Leptin

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Leptin (from Greek λεπτός leptos, "thin" or "light" or "small") also obese protein^[6] is a protein hormone predominantly made by adipocytes (cells of adipose tissue). Its primary role is likely to regulate long-term energy balance.^[7]

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.^[8]

Leptin is coded for by the LEP

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.^{[11][12][13][14][15][16]}

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.^[17]

Effects

Predominantly, the "energy expenditure hormone" leptin is made by

Location of action

The central location of action (effect) of the fat cell-specific hormone leptin is the hypothalamus, a part of the brain, which is a part of the central nervous system. Non-hypothalamic targets of leptin are referred to as peripheral targets. There is a different relative importance of central and peripheral leptin interactions under different physiologic states, and variations between species.^[19]

Mode of action

Leptin acts directly on leptin receptors in the cell membrane of different types of cells in the human body in particular, and in vertebrates in general. The leptin receptor is found on a wide range of cell types. It is a single-transmembrane-domain type I cytokine receptor,^[20] a special class of cytokine receptors. Further, leptin interacts with other hormones and energy regulators, indirectly mediating the effects of: insulin, glucagon, insulin-like growth factor, growth hormone, glucocorticoids, cytokines, and metabolites.^[19]

Function

The primary function of the hormone leptin is the regulation of

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.

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

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

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

Generally, leptin is thought to enter the brain at the choroid plexus, where the intense expression of a form of leptin receptor molecule could act as a transport mechanism.^[28]

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

Mice with type 1 diabetes treated with leptin or leptin plus insulin, compared to insulin alone had better metabolic profiles: blood sugar did not fluctuate so much; cholesterol levels decreased; less body fat formed.^[32]

Hypothalamus

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

• In the lateral hypothalamus, leptin inhibits hunger^[34] by
  • counteracting the effects of neuropeptide Y, a potent hunger promoter secreted by cells in the gut and in the hypothalamus
  • counteracting the effects of
    THC
• In the medial hypothalamus, leptin stimulates satiety^[35] by
  • promoting the synthesis of
    α-MSH
    , a hunger suppressant

Thus, a lesion in the lateral hypothalamus causes anorexia (due to a lack of hunger signals) and a lesion in the medial hypothalamus causes excessive hunger (due to a lack of satiety signals).^[33] This appetite inhibition is long-term, in contrast to the rapid inhibition of hunger by

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

Leptin binds to neuropeptide Y (NPY) neurons in the arcuate nucleus in such a way as to decrease the activity of these neurons. Leptin signals to the hypothalamus which produces a feeling of satiety. Moreover, leptin signals may make it easier for people to resist the temptation of foods high in calories.^[44]

Leptin receptor activation inhibits neuropeptide Y and

Leptin interacts with six types of receptors (Ob-Ra–Ob-Rf, or LepRa-LepRf), which in turn are encoded by a single gene,

The role of leptin/leptin receptors in modulation of T cell activity and the innate immune system was shown in experimentation with mice. It modulates the immune response to atherosclerosis, of which obesity is a predisposing and exercise a mitigating factor.^[49][50]

Exogenous leptin can promote angiogenesis by increasing vascular endothelial growth factor levels.

Hyperleptinemia produced by infusion or adenoviral gene transfer decreases blood pressure in rats.^[51][52]

Leptin microinjections into the

In mice, and to a lesser extent in humans, leptin is required for male and female fertility. Ovulatory cycles in females are linked to energy balance (positive or negative depending on whether a female is losing or gaining weight) and energy flux (how much energy is consumed and expended) much more than energy status (fat levels). When energy balance is highly negative (meaning the woman is starving) or energy flux is very high (meaning the woman is exercising at extreme levels, but still consuming enough calories), the ovarian cycle stops and females stop menstruating. Only if a female has an extremely low body fat percentage does energy status affect menstruation. Leptin levels outside an ideal range may have a negative effect on egg quality and outcome during in vitro fertilization.^[55] Leptin is involved in reproduction by stimulating gonadotropin-releasing hormone from the hypothalamus.^[56]

Pregnancy

The placenta produces leptin.^[57] Leptin levels rise during pregnancy and fall after childbirth. Leptin is also expressed in fetal membranes and the uterine tissue. Uterine contractions are inhibited by leptin.^[58] Leptin plays a role in hyperemesis gravidarum (severe morning sickness of pregnancy),^[59] in polycystic ovary syndrome^[60] and hypothalamic leptin is implicated in bone growth in mice.^[61]

Lactation

Immunoreactive leptin has been found in human breast milk; and leptin from mother's milk has been found in the blood of suckling infant animals.^[62]

Puberty

Leptin along with

Bone

Leptin's role in regulating bone mass was identified in 2000.

In terms of both structure and function, leptin resembles IL-6 and is a member of the cytokine superfamily.^[5][74][76] Circulating leptin seems to affect the HPA axis, suggesting a role for leptin in stress response.^[77] Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.^[78]

Similar to what is observed in chronic inflammation, chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including hypertension, metabolic syndrome, and cardiovascular disease. While leptin is associated with body fat mass, the size of individual fat cells, and overeating, it is not affected by exercise (for comparison, IL-6 is released in response to muscular contractions). Thus, it is speculated that leptin responds specifically to adipose-derived inflammation.^[79] Leptin is a pro-angiogenic, pro-inflammatory and mitogenic factor, the actions of which are reinforced through crosstalk with IL-1 family cytokines in cancer.^[80] High leptin levels have been also demonstrated in patients with COVID-19 pneumonia.^[81]

Taken as such, increases in leptin levels (in response to caloric intake) function as an acute pro-inflammatory response mechanism to prevent excessive cellular stress induced by overeating. When high caloric intake overtaxes the ability of fat cells to

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

Location of gene and structure of hormone

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

Mutations

A human mutant leptin was first described in 1997,

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.^[15]

Frameshift

A recessive

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

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

Transversion

A single case of a homozygous

Blood levels

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

Physiologic variation

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

In specific conditions

In humans, many instances are seen where leptin dissociates from the strict role of communicating nutritional status between body and brain and no longer correlates with body fat levels:

• Leptin plays a critical role in the adaptive response to starvation.^[105][106]
• Leptin level is decreased after short-term fasting (24–72 hours), even when changes in fat mass are not observed.^{[107][108][109]}
• Serum level of leptin is reduced by sleep deprivation.^[110][111]
• Leptin levels are paradoxically increased in obesity.^[85]
• Leptin level is increased by
  emotional stress.^[112]
• Leptin level is chronically reduced by
  physical exercise training.^{[113][114][115]}
• Leptin level is decreased by increases in testosterone levels and increased by increases in estrogen levels.^[116]
• Leptin level is increased by insulin.^[117]
• Leptin release is increased by dexamethasone.^[118]
• In obese patients with obstructive sleep apnea, leptin level is increased, but decreased after the administration of continuous positive airway pressure.^[119][120] In non-obese individuals, however, restful sleep (i.e., 8–12 hours of unbroken sleep) can increase leptin to normal levels.

In mutations

All known leptin mutations except one are associated with low to undetectable immunoreactive leptin blood levels. The exception is a mutant leptin reported in January 2015 which is not functional, but is detected with standard immunoreactive methods. It was found in a massively obese 2+1⁄2-year-old boy who had high levels of circulating leptin which had no effect on leptin receptors, so he was functionally leptin-deficient.^[88]

Role in disease

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

Leptin is known to interact with amylin, a hormone involved in gastric emptying and creating a feeling of fullness. When both leptin and amylin were given to obese, leptin-resistant rats, sustained weight loss was seen. Due to its apparent ability to reverse leptin resistance, amylin has been suggested as possible therapy for obesity.^[126]

It has been suggested that the main role of leptin is to act as a starvation signal when levels are low, to help maintain fat stores for survival during times of starvation, rather than a satiety signal to prevent overeating. Leptin levels signal when an animal has enough stored energy to spend it in pursuits besides acquiring food.^[125][127] This would mean that leptin resistance in obese people is a normal part of mammalian physiology and possibly, could confer a survival advantage.^[128] Leptin resistance (in combination with insulin resistance and weight gain) is seen in rats after they are given unlimited access to palatable, energy-dense foods.^[129] This effect is reversed when the animals are put back on a low-energy diet.^[130] This also may have an evolutionary advantage: allowing energy to be stored efficiently when food is plentiful would be advantageous in populations where food frequently may be scarce.^[131]

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

Role in osteoarthritis with obesity

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).^[133] Consequently, it has been shown that decreasing body fat lessens osteoarthritis to a greater extent than weight loss per se.^[134] This metabolic component related with the release of systemic factors, of a pro-inflammatory nature, by the adipose tissues, which frequently are critically associated with the development of osteoarthritis.^{[135][136][137][138][139]}

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

Leptin and osteoarthritis

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.^[16] In obese individuals, the increased circulating leptin levels induce unwanted responses, that is, reduced food intake or losing body weight does not occur as there is a resistance to leptin (ref 9). In addition to the function of regulating energy homeostasis, leptin carries out a role in other physiological functions such as neuroendocrine communication, reproduction, angiogenesis and bone formation. More recently, leptin has been recognised as a cytokine factor as well as with pleiotropic actions also in the immune response and inflammation.^{[140][141][142][143]} For example, leptin can be found in the synovial fluid in correlation with the body mass index, and the leptin receptors are expressed in the cartilage, where leptin mediates and modulates many inflammatory responses that can damage cartilage and other joint tissues. Leptin has thus emerged as a candidate to link obesity and osteoarthritis and serves as an apparent objective as a nutritional treatment for osteoarthritis.

As in the plasma, the leptin levels in the synovial fluid are positively correlated with BMI.^{[144][145][146][147]} The leptin of the synovial fluid is synthesised at least partially in the joint and may originate in part in the circulation. Leptin has been shown to be produced by chondrocytes, as well as by other tissues in the joints, including the synovial tissue, osteophytes, the meniscus and bone.^{[144][145][148][149][150][151]} An infrapatellar fat pad located extrasynovially within the knee joint is also adjacent to the synovial membrane and cartilage, and has recently been highly appreciated as an important source of leptin, as well as other adipokines and mediators which contribute to the pathogenesis of osteoarthritis ^{[151][152][153][154]}

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

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

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

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

Therapeutic use

Leptin

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

Analog metreleptin

An analog of human leptin

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

Research

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

History

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

Identification of the encoding gene

In 1949, a non-obese mouse colony being studied at the Jackson Laboratory produced a strain of obese offspring, suggesting that a mutation had occurred in a hormone regulating hunger and energy expenditure. Mice homozygous for the so-called ob mutation (ob/ob) ate voraciously and were massively obese.^[163] In the 1960s, a second mutation causing obesity and a similar phenotype was identified by Douglas Coleman, also at the Jackson Laboratory, and was named diabetes (db), as both ob/ob and db/db were obese.^{[164][165][166]} In 1990 Rudolph Leibel and Jeffrey M. Friedman reported mapping of the db gene.^{[167][168][169]}

Consistent with Coleman's and Leibel's hypothesis, several subsequent studies from Leibel's and Friedman's labs and other groups confirmed that the ob gene encoded a novel hormone that circulated in blood and that could suppress food intake and body weight in ob and wild type mice, but not in db mice.^{[11][12][13][14]}

In 1994, Friedman's laboratory reported the identification of the gene.^[166] In 1995, Jose F. Caro's laboratory provided evidence that the mutations in the mouse ob gene did not occur in humans. Furthermore, since ob gene expression was increased, not decreased, in human obesity, it suggested resistance to leptin to be a possibility.^[15] At the suggestion of Roger Guillemin, Friedman named this new hormone "leptin" from the Greek lepto meaning thin.^[11][170] Leptin was the first fat cell-derived hormone (adipokine) to be discovered.^[171]

Subsequent studies in 1995 confirmed that the db gene encodes the leptin receptor, and that it is expressed in the hypothalamus, a region of the brain known to regulate the sensation of hunger and body weight.^{[172][173][174][175]}

Recognition of scientific advances

Coleman and Friedman have been awarded numerous prizes acknowledging their roles in discovery of leptin, including the

The discovery of leptin also is documented in a series of books including Fat: Fighting the Obesity Epidemic by Robert Pool,[183] The Hungry Gene by Ellen Ruppel Shell, and Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting by Gina Kolata.^[184][185] Fat: Fighting the Obesity Epidemic and Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting review the work in the Friedman laboratory that led to the cloning of the ob gene, while The Hungry Gene draws attention to the contributions of Leibel.^{[citation needed]}

See also

• Ghrelin
• NAPEs
• Teleost leptins

References

External links

• Leptin: Your brain, appetite and obesity by the British Society of Neuroendocrinology
• Leptin by Colorado State University – last updated 1998
• Leptin at 3Dchem.com, description and structure diagrams
• Overview of all the structural information available in the PDB for UniProt: P41159 (Leptin) at the PDBe-KB.

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