajpendo.1997.272.4.E562 .
  106. Ahima RS, Flier JS . Leptin . Annual Review of Physiology . 62 . 1 . 413–437 . 2000 . 10845097 . 10.1146/annurev.physiol.62.1.413 .
  107. Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, Mudaliar SR, Olefsky J, Caro JF . 6 . Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro . Diabetes . 45 . 5 . 699–701 . May 1996 . 8621027 . 10.2337/diabetes.45.5.699 .
  108. Considine RV, Nyce MR, Kolaczynski JW, Zhang PL, Ohannesian JP, Moore JH, Fox JW, Caro JF . 6 . Dexamethasone stimulates leptin release from human adipocytes: unexpected inhibition by insulin . Journal of Cellular Biochemistry . 65 . 2 . 254–258 . May 1997 . 9136082 . 10.1002/(SICI)1097-4644(199705)65:2<254::AID-JCB10>3.0.CO;2-I . 29205104 .
  109. Zirlik S, Hauck T, Fuchs FS, Neurath MF, Konturek PC, Harsch IA . Leptin, obestatin and apelin levels in patients with obstructive sleep apnoea syndrome . Medical Science Monitor . 17 . 3 . CR159-164 . February 2011 . 21358603 . 3524733 . 10.12659/MSM.881450 .
  110. Harsch IA, Konturek PC, Koebnick C, Kuehnlein PP, Fuchs FS, Pour Schahin S, Wiest GH, Hahn EG, Lohmann T, Ficker JH . 6 . Leptin and ghrelin levels in patients with obstructive sleep apnoea: effect of CPAP treatment . The European Respiratory Journal . 22 . 2 . 251–257 . August 2003 . 12952256 . 10.1183/09031936.03.00010103 . 7924198 . free .
  111. Forny-Germano L, De Felice FG, Vieira MN . The Role of Leptin and Adiponectin in Obesity-Associated Cognitive Decline and Alzheimer's Disease . Frontiers in Neuroscience . 12 . 1027 . 2019 . 30692905 . 6340072 . 10.3389/fnins.2018.01027 . free .
  112. Veyrat-Durebex C, Poher AL, Caillon A, Somm E, Vallet P, Charnay Y, Rohner-Jeanrenaud F . Improved leptin sensitivity as a potential candidate responsible for the spontaneous food restriction of the Lou/C rat . PLOS ONE . 8 . 9 . e73452 . 2013 . 24039946 . 3765307 . 10.1371/journal.pone.0073452 . free . 2013PLoSO...873452V .
  113. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV . 6 . Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance . Lancet . 348 . 9021 . 159–161 . July 1996 . 8684156 . 10.1016/S0140-6736(96)03173-X . 22084041 .
  114. Considine RV, Considine EL, Williams CJ, Hyde TM, Caro JF . The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations . Diabetes . 45 . 7 . 992–994 . July 1996 . 8666155 . 10.2337/diabetes.45.7.992 .
  115. Considine RV, Caro JF . Leptin and the regulation of body weight . The International Journal of Biochemistry & Cell Biology . 29 . 11 . 1255–1272 . November 1997 . 9451823 . 10.1016/S1357-2725(97)00050-2 .
  116. Roth JD, Roland BL, Cole RL, Trevaskis JL, Weyer C, Koda JE, Anderson CM, Parkes DG, Baron AD . 6 . Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies . Proceedings of the National Academy of Sciences of the United States of America . 105 . 20 . 7257–7262 . May 2008 . 18458326 . 2438237 . 10.1073/pnas.0706473105 . free . 2008PNAS..105.7257R .
  117. Oswal A, Yeo G . Leptin and the control of body weight: a review of its diverse central targets, signaling mechanisms, and role in the pathogenesis of obesity . Obesity . 18 . 2 . 221–229 . February 2010 . 19644451 . 10.1038/oby.2009.228 . 9158376 . free .
  118. Banks WA, Farr SA, Morley JE . The effects of high fat diets on the blood-brain barrier transport of leptin: failure or adaptation? . Physiology & Behavior . 88 . 3 . 244–248 . June 2006 . 16781741 . 10.1016/j.physbeh.2006.05.037 . 37806313 .
  119. Myers MG, Cowley MA, Münzberg H . Mechanisms of leptin action and leptin resistance . Annual Review of Physiology . 70 . 1 . 537–556 . 2008 . 17937601 . 10.1146/annurev.physiol.70.113006.100707 . 7572231 .
  120. Wang J, Obici S, Morgan K, Barzilai N, Feng Z, Rossetti L . Overfeeding rapidly induces leptin and insulin resistance . Diabetes . 50 . 12 . 2786–2791 . December 2001 . 11723062 . 10.2337/diabetes.50.12.2786 . free .
  121. 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 . 6 . Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons . Cell Metabolism . 5 . 3 . 181–194 . March 2007 . 17339026 . 10.1016/j.cmet.2007.02.004 . free .
  122. Obici S, Rossetti L . Minireview: nutrient sensing and the regulation of insulin action and energy balance . Endocrinology . 144 . 12 . 5172–5178 . December 2003 . 12970158 . 10.1210/en.2003-0999 . 2006530 . free .
  123. Web site: Harriet Hall . 2 June 2015 . . The Rosedale Diet: Here We Go Again .
  124. Yusuf E, Nelissen RG, Ioan-Facsinay A, Stojanovic-Susulic V, DeGroot J, van Osch G, Middeldorp S, Huizinga TW, Kloppenburg M . 6 . Association between weight or body mass index and hand osteoarthritis: a systematic review . Annals of the Rheumatic Diseases . 69 . 4 . 761–765 . April 2010 . 19487215 . 10.1136/ard.2008.106930 . 43044428 . 1765/17588 . free .
  125. Sowers MR, Karvonen-Gutierrez CA . The evolving role of obesity in knee osteoarthritis . Current Opinion in Rheumatology . 22 . 5 . 533–537 . September 2010 . 20485173 . 3291123 . 10.1097/BOR.0b013e32833b4682 .
  126. Aspden RM, Scheven BA, Hutchison JD . Osteoarthritis as a systemic disorder including stromal cell differentiation and lipid metabolism . Lancet . 357 . 9262 . 1118–1120 . April 2001 . 11297982 . 10.1016/S0140-6736(00)04264-1 . 21487529 .
  127. Pottie P, Presle N, Terlain B, Netter P, Mainard D, Berenbaum F . Obesity and osteoarthritis: more complex than predicted! . Annals of the Rheumatic Diseases . 65 . 11 . 1403–1405 . November 2006 . 17038451 . 1798356 . 10.1136/ard.2006.061994 .
  128. Griffin TM, Guilak F . Why is obesity associated with osteoarthritis? Insights from mouse models of obesity . Biorheology . 45 . 3–4 . 387–398 . 2008 . 18836239 . 2748656 . 10.3233/BIR-2008-0485 .
  129. Masuko K, Murata M, Suematsu N, Okamoto K, Yudoh K, Nakamura H, Kato T . A metabolic aspect of osteoarthritis: lipid as a possible contributor to the pathogenesis of cartilage degradation . Clinical and Experimental Rheumatology . 27 . 2 . 347–353 . 2009 . 19473582 .
  130. Hu PF, Bao JP, Wu LD . The emerging role of adipokines in osteoarthritis: a narrative review . Molecular Biology Reports . 38 . 2 . 873–878 . February 2011 . 20480243 . 10.1007/s11033-010-0179-y . 1801387 .
  131. Coppari R, Bjørbæk C . Leptin revisited: its mechanism of action and potential for treating diabetes . Nature Reviews. Drug Discovery . 11 . 9 . 692–708 . September 2012 . 22935803 . 4019022 . 10.1038/nrd3757 .
  132. Gualillo O . Further evidence for leptin involvement in cartilage homeostases . Osteoarthritis and Cartilage . 15 . 8 . 857–860 . August 2007 . 17560812 . 10.1016/j.joca.2007.04.015 . free .
  133. Ouchi N, Parker JL, Lugus JJ, Walsh K . Adipokines in inflammation and metabolic disease . Nature Reviews. Immunology . 11 . 2 . 85–97 . February 2011 . 21252989 . 3518031 . 10.1038/nri2921 .
  134. Scotece M, Conde J, Vuolteenaho K, Koskinen A, López V, Gómez-Reino J, Lago F, Moilanen E, Gualillo O . 6 . Adipokines as drug targets in joint and bone disease . Drug Discovery Today . 19 . 3 . 241–258 . March 2014 . 23906693 . 10.1016/j.drudis.2013.07.012 .
  135. Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P, Pottie P . Evidence for a key role of leptin in osteoarthritis . Arthritis and Rheumatism . 48 . 11 . 3118–3129 . November 2003 . 14613274 . 10.1002/art.11303 .
  136. Simopoulou T, Malizos KN, Iliopoulos D, Stefanou N, Papatheodorou L, Ioannou M, Tsezou A . Differential expression of leptin and leptin's receptor isoform (Ob-Rb) mRNA between advanced and minimally affected osteoarthritic cartilage; effect on cartilage metabolism . Osteoarthritis and Cartilage . 15 . 8 . 872–883 . August 2007 . 17350295 . 10.1016/j.joca.2007.01.018 . free .
  137. Vuolteenaho K, Koskinen A, Moilanen T, Moilanen E . Leptin levels are increased and its negative regulators, SOCS-3 and sOb-R are decreased in obese patients with osteoarthritis: a link between obesity and osteoarthritis . Annals of the Rheumatic Diseases . 71 . 11 . 1912–1913 . November 2012 . 22689314 . 10.1136/annrheumdis-2011-201242 . 37657650 .
  138. Gandhi R, Takahashi M, Syed K, Davey JR, Mahomed NN . Relationship between body habitus and joint leptin levels in a knee osteoarthritis population . Journal of Orthopaedic Research . 28 . 3 . 329–333 . March 2010 . 19780190 . 10.1002/jor.21000 . 30527738 . free .
  139. Presle N, Pottie P, Dumond H, Guillaume C, Lapicque F, Pallu S, Mainard D, Netter P, Terlain B . 6 . Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production . Osteoarthritis and Cartilage . 14 . 7 . 690–695 . July 2006 . 16527497 . 10.1016/j.joca.2006.01.009 . free .
  140. Morroni M, De Matteis R, Palumbo C, Ferretti M, Villa I, Rubinacci A, Cinti S, Marotti G . 6 . In vivo leptin expression in cartilage and bone cells of growing rats and adult humans . Journal of Anatomy . 205 . 4 . 291–296 . October 2004 . 15447688 . 1571344 . 10.1111/j.0021-8782.2004.00333.x .
  141. Järvinen K, Vuolteenaho K, Nieminen R, Moilanen T, Knowles RG, Moilanen E . Selective iNOS inhibitor 1400W enhances anti-catabolic IL-10 and reduces destructive MMP-10 in OA cartilage. Survey of the effects of 1400W on inflammatory mediators produced by OA cartilage as detected by protein antibody array . Clinical and Experimental Rheumatology . 26 . 2 . 275–282 . 2008 . 18565249 .
  142. Distel E, Cadoudal T, Durant S, Poignard A, Chevalier X, Benelli C . The infrapatellar fat pad in knee osteoarthritis: an important source of interleukin-6 and its soluble receptor . Arthritis and Rheumatism . 60 . 11 . 3374–3377 . November 2009 . 19877065 . 10.1002/art.24881 . 29783077 .
  143. Clockaerts S, Bastiaansen-Jenniskens YM, Runhaar J, Van Osch GJ, Van Offel JF, Verhaar JA, De Clerck LS, Somville J . 6 . The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review . Osteoarthritis and Cartilage . 18 . 7 . 876–882 . July 2010 . 20417297 . 10.1016/j.joca.2010.03.014 . free .
  144. Klein-Wieringa IR, Kloppenburg M, Bastiaansen-Jenniskens YM, Yusuf E, Kwekkeboom JC, El-Bannoudi H, Nelissen RG, Zuurmond A, Stojanovic-Susulic V, Van Osch GJ, Toes RE, Ioan-Facsinay A . 6 . The infrapatellar fat pad of patients with osteoarthritis has an inflammatory phenotype . Annals of the Rheumatic Diseases . 70 . 5 . 851–857 . May 2011 . 21242232 . 10.1136/ard.2010.140046 . 23009219 .
  145. Hui W, Litherland GJ, Elias MS, Kitson GI, Cawston TE, Rowan AD, Young DA . Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases . Annals of the Rheumatic Diseases . 71 . 3 . 455–462 . March 2012 . 22072016 . 10.1136/annrheumdis-2011-200372 . 29600605 .
  146. Sinha G . Leptin therapy gains FDA approval . Nature Biotechnology . 32 . 4 . 300–302 . April 2014 . 24714458 . 10.1038/nbt0414-300b . 205267285 .
  147. Chou K, Perry CM . Metreleptin: first global approval . Drugs . 73 . 9 . 989–997 . June 2013 . 23740412 . 10.1007/s40265-013-0074-7 . 7740045 .
  148. Web site: FDA approves Myalept to treat rare metabolic disease . FDA . 25 February 2014 . 30 April 2014.
  149. Web site: Myalepta European Medicines Agency. www.ema.europa.eu. 2019-01-09. 2018-09-17.
  150. Web site: NHS England » Metreleptin for congenital leptin deficiency (all ages). www.england.nhs.uk. 2019-01-18.
  151. 6 . Hebebrand J, Hildebrandt T, Schlögl H, Seitz J, Denecke S, Vieira D, Gradl-Dietsch G, Peters T, Antel J, Lau D, Fulton S . October 2022 . The role of hypoleptinemia in the psychological and behavioral adaptation to starvation: Implications for anorexia nervosa . Neuroscience and Biobehavioral Reviews . 141 . 104807 . 10.1016/j.neubiorev.2022.104807 . 35931221 . 251259742.
  152. Milos G, Antel J, Kaufmann LK, Barth N, Koller A, Tan S, Wiesing U, Hinney A, Libuda L, Wabitsch M, von Känel R, Hebebrand J . 6 . Short-term metreleptin treatment of patients with anorexia nervosa: rapid on-set of beneficial cognitive, emotional, and behavioral effects . Translational Psychiatry . 10 . 1 . 303 . August 2020 . 32855384 . 10.1038/s41398-020-00977-1 . 7453199 .
  153. Web site: The Rockefeller University » Hospital Centennial. centennial.rucares.org. en. 2018-10-11.
  154. Dickie MM, Lane PW . Mouse News Lett. . Plus letter to Roy Robinson 7/7/70 . 1957 . 17 . 52.
  155. Bahary N, Siegel DA, Walsh J, Zhang Y, Leopold L, Leibel R, Proenca R, Friedman JM . 6 . Microdissection of proximal mouse chromosome 6: identification of RFLPs tightly linked to the ob mutation . Mammalian Genome . 4 . 9 . 511–515 . September 1993 . 7906968 . 10.1007/BF00364786 . 2130385 .
  156. Friedman JM, Leibel RL, Siegel DS, Walsh J, Bahary N . Molecular mapping of the mouse ob mutation . Genomics . 11 . 4 . 1054–1062 . December 1991 . 1686014 . 10.1016/0888-7543(91)90032-A .
  157. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM . Positional cloning of the mouse obese gene and its human homologue . Nature . 372 . 6505 . 425–432 . December 1994 . 7984236 . 10.1038/372425a0 . 4359725 . 1994Natur.372..425Z .
  158. Book: Leibel RL, Bahary N, Friedman JM . Genetic variation and nutrition in obesity: approaches to the molecular genetics of obesity . Genetic Variation and Nutrition in Obesity: Approaches to the Molecular Genetics of Obesity1 . World Rev Nutr Diet. . 63 . 1 . 90–101 . January 1990 . 1973864 . 10.1159/000418501 . World Review of Nutrition and Dietetics . 978-3-8055-5126-7 .
  159. Bahary N, Leibel RL, Joseph L, Friedman JM . Molecular mapping of the mouse db mutation . Proceedings of the National Academy of Sciences of the United States of America . 87 . 21 . 8642–8646 . November 1990 . 1978328 . 55013 . 10.1073/pnas.87.21.8642 . free . 1990PNAS...87.8642B.
  160. Leibel RL, Bahary N, Friedman JM . Strategies for the molecular genetic analysis of obesity in humans . Critical Reviews in Food Science and Nutrition . 33 . 4–5 . 351–358 . January 1993 . 8357496 . 10.1080/10408399309527632 .
  161. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM . 6 . Weight-reducing effects of the plasma protein encoded by the obese gene . Science . 269 . 5223 . 543–546 . July 1995 . 7624777 . 10.1126/science.7624777 . 1995Sci...269..543H .
  162. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P . Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks . Science . 269 . 5223 . 546–549 . July 1995 . 7624778 . 10.1126/science.7624778 . 1995Sci...269..546C .
  163. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F . Effects of the obese gene product on body weight regulation in ob/ob mice . Science . 269 . 5223 . 540–543 . July 1995 . 7624776 . 10.1126/science.7624776 . 1995Sci...269..540P .
  164. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S . 6 . Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects . Nature Medicine . 1 . 11 . 1155–1161 . November 1995 . 7584987 . 10.1038/nm1195-1155 . 19066834 .
  165. Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, Wenner BR, Bain JR, Charron MJ, Newgard CB, Unger RH . 6 . Leptin therapy in insulin-deficient type I diabetes . Proceedings of the National Academy of Sciences of the United States of America . 107 . 11 . 4813–4819 . March 2010 . 10.1073/pnas.0909422107 . 20194735 . 2841945 . 2010PNAS..107.4813W . free .
  166. Conde J, Scotece M, Gómez R, López V, Gómez-Reino JJ, Lago F, Gualillo O . Adipokines: biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immunity . BioFactors . 37 . 6 . 413–420 . 2011 . 22038756 . 10.1002/biof.185 .
  167. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI . 6 . Identification and expression cloning of a leptin receptor, OB-R . Cell . 83 . 7 . 1263–1271 . December 1995 . 8548812 . 10.1016/0092-8674(95)90151-5 . 6534085 . free .
  168. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP . 6 . Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice . Cell . 84 . 3 . 491–495 . February 1996 . 8608603 . 10.1016/S0092-8674(00)81294-5 . 13885070 . free .
  169. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM . Abnormal splicing of the leptin receptor in diabetic mice . Nature . 379 . 6566 . 632–635 . February 1996 . 8628397 . 10.1038/379632a0 . 4359340 . 1996Natur.379..632L .
  170. Chua SC, Chung WK, Wu-Peng XS, Zhang Y, Liu SM, Tartaglia L, Leibel RL . Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor . Science . 271 . 5251 . 994–996 . February 1996 . 8584938 . 10.1126/science.271.5251.994 . 33646952 . 1996Sci...271..994C .
  171. Web site: Bonner J . 2005 . Jeffrey Friedman, discoverer of leptin, receives Gairdner, Passano awards . Newswire . The Rockefeller University . 2013-08-08 . https://web.archive.org/web/20130829091938/http://newswire.rockefeller.edu/2005/04/13/jeffrey-friedman-discoverer-of-leptin-receives-gairdner-passano-awards/ . 2013-08-29 . dead .
  172. Web site: News-Medical.net . 2009 . Jeffrey Friedman receives Shaw Prize for discovery of leptin .
  173. Web site: The Lasker Foundation – 2010 Awards . 2010 . Lasker Foundation . 2013-08-08 . 2016-02-24 . https://web.archive.org/web/20160224094920/http://www.laskerfoundation.org/awards/2010_b_description.htm . dead .
  174. Web site: BBVA Foundation Frontiers of Knowledge Awards . 2012 . BBVA Foundation . 2013-08-08 . https://web.archive.org/web/20161006010639/http://www.fbbva.es/TLFU/tlfu/ing/microsites/premios/fronteras/galardonados/2012/biomedicina.jsp . 2016-10-06 . dead .
  175. Web site: KFF – KFIP – Winners 2013 – Medicine . 2013 . King Faisal Foundation . 2013-08-08 . 2013-12-02 . https://web.archive.org/web/20131202022141/http://www.kff.com/en01/kfip/1434H2013G/KFIPWinners4MED1434H2013G.html . dead .
  176. Book: Shell E . The Hungry Gene: The Inside Story of the Obesity Industry . Atlantic Monthly Press . 2002 . On the Cutting Edge . 978-1-4223-5243-4 .
  177. Book: Shell E . The Hungry Gene: The Inside Story of the Obesity Industry . Atlantic Monthly Press . 2002 . Hunger . 978-1-4223-5243-4.
  178. Book: Pool R . Fat: fighting the obesity epidemic . 2001 . Oxford University Press . New York . 978-0-19-511853-7 .
  179. Book: Kolata GB . Rethinking thin: the new science of weight loss – and the myths and realities of dietin . 2007 . Farrar . New York . 978-0-374-10398-9 .
  180. Book: Castracane VD, Henson MC . The Obese (Ob/Ob) Mouse and the Discovery of Leptin . https://books.google.com/books?id=nQNSJ6XvL6AC&pg=PA1 . 1–9 . 10.1007/978-0-387-31416-7_1 . 2006 . Castracane VD, Henson MC . Leptin . Endocrine Updates . 25 . 978-0-387-31415-0 .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Leptin".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.