Clothing

From Wikipedia, the free encyclopedia

 

Clothing in history, showing (from top) Egyptians, Ancient Greeks, Romans, Byzantines, Franks, and 13th through 15th century Europeans.

 

Clothing (also known as clothes, apparel and attire) is a collective term for items worn on the body. Clothing is typically made of fabrics or textiles but over time has included garments made from animal skin or other thin sheets of materials put together. The wearing of clothing is mostly restricted to human beings and is a feature of all human societies. The amount and type of clothing worn depends on gender, body type, social, and geographic considerations.

Clothing serves many purposes: it can serve as protection from the elements, rough surfaces, rash-causing plants, insect bites, splinters, thorns and prickles by providing a barrier between the skin and the environment. Clothes can insulate against cold or hot conditions, and they can provide a hygienic barrier, keeping infectious and toxic materials away from the body. Clothing also provides protection from ultraviolet radiation. 

Wearing clothes is also a social norm, and being deprived of clothing in front of others may be embarrassing. Not wearing clothes in public so that genitals, breasts or buttocks are visible could be considered indecent exposure.

Origin of clothing

There is no easy way to determine when clothing was first developed, but some information has been inferred by studying lice which estimates the introduction of clothing roughly 42,000–72,000 years ago.

Functions

A baby wearing many items of winter clothing: headband, cap, fur-lined coat, scarf and sweater.

 

Four types of women's clothing which end above the knees: (clockwise from top) minidress, miniskirt, shorts and romper, all worn by the same model.

 

The most obvious function of clothing is to protect the wearer from the elements. In hot weather, clothing provides protection from sunburn or wind damage. In the cold it offers thermal insulation. Shelter can reduce the functional need for clothing. For example, coats, hats, gloves and other outer layers are normally removed when entering a warm place. Similarly, clothing has seasonal and regional aspects, so that thinner materials and fewer layers of clothing are generally worn in warmer regions and seasons than in colder ones.

Clothing performs a range of social and cultural functions, such as individual, occupational and gender differentiation, and social status. In many societies, norms about clothing reflect standards of modesty, religion, gender, and social status. Clothing may also function as adornment and an expression of personal taste or style. 

Clothing has been made from a very wide variety of materials, ranging from leather and furs to woven fabrics to elaborate and exotic natural and synthetic fabrics. Not all body coverings are regarded as clothing. Articles carried rather than worn (such as purses), worn on a single part of the body and easily removed (scarves), worn purely for adornment (jewelry), or those that serve a function other than protection (eyeglasses), are normally considered accessories rather than clothing.

Clothing protects against many things that might injure or irritate the uncovered human body, including rain, snow, wind, and other weather, as well as from the sun. Garments that are too sheer, thin, small or tight offer less protection. Appropriate clothes can also reduce risk during activities such as work or sport. Some clothing protects from specific hazards, such as insects, noxious chemicals, weather, weapons, and contact with abrasive substances. 

Humans have devised clothing solutions to environmental or other hazards: such as space suits, air conditioned clothing, armor, diving suits, swimsuits, bee-keeper gear, motorcycle leathers, high-visibility clothing, and other pieces of protective clothing. The distinction between clothing and protective equipment is not always clear-cut, since clothes designed to be fashionable often have protective value and clothes designed for function often consider fashion in their design. The choice of clothes also has social implications. They cover parts of the body that social norms require to be covered, act as a form of adornment, and serve other social purposes. Someone who lacks the means to procure reasonable clothing due to poverty or affordability, or simply lack of inclination, is sometimes said to be scruffy, ragged, or shabby.

Scholarship

Serious books on clothing and its functions appear from the 19th century as imperialists dealt with new environments such as India and the tropics. Some scientific research into the multiple functions of clothing in the first half of the 20th century, with publications such as J.C. Flügel's Psychology of Clothes in 1930, and Newburgh's seminal Physiology of Heat Regulation and The Science of Clothing in 1949. By 1968, the field of environmental physiology had advanced and expanded significantly, but the science of clothing in relation to environmental physiology had changed little. There has since been considerable research, and the knowledge base has grown significantly, but the main concepts remain unchanged, and indeed Newburgh's book is still cited by contemporary authors, including those attempting to develop thermoregulatory models of clothing development.

Cultural aspects

Gender differentiation

In most cultures, gender differentiation of clothing is considered appropriate. The differences are in styles, colors, fabrics and types.

In Western societies, skirts, dresses and high-heeled shoes are usually seen as women's clothing, while neckties are usually seen as men's clothing. Trousers were once seen as exclusively male clothing, but can nowadays be worn by both genders. Male clothes are often more practical (that is, they can function well under a wide variety of situations), but a wider range of clothing styles are available for females. Males are typically allowed to bare their chests in a greater variety of public places. It is generally acceptable for a woman to wear clothing perceived as masculine, while the opposite is seen as unusual.

In some cultures, sumptuary laws regulate what men and women are required to wear. Islam requires women to wear more modest forms of attire, usually hijab. What qualifies as "modest" varies in different Muslim societies. However, women are usually required to cover more of their bodies than men are. Articles of clothing Muslim women wear for modesty range from the head-scarf to the burqa. 

Men may sometimes choose to wear men's skirts such as togas or kilts in particular cultures, especially on ceremonial occasions. Such garments were (in previous times) often worn as normal daily clothing by men.

Clothing designed to be worn by either sex is called unisex clothing. Unisex clothes, such as T-shirts, tend to be cut straighter to fit a wider variety of bodies. The majority of unisex clothing styles have started out as menswear, but some articles, like the fedora, were originally worn by women.

Social status

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  Achkan sherwani and churidar (lower body) worn by Arvind Singh Mewar and his kin during a Hindu wedding in Rajasthan, India. Traditionally, these clothes were worn by the elites of the Indian subcontinent.
  
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  A Barong Tagalog made for a wedding ceremony.
  
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  Alim Khan's bemedaled robe sends a social message about his wealth, status, and power.
  

In some societies, clothing may be used to indicate rank or status. In ancient Rome, for example, only senators could wear garments dyed with Tyrian purple. In traditional Hawaiian society, only high-ranking chiefs could wear feather cloaks and palaoa, or carved whale teeth. In China, before establishment of the republic, only the emperor could wear yellow. History provides many examples of elaborate sumptuary laws that regulated what people could wear. In societies without such laws, which includes most modern societies, social status is instead signaled by the purchase of rare or luxury items that are limited by cost to those with wealth or status. In addition, peer pressure influences clothing choice.

Religion

Some religious clothing might be considered a special case of occupational clothing. Sometimes it is worn only during the performance of religious ceremonies. However, it may also be worn every day as a marker for special religious status.

For example, Jains and Muslim men wear unstitched cloth pieces when performing religious ceremonies. The unstitched cloth signifies unified and complete devotion to the task at hand, with no digression.^{[citation needed]} Sikhs wear a turban as it is a part of their religion.

The cleanliness of religious dresses in some religions such as Hinduism, Sikhism, Buddhism, Islam and Jainism is of paramount importance since it indicates purity. 

Clothing appears in numerous contexts in the Bible; the most prominent passages are: the story of Adam and Eve who made coverings for themselves out of fig leaves, Joseph's cloak, Judah and Tamar, Mordecai and Esther. Furthermore, the priests officiating in the Temple in Jerusalem had very specific garments, the lack of which made one liable to death.

The Quran says about husbands and wives, regarding clothing: "...They are clothing/covering (Libaas) for you; and you for them" (chapter 2:187). 

Jewish ritual also requires rending of one's upper garment as a sign of mourning.

Origin and history

Early use

According to archaeologists and anthropologists, the earliest clothing likely consisted of fur, leather, leaves, or grass that were draped, wrapped, or tied around the body. Knowledge of such clothing remains inferential, since clothing materials deteriorate quickly compared to stone, bone, shell and metal artifacts. Archeologists have identified very early sewing needles of bone and ivory from about 30,000 BC, found near Kostenki, Russia in 1988. Dyed flax fibers that could have been used in clothing have been found in a prehistoric cave in the Republic of Georgia that date back to 34,000 BC.

Scientists are still debating when people started wearing clothes. Ralf Kittler, Manfred Kayser and Mark Stoneking, anthropologists at the Max Planck Institute for Evolutionary Anthropology, have conducted a genetic analysis of human body lice that suggests clothing originated around 170,000 years ago. Body lice are an indicator of clothes-wearing, since most humans have sparse body hair, and lice thus require human clothing to survive. Their research suggests that the invention of clothing may have coincided with the northward migration of modern Homo sapiens away from the warm climate of Africa, thought to have begun between 50,000 and 100,000 years ago. However, a second group of researchers using similar genetic methods estimate that clothing originated around 540,000 years ago. For now, the date of the origin of clothing remains unresolved.

Making clothing

Hindu Indian lady wearing sari, painting by Raja Ravi Varma. One of the most ancient and popular pieces of clothing in the Indian subcontinent.

 

Some human cultures, such as the various peoples of the Arctic Circle, traditionally make their clothing entirely of prepared and decorated furs and skins. Other cultures supplemented or replaced leather and skins with cloth: woven, knitted, or twined from various animal and vegetable fibers including wool, linen, cotton, silk, hemp, and ramie. 

Although modern consumers may take the production of clothing for granted, making fabric by hand is a tedious and labor-intensive process involving fiber making, spinning, and weaving. The textile industry was the first to be mechanized – with the powered loom – during the Industrial Revolution.

Different cultures have evolved various ways of creating clothes out of cloth. One approach simply involves draping the cloth. Many people wore, and still wear, garments consisting of rectangles of cloth wrapped to fit – for example, the dhoti for men and the sari for women in the Indian subcontinent, the Scottish kilt and the Javanese sarong. The clothes may simply be tied up (dhoti and sari); or pins or belts hold the garments in place (kilt and sarong). The cloth remains uncut, and people of various sizes can wear the garment.

Another approach involves measuring, cutting, and sewing the cloth by hand or with a sewing machine. Clothing can be cut from a sewing pattern and adjusted by a tailor to the wearer's measurements. An adjustable sewing mannequin or dress form is used to create form-fitting clothing. If the fabric is expensive, the tailor tries to use every bit of the cloth rectangle in constructing the clothing; perhaps cutting triangular pieces from one corner of the cloth, and adding them elsewhere as gussets. Traditional European patterns for men's shirts and women's chemises take this approach. These remnants can also be reused to make patchwork hats, vests, and skirts. 

Modern European fashion treats cloth much less conservatively, typically cutting in such a way as to leave various odd-shaped cloth remnants. Industrial sewing operations sell these as waste; home sewers may turn them into quilts.

In the thousands of years that humans have been making clothing, they have created an astonishing array of styles, many of which have been reconstructed from surviving garments, photos, paintings, mosaics, etc., as well as from written descriptions. Costume history can inspire current fashion designers, as well as costumiers for plays, films, television, and historical reenactment.

Contemporary clothing

Western dress code

The Western dress code has changed over the past 500+ years. The mechanization of the textile industry made many varieties of cloth widely available at affordable prices. Styles have changed, and the availability of synthetic fabrics has changed the definition of "stylish". In the latter half of the 20th century, blue jeans became very popular, and are now worn to events that normally demand formal attire. Activewear has also become a large and growing market. 

Jeans in the Western dress code are worn by both men and women. There are several unique styles of jeans found which include: high rise jeans, mid rise jeans, low rise jeans, bootcut jeans, straight jeans, cropped jeans, skinny jeans, cuffed jeans, boyfriend jeans, and capri jeans.

The licensing of designer names was pioneered by designers like Pierre Cardin in the 1960s and has been a common practice within the fashion industry from about the 1970s. Among the more popular include Marc Jacobs and Gucci, named for Marc Jacobs and Guccio Gucci respectively.

Spread of western styles

University students in casual clothes in the US.

 

By the early years of the 21st century, western clothing styles had, to some extent, become international styles. This process began hundreds of years earlier, during the periods of European colonialism. The process of cultural dissemination has perpetuated over the centuries as Western media corporations have penetrated markets throughout the world, spreading Western culture and styles. Fast fashion clothing has also become a global phenomenon. These garments are less expensive, mass-produced Western clothing. Donated used clothing from Western countries are also delivered to people in poor countries by charity organizations.

Ethnic and cultural heritage

People may wear ethnic or national dress on special occasions or in certain roles or occupations. For example, most Korean men and women have adopted Western-style dress for daily wear, but still wear traditional hanboks on special occasions, like weddings and cultural holidays. Items of Western dress may also appear worn or accessorized in distinctive, non-Western ways. A Tongan man may combine a used T-shirt with a Tongan wrapped skirt, or tupenu.

Sport and activity

Most sports and physical activities are practiced wearing special clothing, for practical, comfort or safety reasons. Common sportswear garments include shorts, T-shirts, tennis shirts, leotards, tracksuits, and trainers. Specialized garments include wet suits (for swimming, diving or surfing), salopettes (for skiing) and leotards (for gymnastics). Also, spandex materials are often used as base layers to soak up sweat. Spandex is also preferable for active sports that require form fitting garments, such as volleyball, wrestling, track & field, dance, gymnastics and swimming.

Fashion shows are often the source of the latest trends in clothing fashions. Photo of a model in a modern gown reflecting the current fashion trend at a Haute couture fashion show.

Fashion

Paris set the fashion trends for Europe and North America 1900–1940. In the 1920s the goal was all about getting loose. Women wore dresses all day, everyday. Day dresses had a drop waist, which was a sash or belt around the low waist or hip and a skirt that hung anywhere from the ankle on up to the knee, never above. Daywear had sleeves (long to mid-bicep) and a skirt that was straight, pleaded, hank hem, or tired. Jewelry was less conspicuous. Hair was often bobbed, giving a boyish look.

In the 21st century a diverse range of styles exist in fashion, varying by geography, exposure to modern media, economic conditions, and ranging from expensive haute couture to traditional garb, to thrift store grunge. Fashion shows are events for designers to show off new and often extravagant designs.

Political issues

Working conditions in the garments industry

Garments factory in Bangladesh.

 

Safety garb for women workers in Los Angeles, c. 1943, was designed to prevent occupational accidents among female war workers.

 

Although mechanization transformed most aspects of human industry by the mid-20th century, garment workers have continued to labor under challenging conditions that demand repetitive manual labor. Mass-produced clothing is often made in what are considered by some to be sweatshops, typified by long work hours, lack of benefits, and lack of worker representation. While most examples of such conditions are found in developing countries, clothes made in industrialized nations may also be manufactured similarly.

Coalitions of NGOs, designers (including Katharine Hamnett, American Apparel, Veja, Quiksilver, eVocal, and Edun) and campaign groups like the Clean Clothes Campaign (CCC) and the Institute for Global Labour and Human Rights as well as textile and clothing trade unions have sought to improve these conditions as much as possible by sponsoring awareness-raising events, which draw the attention of both the media and the general public to the workers.

Outsourcing production to low wage countries like Bangladesh, China, India, Indonesia, Pakistan and Sri Lanka became possible when the Multi Fibre Agreement (MFA) was abolished. The MFA, which placed quotas on textiles imports, was deemed a protectionist measure.^{[citation needed]} Although many countries recognize treaties like the International Labour Organization, which attempt to set standards for worker safety and rights, many countries have made exceptions to certain parts of the treaties or failed to thoroughly enforce them. India for example has not ratified sections 87 and 92 of the treaty.

Despite the strong reactions that "sweatshops" evoked among critics of globalization, the production of textiles has functioned as a consistent industry for developing nations providing work and wages, whether construed as exploitative or not, to many thousands of people.

Fur

The use of animal fur in clothing dates to prehistoric times. It is currently associated in developed countries with expensive, designer clothing, although fur is still used by indigenous people in arctic zones and higher elevations for its warmth and protection. Once uncontroversial, it has recently been the focus of campaigns on the grounds that campaigners consider it cruel and unnecessary. PETA, along with other animal rights and animal liberation groups have called attention to fur farming and other practices they consider cruel.

Life cycle

Clothing maintenance

Clothing suffers assault both from within and without. The human body sheds skin cells and body oils, and exudes sweat, urine, and feces. From the outside, sun damage, moisture, abrasion, and dirt assault garments. Fleas and lice can hide in seams. Worn clothing, if not cleaned and refurbished, itches, becomes outworn, and loses functionality (as when buttons fall off, seams come undone, fabrics thin or tear, and zippers fail). 

Often, people wear an item of clothing until it falls apart. Some materials present problems. Cleaning leather is difficult, and bark cloth (tapa) cannot be washed without dissolving it. Owners may patch tears and rips, and brush off surface dirt, but materials like these inevitably age.

However, most clothing consists of cloth, and most cloth can be laundered and mended (patching, darning, but compare felt).

Laundry, ironing, storage

Humans have developed many specialized methods for laundering, ranging from early methods of pounding clothes against rocks in running streams, to the latest in electronic washing machines and dry cleaning (dissolving dirt in solvents other than water). Hot water washing (boiling), chemical cleaning and ironing are all traditional methods of sterilizing fabrics for hygiene purposes.

Many kinds of clothing are designed to be ironed before they are worn to remove wrinkles. Most modern formal and semi-formal clothing is in this category (for example, dress shirts and suits). Ironed clothes are believed to look clean, fresh, and neat. Much contemporary casual clothing is made of knit materials that do not readily wrinkle, and do not require ironing. Some clothing is permanent press, having been treated with a coating (such as polytetrafluoroethylene) that suppresses wrinkles and creates a smooth appearance without ironing. 

Once clothes have been laundered and possibly ironed, they are usually hung on clothes hangers or folded, to keep them fresh until they are worn. Clothes are folded to allow them to be stored compactly, to prevent creasing, to preserve creases or to present them in a more pleasing manner, for instance when they are put on sale in stores.

Certain types of insects and larvae feed on clothing and textiles, such as the Black carpet beetle and Clothing moths. To deter such pests, clothes may be stored in cedar-lined closets or chests, or placed in drawers or containers with materials having pest repellent properties, such as Lavender or mothballs. Airtight containers (such as sealed, heavy-duty plastic bags) may also deter insect pest damage to clothing materials.

Non-iron

A resin used for making non-wrinkle shirts releases formaldehyde, which could cause contact dermatitis for some people; no disclosure requirements exist, and in 2008 the U.S. Government Accountability Office tested formaldehyde in clothing and found that generally the highest levels were in non-wrinkle shirts and pants. In 1999, a study of the effect of washing on the formaldehyde levels found that after 6 months after washing, 7 of 27 shirts had levels in excess of 75 ppm, which is a safe limit for direct skin exposure.

Mending

When the raw material – cloth – was worth more than labor, it made sense to expend labor in saving it. In past times, mending was an art. A meticulous tailor or seamstress could mend rips with thread raveled from hems and seam edges so skillfully that the tear was practically invisible. Today clothing is considered a consumable item. Mass-manufactured clothing is less expensive than the labor required to repair it. Many people buy a new piece of clothing rather than spend time mending. The thrifty still replace zippers and buttons and sew up ripped hems.

Recycling

Used, unwearable clothing can be repurposed for quilts, rags, rugs, bandages, and many other household uses. It can also be recycled into paper. In Western societies, used clothing is often thrown out or donated to charity (such as through a clothing bin). It is also sold to consignment shops, dress agencies, flea markets, and in online auctions. Used clothing is also often collected on an industrial scale to be sorted and shipped for re-use in poorer countries. Globally, used clothes are worth $4 billion with the US as the leading exporter at $575 million.

There are many concerns about the life cycle of synthetics, which come primarily from petrochemicals. Unlike natural fibers, their source is not renewable and they are not biodegradable.

Excess inventory of clothing is sometimes destroyed to preserve brand value.

Leptin

From Wikipedia, the free encyclopedia

 

LEP
Available structures PDB Ortholog search: PDBe RCSB

List of PDB id codes
Identifiers
Aliases	LEP, LEPD, OB, OBS, leptin
External IDs	OMIM: 164160 MGI: 104663 HomoloGene: 193 GeneCards: LEP

Gene location (Human) Chr. Chromosome 7 (human) Band 7q32.1 Start 128,241,278 bp End 128,257,629 bp

RNA expression pattern More reference expression data

Gene ontology
Orthologs
Species	Human	Mouse
Entrez	3952	16846
Ensembl	ENSG00000174697	ENSMUSG00000059201
UniProt	P41159	P41160
RefSeq (mRNA)	NM_000230	NM_008493
RefSeq (protein)	NP_000221	NP_032519
Location (UCSC)	Chr 7: 128.24 – 128.26 Mb	Chr 6: 29.06 – 29.07 Mb

Identifiers
Symbol	Leptin
Pfam	PF02024
Pfam clan	CL0053
InterPro	IPR000065
SCOPe	1ax8 / SUPFAM

Leptin (from Greek λεπτός leptos, "thin") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance by inhibiting hunger, which in turn diminishes fat storage in adipocytes. Leptin acts on cell receptors in the arcuate nucleus of the hypothalamus.

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 defined.

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.

Effects

A comparison of a mouse unable to produce leptin, resulting in obesity, constant hunger, and lethargy (left), and an active normal weight mouse (right)

 

Predominantly, the "energy expenditure hormone" leptin is made by adipose cells, thus it is labeled fat cell-specific. In the context of its effects, it is important to recognize that the short describing words direct, central, 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.

Location 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, 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.

Mode 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.

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:

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

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

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.

Hypothalamus

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

• In the lateral hypothalamus, leptin inhibits hunger by
  • counteracting the effects of neuropeptide Y, a potent hunger promoter secreted by cells in the gut and in the hypothalamus
  • counteracting the effects of anandamide, another potent hunger promoter that binds to the same receptors as THC
• In the medial hypothalamus, leptin stimulates satiety 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). 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. Leptin levels change more when food intake decreases than when it increases. 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.

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

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.

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.^[40] Ob-Rb is the only receptor isoform that can signal intracellularly via the Jak-Stat and MAPK signal transduction pathways, and is present in hypothalamic nuclei.

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. 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.

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.

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.

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.

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. Leptin is involved in reproduction by stimulating gonadotropin-releasing hormone from the hypothalamus.

Pregnancy

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

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.

Puberty

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

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

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, 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. Circulating leptin seems to affect the HPA axis, suggesting a role for leptin in stress response. Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.

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, however, the size of individual fat cells, and the act of overeating, it is interesting that it is not affected by exercise (for comparison, IL-6 is released in response to muscular contractions). Thus, it is speculated that leptin responds specifically to adipose-derived inflammation. 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.

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

Location of gene and structure of hormone

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

Mutations

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

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.

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.

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

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

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

Transversion

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

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, gastric chief cells and P/D1 cells.

Blood levels

Leptin circulates in blood in free form and bound to proteins.

Physiologic variation

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

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.
• Leptin level is decreased after short-term fasting (24–72 hours), even when changes in fat mass are not observed.
• Serum level of leptin is reduced by sleep deprivation.
• Leptin levels are paradoxically increased in obesity.
• Leptin level is increased by emotional stress.
• Leptin level is chronically reduced by physical exercise training.
• Leptin level is decreased by increases in testosterone levels and increased by increases in estrogen levels.
• Leptin level is increased by insulin.
• Leptin release is increased by dexamethasone.
• In obese patients with obstructive sleep apnea, leptin level is increased, but decreased after the administration of continuous positive airway pressure. 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.

Role in disease

Obesity

Leptin and Ghrelin on the metabolism control

 

Although leptin reduces appetite as a circulating signal, obese individuals generally exhibit a higher circulating concentration of leptin than normal weight individuals due to their higher percentage body fat. These people show resistance to leptin, similar to resistance of insulin in type 2 diabetes, with the elevated levels failing to control hunger and modulate their weight. A number of explanations have been proposed to explain this. An important contributor to leptin resistance is changes to leptin receptor signalling, particularly in the arcuate nucleus, however, deficiency of, or major changes to, the leptin receptor itself are not thought to be a major cause. Other explanations suggested include changes to the way leptin crosses the blood brain barrier (BBB) or alterations occurring during development.

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. 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. 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. 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. 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), 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.

When leptin binds with the leptin receptor, it activates a number of pathways. Leptin resistance may be caused by defects in one or more part of this process, particularly the JAK/STAT pathway. Mice with a mutation in the leptin receptor gene 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.

The consumption of a high fructose diet from birth has been associated with a reduction in leptin levels and reduced expression of leptin receptor mRNA in rats. Long-term consumption of fructose in rats has been shown to increase levels of triglycerides and trigger leptin and insulin resistance, however, another study found that leptin resistance only developed in the presence of both high fructose and high fat levels in the diet. A third study found that high fructose levels reversed leptin resistance in rats given a high fat diet. The contradictory results mean that it is uncertain whether leptin resistance is caused by high levels of carbohydrates or fats, or if an increase of both, is needed.

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.

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

Response to weight loss

Dieters who lose weight, particularly those with an overabundance of fat cells, experience a drop in levels of circulating leptin. This drop causes reversible decreases in thyroid activity, sympathetic tone, and energy expenditure in skeletal muscle, and increases in muscle efficiency and parasympathetic tone. Many of these changes are reversed by peripheral administration (⁠ ⁠intravenously into the veins of the arms, hands, legs, or feet⁠ ⁠) of recombinant leptin to restore pre-diet levels.

A decline in levels of circulating leptin also changes brain activity in areas involved in the regulatory, emotional, and cognitive control of appetite that are reversed by administration of leptin.

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). Consequently, it has been shown that decreasing body fat lessens osteoarthritis to a greater extent than weight loss per se. 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.

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. 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. 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. 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 

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.

Analog 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. 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.

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

History

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

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. 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. In 1990 Rudolph Leibel and Jeffrey M. Friedman reported mapping of the db gene.

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.

In 1994, Friedman's laboratory reported the identification of the gene. 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. Leptin was the first fat cell-derived hormone (adipokine) to be discovered.

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.

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), the Shaw Prize (2009), the Lasker Award, the BBVA Foundation Frontiers of Knowledge Award and the King Faisal International Prize, 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.

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