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Leptin (Greek leptos meaning thin) is a 16 kDa
Atomic mass unit

The unified atomic mass unit , or dalton or, sometimes, universal mass unit, is a Units of measurement of mass used to express atomic weight and molecular masses....
 protein
Protein

Proteins are organic compounds made of amino acids arranged in a linear chain and joined together by peptide bonds between the carboxyl and amino groups of adjacent amino acid Residue ....
 hormone
Hormone

Hormones are chemicals released by cells that affect cells in other parts of the body. Only a small amount of hormone is required to alter cell metabolism....
 that plays a key role in regulating energy intake and energy expenditure, including appetite
Appetite

The appetite is the desire to eating food, felt as hunger. Appetite exists in all higher lifeforms, and serves to regulate adequate energy intake to maintain metabolism needs....
 and metabolism
Metabolism

Metabolism is the set of chemical reactions that occur in living organisms in order to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments....
. Leptin is one of the most important adipose derived hormones
Adipose derived hormones

Adipose tissue is an important endocrine organ that secretes numerous protein hormones into circulation. These factors are generally referred to as adipocytokines or adipokines, however the strict definition of an adipokine is that it interacts with the immune system....
. The Ob(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans.

Discovery
The effects of leptin were observed by studying mutant
Mutant

A mutant is an individual, organism, or new genetic character arising or resulting from an instance of mutation, which is a base-pair sequence change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or Trait not found in the wild type....
 obese
Obesity

Obesity is a condition in which excess body fat has accumulated to an extent that health may be negatively affected. It is commonly defined as a body mass index of 30 kg/m2 or higher....
 mice
MICE

MICE is an acronym for:*International Muon Ionization Cooling Experiment*"Money, Ideology, Compromise, Ego", four factors by which spies may be recruited....
 that arose at random within a mouse colony at the Jackson Laboratory
Jackson Laboratory

The Jackson Laboratory was founded in Bar Harbor , Maine in 1929 by former University of Maine and University of Michigan president C. C. Little under the name Roscoe B....
 in 1950.






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Leptin (Greek leptos meaning thin) is a 16 kDa
Atomic mass unit

The unified atomic mass unit , or dalton or, sometimes, universal mass unit, is a Units of measurement of mass used to express atomic weight and molecular masses....
 protein
Protein

Proteins are organic compounds made of amino acids arranged in a linear chain and joined together by peptide bonds between the carboxyl and amino groups of adjacent amino acid Residue ....
 hormone
Hormone

Hormones are chemicals released by cells that affect cells in other parts of the body. Only a small amount of hormone is required to alter cell metabolism....
 that plays a key role in regulating energy intake and energy expenditure, including appetite
Appetite

The appetite is the desire to eating food, felt as hunger. Appetite exists in all higher lifeforms, and serves to regulate adequate energy intake to maintain metabolism needs....
 and metabolism
Metabolism

Metabolism is the set of chemical reactions that occur in living organisms in order to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments....
. Leptin is one of the most important adipose derived hormones
Adipose derived hormones

Adipose tissue is an important endocrine organ that secretes numerous protein hormones into circulation. These factors are generally referred to as adipocytokines or adipokines, however the strict definition of an adipokine is that it interacts with the immune system....
. The Ob(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans.

Discovery


The effects of leptin were observed by studying mutant
Mutant

A mutant is an individual, organism, or new genetic character arising or resulting from an instance of mutation, which is a base-pair sequence change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or Trait not found in the wild type....
 obese
Obesity

Obesity is a condition in which excess body fat has accumulated to an extent that health may be negatively affected. It is commonly defined as a body mass index of 30 kg/m2 or higher....
 mice
MICE

MICE is an acronym for:*International Muon Ionization Cooling Experiment*"Money, Ideology, Compromise, Ego", four factors by which spies may be recruited....
 that arose at random within a mouse colony at the Jackson Laboratory
Jackson Laboratory

The Jackson Laboratory was founded in Bar Harbor , Maine in 1929 by former University of Maine and University of Michigan president C. C. Little under the name Roscoe B....
 in 1950. These mice were massively obese and excessively voracious. Leptin itself was discovered in 1994 by Jeffrey M. Friedman
Jeffrey M. Friedman

Jeffrey Friedman, Doctor of Medicine, PhD, is a molecular geneticist at New York City's Rockefeller University. His discovery of the hormone leptin and its role in regulating body weight has had a major role in the area of human obesity....
 and colleagues at the Rockefeller University
Rockefeller University

The Rockefeller University is a private university which focuses primarily on basic research in the biomedical fields and offers graduate and postgraduate education....
 through the study of such mice.

Synthesis


In addition to white adipose tissue - the major source of leptin - it can also be produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (lower part of fundic glands), mammary epithelial cells, bone marrow, pituitary and liver.

Function


In addition to being a biomarker for body fat, serum leptin levels also reflect individual energy balance. Several studies have shown that fasting
Fasting

Fasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. A fast may be total or partial concerning that from which one fasts, and may be prolonged or intermittent as to the period of fasting....
 or following a very low calorie diet
Very Low Calorie Diet

Very low calorie diet is a Diet with very or extremely low calorie consumption per day. It is defined medically as a diet of 800 calorie per day or less....
 (VLCD) lowers leptin levels. It might be that on short term leptin is an indicator of energy balance. This system is more sensitive to starvation than to overfeeding, i.e. leptin levels do not rise extensively after overfeeding. It might be that the dynamics of leptin due to an acute change in energy balance are related to appetite and eventually to food intake. Although this is a new hypothesis, there are already some data that support it.

There is some controversy regarding the regulation of leptin by melatonin
Melatonin

Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring hormone found in most animals, including humans, and some other living organisms, including algae....
 during the night. One research group suggested that increased levels of melatonin
Melatonin

Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring hormone found in most animals, including humans, and some other living organisms, including algae....
 caused a downregulation of leptin. However, in 2004, Brazilian researchers found that in the presence of insulin
Insulin

Insulin is a hormone with extensive effects on both metabolism and several other body systems . Insulin causes most of the body's cells to take up glucose from the blood , storing it as glycogen in the liver and muscle, and stops use of fat as an energy source....
, "melatonin interacts with insulin and upregulates insulin-stimulated leptin expression", therefore causing a decrease in appetite whilst sleeping.

Professor Cappuccio of the University of Warwick
University of Warwick

The University of Warwick is a British campus university located on the outskirts of Coventry, West Midlands , England and is University of Warwick#Academic standards as one of the country's leading universities....
 has recently discovered that short sleep duration may lead to obesity
Obesity

Obesity is a condition in which excess body fat has accumulated to an extent that health may be negatively affected. It is commonly defined as a body mass index of 30 kg/m2 or higher....
 through an increase of appetite via hormonal changes. Lack of sleep produces ghrelin
Ghrelin

Ghrelin is a hormone produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates appetite....
, a hormone that stimulates appetite by lowering leptin levels.

Adiposity signal


To date, only leptin and insulin
Insulin

Insulin is a hormone with extensive effects on both metabolism and several other body systems . Insulin causes most of the body's cells to take up glucose from the blood , storing it as glycogen in the liver and muscle, and stops use of fat as an energy source....
 are known to act as an adiposity signal. In general,

  • Leptin circulates at levels proportional to body fat
    Adipose tissue

    In histology, adipose tissue or fat is loose connective tissue composed of adipocytes. Adipose tissue is derived from lipoblasts. Its main role is to store energy in the form of fat, although it also cushions and Thermal insulation the body....
    .
  • It enters the central nervous system
    Central nervous system

    The central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of multicellular organisms....
     (CNS) in proportion to its plasma
    Blood plasma

    Blood plasma is the liquid component of blood, in which the blood cells are suspended. It makes up about 55% of total blood volume. It is composed of mostly water , and contains dissolved proteins, glucose, clotting factors, mineral ions, Hormone and carbon dioxide ....
     concentration.
  • Its receptors are found in brain neurons involved in regulating energy intake and expenditure.
  • Controls food intake and energy expenditure by acting on receptors in the mediobasal hypothalamus
    Hypothalamus

    The hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland ....


Satiety: appetite control


Leptin binds to the ventromedial nucleus
Ventromedial nucleus

The ventromedial nucleus is a nucleus of the hypothalamus.DivisionIt has four subdivisions:* anterior * dorsomedial * ventrolateral ...
 of the hypothalamus
Hypothalamus

The hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland ....
, known as the "appetite center." Leptin signals to the brain that the body has had enough to eat, or satiety. A very small group of humans possess homozygous (same on both of the pair) mutations for the leptin gene which leads to a constant desire for food, resulting in severe obesity. This condition can be treated successfully by the administration of recombinant human leptin.

Thus, circulating leptin levels give the brain input regarding energy storage so it can regulate appetite
Appetite

The appetite is the desire to eating food, felt as hunger. Appetite exists in all higher lifeforms, and serves to regulate adequate energy intake to maintain metabolism needs....
 and metabolism
Metabolism

Metabolism is the set of chemical reactions that occur in living organisms in order to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments....
. Leptin works by inhibiting the activity of neurons that contain neuropeptide Y
Neuropeptide Y

Neuropeptide Y is a 36 amino acid peptide neurotransmitter found in the brain and autonomic nervous system.NPY has been associated with a number of physiologic processes in the brain, including the regulation of energy balance, memory and learning, and epilepsy....
 (NPY) and agouti-related peptide
Agouti-related peptide

Agouti-related protein also called Agouti-related peptide is a neuropeptide produced in the brain by the AgRP/NPY neuron that increases appetite and decreases metabolism and energy expenditure....
 (AgRP), and by increasing the activity of neurons expressing a-melanocyte-stimulating hormone
Melanocyte-stimulating hormone

The melanocyte-stimulating hormones are a class of peptide hormones that in nature are produced by cells in the intermediate lobe of the pituitary gland....
 (a-MSH). The NPY neurons are a key element in the regulation of appetite; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic
Anorexia (symptom)

Anorexia is the decreased sensation of appetite. While the term in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a decreased appetite, some of which may be harmless, while others indicate a serious clinical condition, or pose a significant risk....
. Conversely, a-MSH is an important mediator of satiety, and differences in the gene
Gene

A gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cell and pass genetic trait to offspring....
 for the receptor at which a-MSH acts in the brain are linked to obesity
Obesity

Obesity is a condition in which excess body fat has accumulated to an extent that health may be negatively affected. It is commonly defined as a body mass index of 30 kg/m2 or higher....
 in humans.

Circulatory system


The role of Leptin/Leptin receptors in modulation of T cell
T cell

T cells belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and natural killer cells by the presence of a special receptor on their cell surface called T cell receptors ....
 activity in immune system was shown in experimentation with mice. It modulates the immune response to atherosclerosis, which is a predisposing factor in patients with obesity.

Leptin is also strongly linked with angiogenesis
Angiogenesis

Angiogenesis is a physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over this, vasculogenesis is the term used for spontaneous blood-vessel formation, and Intussusception is the term for new blood vessel formation by splitting off existing ones....
, increasing Vascular endothelial growth factor (VEGF
Vascular endothelial growth factor

Vascular endothelial growth factor a sub-family of growth factors, more specifically of platelet-derived growth factor family of cystine-knot growth factors....
) levels.

Lung surfactant activity

In fetal lung leptin is induced in the alveolar interstitial fibroblasts ("lipofibroblasts") by the action of PTHrP secreted by formative alveolar epithelium (endoderm) under moderate stretch. The leptin from the mesenchyme in turn acts back on the epithelium at the leptin receptor carried in the alveolar type II pneumocytes and induces surfactant expression which is one of the main functions of these type II pneumocytes.

Reproduction


In mice, leptin is also required for male and female fertility
Fertility

Fertility is the natural capability of giving life. As a measure, "fertility rate" is the number of children born per couple, person or population....
. In mammals such as humans puberty in females is linked to a critical level of body fat. When fat levels fall below this threshold (as in anorexia
Anorexia

Anorexia can refer to:Eating conditions* Anorexia , the symptom of poor appetite whatever the cause* Anorexia nervosa, an eating disorder of excessive weight loss and usually undue concern about body shape...
), the ovarian cycle stops and females stop menstruating.

The body's fat cells, under normal conditions, are responsible for the constant production and release of leptin. This can also be produced by the placenta
Placenta

The placenta or afterbirth is a highly vascularized ephemeral organ present in Placentalia vertebrates that connects the developing fetal tissues to the uterine wall....
. Leptin levels rise during pregnancy and fall after parturition (childbirth). Leptin is also expressed in fetal membranes and the uterine tissue. Uterine contractions are inhibited by leptin.

There is also evidence that leptin plays a role in hyperemesis gravidarum
Hyperemesis gravidarum

Hyperemesis gravidarum is a severe form of morning sickness, with unrelenting, excessive pregnancy-related nausea and/or vomiting that prevents adequate intake of food and fluids. Hyperemesis is considered a rare complication of pregnancy but, because nausea and vomiting during pregnancy exist on a continuum, there is often not a good d...
 (severe morning sickness
Morning sickness

Morning sickness, also called nausea gravidarum, nausea, vomiting of pregnancy , or pregnancy sickness is a condition that affects more than half of all pregnant women, as well as some women who use hormonal contraception or hormone replacement therapy....
), in polycystic ovary syndrome
Polycystic ovary syndrome

Polycystic ovary syndrome is an endocrine disorder that affects approximately 5% of all women.It occurs amongst all races and nationalities, is the most common hormonal disorder among women of reproductive age, and is a leading cause of infertility....
 and a 2007 research suggests that hypothalamic leptin is implicated in bone growth.

Leptin resistance and obesity

Although leptin is a circulating signal that reduces appetite, in general, obese people have an unusually high circulating concentration of leptin. These people are said to be resistant to the effects of leptin, in much the same way that people with type 2 diabetes are resistant
Insulin resistance

Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal Insulin#Physiological_effects from fat, muscle and liver cell ....
 to the effects of insulin
Insulin

Insulin is a hormone with extensive effects on both metabolism and several other body systems . Insulin causes most of the body's cells to take up glucose from the blood , storing it as glycogen in the liver and muscle, and stops use of fat as an energy source....
. The high sustained concentrations of leptin from the enlarged adipose stores result in leptin desensitization. The pathway of leptin control in obese people might be flawed at some point so the body doesn't adequately receive the satiety feeling subsequently to eating.

Fructose and leptin resistance


A study published recently suggests that the consumption of high amounts of fructose
Fructose

Fructose is a simple Reducing sugar sugar found in many foods and is one of the three important dietary monosaccharides along with glucose and galactose....
 causes leptin resistance and elevated triglyceride
Triglyceride

is a glyceride in which the glycerol is esterified with three fatty acids. It is the main constituent of vegetable oil and animal fats....
s in rats. The high fructose diet rats subsequently ate more and gained more weight than controls when fed a high fat, high calorie diet.

Mechanism of action


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

Leptin receptor, also known as LEPR, is a human gene. LEPR has also been designated as CD295 ....
. Ob-Rb is the only receptor isoform that can signal intracellular
Intracellular

Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell "....
ly via the Jak
Jak

Jak may refer to:*Jak , a North American Native Americans in the United States*JAK members bank, a Swedish interest-free bank*Janus kinase, an intracellular signaling molecule; component of the JAK-STAT signal system....
-Stat
STAT

STAT may mean:*STAT protein, the Signal Transducers and Activators of Transcription protein,*Special Tertiary Admissions Test, a set of tests aimed at assessing the critical reasoning abilities of university applicants who lack other formal qualifications....
 and MAPK signal transduction pathways, and is present in hypothalamic nuclei
Hypothalamus

The hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland ....
.

It is unknown whether leptin can cross the blood-brain barrier
Blood-brain barrier

The blood-brain barrier is a metabolic or cellular structure in the central nervous system that restricts the passage of various chemical substances and microscopic objects between the bloodstream and the neural tissue itself, while still allowing the passage of substances essential to metabolism function ....
 to access receptor neurons, because the blood-brain barrier is somewhat absent in the area of the median eminence
Median eminence

The median eminence is part of the inferior boundary for the hypothalamus part of the human brain. A small swelling on the tuber cinereum posterior to the infundibulum - atop the pituitary stalk - the median eminence lies in the area roughly bounded on its posterolateral region by the cerebral peduncles, and on its anterolateral region...
, close to where the NPY neurons of the arcuate nucleus
Nucleus (neuroanatomy)

In neuroanatomy, a nucleus is a brain structure consisting of a relatively compact cluster of neurons. It is one of the two most common forms of nerve cell organization, the other being layered structures such as the cerebral cortex or cerebellum....
 are. It is generally thought that leptin might enter the brain at the choroid plexus
Choroid plexus

The choroid plexus is the area on the ventricle s of the brain where cerebrospinal fluid is produced by modified ependymal cells....
, where there is intense expression of a form of leptin receptor molecule that could act as a transport mechanism.

Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to, presumably, effect changes in gene expression. One of the main effects on gene expression is the down-regulation of the expression of endocannabinoids, responsible for increasing appetite. There are other intracellular pathways activated by leptin, but less is known about how they function in this system. In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them.

There is some recognition that leptin action is more decentralized than previously assumed. In addition to its endocrine action at a distance (from adipose tissue to brain), leptin also acts as a paracrine mediator.

See also

  • Orexin
    Orexin

    Orexins, also called hypocretins, are the common names given to a pair of highly excitatory neuropeptide hormones that were simultaneously discovered by two groups of researchers in rat brains....


Further reading


External links

  • , a weight control website
  • , description and structure diagrams