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Leptin

Leptin

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Leptin is a 16 kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...

 protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...

 that plays a key role in regulating energy intake and energy expenditure, including appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...

 and metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

. It is one of the most important adipose derived hormones
Adipose derived hormones
Adipose tissue is an important endocrine organ that secretes numerous protein hormones, including leptin, adiponectin, and resistin. These hormones generally influence energy metabolism, which is of great interest to the understanding and treatment of type 2 diabetes and obesity.Their relative...

. 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
In biology and especially genetics, 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...

 obese mice 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. Ultimately, several strains of laboratory mice have been found to be homozygous for single-gene mutations that cause them to become grossly obese, and they fall into two classes: "ob/ob", those having mutations in the gene for the protein hormone leptin, and "db/db", those having mutations in the gene that encodes the receptor for leptin. When ob/ob mice are treated with injections of leptin, they lose their excess fat and return to normal body weight.

Leptin itself was discovered in 1994 by Jeffrey M. Friedman
Jeffrey M. Friedman
Jeffrey Friedman, MD, 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.-Biography:...

 and colleagues at the Rockefeller University
Rockefeller University
The Rockefeller University is a private university offering postgraduate and postdoctoral education. It has a strong concentration in the biological sciences. It is also known for producing numerous Nobel laureates...

 through the study of such mice.

Biosynthesis


Human leptin is a protein of 167 amino acids. It is manufactured primarily in the adipocytes of white adipose tissue
White adipose tissue
White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind of adipose tissue is brown adipose tissue....

, and the level of circulating leptin is directly proportional to the total amount of fat in the body.

In addition to white adipose tissue—the major source of leptin—it can also be produced by brown adipose tissue
Brown adipose tissue
Brown adipose tissue or brown fat is one of two types of fat or adipose tissue found in mammals....

, placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...

 (syncytiotrophoblasts), ovaries, skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...

, stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...

 (lower part of fundic glands), mammary epithelial cells, bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...

, pituitary and liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

.

Leptin has also been discovered to be synthesised from gastric chief cell
Gastric chief cell
A gastric chief cell is a cell in the stomach that releases pepsinogen, gastric lipase and Chymosin...

s and P/D1 cell
P/D1 cell
Cells lining the fundus of the human stomach that produce ghrelin. Removal of these cells in gastric bypass surgery has a profound impact on later appetite regulation....

s in the stomach.

Function


Leptin acts on receptors in the hypothalamus of the brain where it inhibits appetite by (1) counteracting the effects of 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." The main effect is increased food...

 (a potent feeding stimulant secreted by cells in the gut and in the hypothalamus); (2) counteracting the effects of anandamide
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...

 (another potent feeding stimulant that binds to the same receptors as THC
THC
THC commonly refers to tetrahydrocannabinol, the main active chemical compound in Cannabis.THC may also refer to:* Tan Holdings Corporation...

), and (3) promoting the synthesis of α-MSH, an appetite suppressant. This inhibition is long-term, in contrast to the rapid inhibition of eating by cholecystokinin
Cholecystokinin
Cholecystokinin is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein...

 (CCK) and the slower suppression of hunger between meals mediated by PYY3-36. The absence of leptin (or its receptor) leads to uncontrolled food intake and resulting obesity. Several studies have shown that fasting
Fasting
Fasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. An absolute fast is normally defined as abstinence from all food and liquid for a defined period, usually a single day , or several days. Other fasts may be only partially restrictive,...

 or following a very-low-calorie diet (VLCD) lowers leptin levels.
It might be that, in the short-term, leptin is an indicator of energy balance. This system is more sensitive to starvation than to overfeeding; leptin levels change more when food intake decreases than when it increases. 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 compound found in animals, plants, and microbes...

 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 compound found in animals, plants, and microbes...

 caused a downregulation of leptin. However, in 2004, Brazilian researchers found that melatonin increases leptin levels in the presence of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

, therefore causing a decrease in appetite during sleeping.

Mice with type 1 diabetes treated with leptin alone or in conjunction with insulin did better (blood sugar did not fluctuate as much; cholesterol levels decreased; mice formed less body fat) than mice with type 1 diabetes treated with insulin alone, raising the prospect of a new treatment for diabetes.

Adiposity signal


To date, only leptin and insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

 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 body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...

    .
  • It enters the central nervous system
    Central nervous system
    The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

     (CNS) in proportion to its plasma
    Blood plasma
    Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

     concentration.
  • Its receptors are found in brain neurons involved in regulating energy intake and expenditure.
  • It controls food intake and energy expenditure by acting on receptors in the mediobasal hypothalamus
    Hypothalamus
    The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...


Interaction with amylin


Co-administration of two neurohormones known to have a role in body weight control, amylin
Amylin
Amylin, or Islet Amyloid Polypeptide , is a 37-residue peptide hormone secreted by pancreatic β-cells at the same time as insulin .-Clinical significance:...

 (produced by beta cells in the pancreas) and leptin (produced by fat cells), results in sustained, fat-specific weight loss in a leptin-resistant animal model of obesity.

Satiety


Leptin binds to 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." The main effect is increased food...

 (NPY) neurons in the arcuate nucleus
Arcuate nucleus
The arcuate nucleus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence...

, in such a way that decreases the activity of these neurons. Leptin signals to the brain that the body has had enough to eat, producing a feeling of satiety. A very small group of humans possess homozygous mutations for the leptin gene that leads to a constant desire for food, resulting in severe obesity. This condition can be treated somewhat successfully by the administration of recombinant human leptin. However, extensive clinical trials using recombinant human leptin as a therapeutic agent for treating obesity in humans have been inconclusive because only the most obese subjects who were given the highest doses of exogenous leptin produced statistically significant weight loss. It was concluded that large and frequent doses are needed to provide only modest benefit because of leptin’s low circulating half-life, low potency, and poor solubility. Furthermore, these injections caused some participants to drop out of the study due to inflammatory responses of the skin at the injection site. Some of these problems can be alleviated by a form of leptin called Fc-leptin, which takes the Fc fragment from the immunoglobulin gamma chain as the N-terminal fusion partner and follows it with leptin. This Fc-leptin fusion has been experimentally proven to be highly soluble, more biologically potent, and contain a much longer serum half-life. As a result, this Fc-leptin was successfully shown to treat obesity in both leptin-deficient and normal mice, although studies have not been undertaken on human subjects. This makes Fc-leptin a potential treatment for obesity in humans after more extensive testing. Circulating leptin levels give the brain input regarding energy storage so it can regulate appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...

 and metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

. Leptin works by inhibiting the activity of neurons that contain neuropeptide Y (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. It is only synthesised in NPY containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus...

 (AgRP), and by increasing the activity of neurons expressing α-melanocyte-stimulating hormone
Melanocyte-stimulating hormone
The melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...

 (α-MSH). The NPY neurons are a key element in the regulation of appetite; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...

. On the converse, α-MSH is an important mediator of satiety, and differences in the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

 for the receptor at which α-MSH acts in the brain are linked to obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...

 in humans.

Circulatory system


The role of leptin/leptin receptors in modulation of T cell
T cell
T cells or T lymphocytes 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 lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...

 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 promotes angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...

 by increasing vascular endothelial growth factor
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....

 (VEGF) levels.

In some epidemiological studies, hyperleptinemia is considered as a risk factor. However, recently a handful of animal experiments demonstrated that systemic hyperleptinemia produced by infusion or adenoviral gene transfer decreases blood pressure in rats.

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 producing offsprings. As a measure, "fertility rate" is the number of children born per couple, person or population. Fertility differs from fecundity, which is defined as the potential for reproduction...

. Leptin has a lesser effect in humans. In mammals such as humans, ovulatory cycles in females are linked to energy balance (positive or negative depending on whether a female is losing or gaining weight) and energy flux (how much energy is consumed and expended) much more than energy status (fat levels). When energy balance is highly negative (meaning that a woman is starving) or energy flux is very high (meaning that a woman is exercising at extreme levels, but still consuming enough calories), the ovarian cycle stops and females stop menstruating. Only if a female has an extremely low body fat percentage does energy status affect menstruation. Some studies have indicated that leptin levels outside an ideal range can have a negative effect on egg quality and outcome during IVF.

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 is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...

. 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...

 (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. Related to increased oestrogen levels, a similar form of nausea is also seen in some women who use hormonal contraception or...

 of pregnancy), in polycystic ovary syndrome
Polycystic ovary syndrome
Polycystic ovary syndrome is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain aetiology, but there is strong evidence that it can to a large degree be classified as a genetic disease....

 and a 2007 research suggests that hypothalamic leptin is implicated in bone growth.

Effects on bone


The fact that leptin, a hormone released from fat tissue, can regulate bone mass first came to prominence in 2000. It is now well established that leptin can affect bone metabolism via direct signalling from the brain and that although leptin acts to reduce cancellous bone, it conversely increases cortical bone
Cortical bone
Cortical bone, synonymous with compact bone, is one of the two types of osseous tissue that form bones. Cortical bone facilitates bone's main functions: to support the whole body, protect organs, provide levers for movement, and store and release chemical elements, mainly calcium. As its name...

. A number of theories have been put forward concerning the cortical-cancellous dichotomy including a recent theory suggesting that increased leptin during obesity may represent a mechanism for enlarging bone size and thus bone resistance to cope with increased body weight.

Bone metabolism is under direct control of the brain and thus nerve fibres are present in bone tissue. A number of brain signalling molecules (neuropeptides and neurotransmitters) have been found in bone including adrenaline, noradrenaline, serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

, calcitonin gene-related peptide
Calcitonin gene-related peptide
Calcitonin gene related peptide is a member of the calcitonin family of peptides, which in humans exists in two forms, α-CGRP and β-CGRP. α-CGRP is a 37-amino acid peptide and is formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11...

, vasoactive intestinal peptide
Vasoactive intestinal peptide
Vasoactive intestinal peptide also known as the vasoactive intestinal polypeptide or VIP is a peptide hormone containing 29 amino acid residues that is produced in many tissues of vertebrates including the gut, pancreas and suprachiasmatic nuclei of the hypothalamus in the brain...

 and 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." The main effect is increased food...

. This evidence supports a direct signalling system between the brain and bone with accumulating evidence suggesting that these molecules are directly involved in the regulation of bone metabolism. Leptin, once released from fat tissue, can cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

 and bind to its receptors in the brain where it acts through the sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...

 to regulate bone metabolism. It is also possible that, in addition to its effects through the brain, leptin may act directly on cells in the bone to regulate bone metabolism. In reality, leptin probably signals to bone on multiple levels, with local and systemic checks and balances impacting the final outcome. As a result, the clinical utility of leptin for treatment of bone diseases remains open but ongoing research may yet provide much needed therapies for stimulating bone formation.

Clinical significance


Leptin has traditionally been regarded as a link between fat mass, food intake, and energy expenditure. This link originally arose from animal research findings, but its application to describing human systems has since been challenged. In humans, there are many instances where leptin dissociates from the strict role of communicating nutritional status between body and brain and no longer correlates with body fat levels:
  • Leptin levels decrease after short-term fasting (24–72 hours), even when changes in fat mass are not observed.
  • In the obese patients with obstructive sleep apnea (OSA), Leptin is increased, but decreases after administration of a CPAP
    CPAP
    CPAP may stand for:* Continuous positive airway pressure, a particular type of ventilation therapy* The Center for Public Administration and Policy, an academic department at Virginia Tech...

    . In non-obese individuals, however, restful sleep (i.e., 8–12 hours of unbroken sleep) can increase leptin within normal ranges.
  • Serum levels of Leptin are reduced by sleep deprivation.
  • Increased by perceived emotional stress.
  • Decreased by testosterone and increased by estrogen.
  • Chronically affected by exercise training; it decreases leptin levels.

Inflammatory marker


Factors that acutely affect leptin levels are also factors that influence other markers of inflammation, e.g., testosterone, sleep, emotional stress, caloric restriction, and body fat levels. While it is well-established that leptin is involved in the regulation of the inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 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
Superfamily
The term superfamily is used to describe several different concepts in different scientific fields:* Superfamily and Superfamily : a level of biological classification; redirects to Taxonomic rank...

. Circulating leptin seems to effect 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
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

, metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...

, and cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...

. However, while leptin is associated with body fat mass, the size of individual fat cells, and the act of overeating, it is interesting that it is not affected by exercise (for comparison, IL-6 is released in response to muscular contractions). Thus, it is speculated that leptin responds specifically to adipose-derived inflammation. 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 fat cells' ability to grow larger
Hypertrophy
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It should be distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number...

 or increase in number
Hyperplasia
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....

 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
Acipimox
Acipimox is a niacin derivative used as a hypolipidemic agent.It is used in low doses and may have less marked adverse effects, although it is unclear whether the recommended dose is as effective as are standard doses of nicotinic acid . These drug inhibit hepatic triglyceride production and VLDL...

 is administered to prevent lipolysis
Lipolysis
Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...

, concurrent hypocaloric dieting and weight loss notwithstanding. Such findings appear to demonstrate that high caloric loads in excess of fat cells' storage rate capacities lead to stress responses that induce an increase in leptin, which then operates as an adipose-derived inflammation stopgap signaling for the cessation of food intake so as to prevent adipose-derived inflammation from reaching elevated levels. This response may then protect against the harmful process of ectopic fat storage, which perhaps explains the connection between chronically-elevated leptin levels and ectopic fat storage in obese individuals.

Obesity and leptin resistance


Although leptin is a circulating signal that reduces appetite, obese individuals generally exhibit 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 a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

 to the effects of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

. 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 does not adequately receive the satiety feeling subsequent to eating.

Some researchers attempted to explain the failure of leptin to prevent obesity in modern humans as a metabolic disorder, possibly caused by a specific nutrient or a combination of nutrients that were not present or were not common in the prehistoric diet. Some proposed "villain" nutrients include lectin
Lectin
Lectins are sugar-binding proteins that are highly specific for their sugar moieties. They play a role in biological recognition phenomena involving cells and proteins. For example, some viruses use lectins to attach themselves to the cells of the host organism during infection...

s and fructose
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...

.

A signal-to-noise ratio
Signal-to-noise ratio
Signal-to-noise ratio is a measure used in science and engineering that compares the level of a desired signal to the level of background noise. It is defined as the ratio of signal power to the noise power. A ratio higher than 1:1 indicates more signal than noise...

 theory has been proposed to explain the phenomenon of leptin resistance. In healthy individuals, baseline leptin levels are between 1-5 ng/dl in men and 7-13 ng/dl in women. A large intake of calories triggers a leptin response that reduces hunger, thereby preventing an overload of the inflammatory response induced by caloric intake. It has been theorized that, in obese individuals, the leptin response to caloric intake is blunted due to chronic, low-grade hyperleptinemia depressing the signal-to-noise ratio such that acute leptin responses have less of a physiological effect on the body.

Although leptin resistance is sometimes described as a metabolic disorder that contributes to obesity, similar to the way insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

 is sometimes described as a metabolic disorder that has the potential to progress into the type 2 diabetes, it is not certain that it is true in most cases. The mere fact that leptin resistance is extremely common in obese individuals suggests that it may simply be an adaptation to excess body weight. It has been suggested that the major physiological role of leptin is not as a “satiety signal” to prevent obesity in times of energy excess, but as a “starvation signal” to maintain adequate fat stores for survival during times of energy deficit, and that leptin resistance in overweight individuals is the standard feature of mammalian physiology, which possibly confers a survival advantage.

A different form of leptin resistance (in combination with insulin resistance and weight gain) easily arises in laboratory animals (such as rats), as soon as they are given unlimited (ad libitum) access to palatable, energy-dense foods, and it is reversed when these animals are put back on low energy-density chow. That, too, may have an evolutionary advantage: "the ability to efficiently store energy during periods of sporadic feast represented a survival advantage in ancestral societies subjected to periods of starvation." The combination of two mechanisms (one, which temporarily suspends leptin action when presented with excess of high-quality food, and the other, which blunts the processes that could drive the body weight back to "normal"), could explain the current obesity epidemic without invoking any metabolic disorders or "villain" nutrients.

Interactions with fructose


A study published suggests that the consumption of high amounts of fructose
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...

 causes leptin resistance and elevated triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....

s in rats. The rats consuming the high-fructose diet subsequently ate more and gained more weight than controls when fed a high-fat, high-calorie diet. These studies however did not control against other monosaccharides or polysaccharides, therefore leptin resistance may be a result of a diet that contains high saccharide indexes (soda, candy, and other easily sugar-liberated foods).

Mechanism of action


Leptin interacts with six types of receptors (Ob-Ra–Ob-Rf, or LepRa-LepRf) that in turn are encoded by a single gene, LEPR
Leptin receptor
Leptin receptor also known as LEP-R is a protein that in humans is encoded by the LEPR gene. LEP-R functions as a receptor for the fat cell-specific hormone leptin...

. 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".It is used in contrast to extracellular...

ly via the Jak-Stat
JAK-STAT signaling pathway
The JAK-STAT signaling pathway transmits information from chemical signals outside the cell, through the cell membrane, and into gene promoters on the DNA in the cell nucleus, which causes DNA transcription and activity in the cell. The JAK-STAT system is a major signaling alternative to the second...

 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...

.

It is unknown as to whether leptin can cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

 to access receptor neurons, because the blood-brain barrier is attenuated 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...

, 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 cerebellar cortex. In anatomical sections, a nucleus shows up...

 are. It is generally thought that leptin might enter the brain at the choroid plexus
Choroid plexus
The choroid plexus is a structure in the ventricles of the brain where cerebrospinal fluid is produced...

, 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, it is presumed, 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.

Metreleptin


An analog of human leptin, metreleptin is under investigation for the treatment of diabetes and/or hypertriglyceridemia
Hypertriglyceridemia
In medicine, hypertriglyceridemia denotes high blood levels of triglycerides, the most abundant fatty molecule in most organisms. It has been associated with atherosclerosis, even in the absence of hypercholesterolemia . It can also lead to pancreatitis in excessive concentrations In medicine,...

, in patients with rare forms of lipodystrophy
Lipodystrophy
Lipodystrophy is a medical condition characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy is used when describing the loss of fat from one area...

, syndromes characterized by abnormalities in adipose tissue distribution, and severe metabolic abnormalities. Amylin Pharmaceuticals
Amylin Pharmaceuticals
Amylin Pharmaceuticals is a biopharmaceutical company based in San Diego, CA, that was founded in 1987. The company is engaged in the discovery, development and commercialization of drug candidates for the treatment of diabetes, obesity and other diseases. Currently, Amylin produces two drugs,...

, the drug's developer, has received orphan drug designation for metreleptin from the U.S. Food and Drug Administration (FDA) for this indication, and plans to complete submission of metreleptin to the FDA by the end of 2011. In a three-year-long study of metreleptin in patients with lipodystrophy organized by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH), metreleptin treatment was associated with a significant decrease in blood glucose (A1c decrease from 9.4% at baseline to 7.0% at study end) and triglyceride concentration (from 500 mg/dL at baseline to 200 mg/dL at study end).

Metreleptin is also under clinical investigation in combination with pramlintide, an analog of the hormone amylin, for the treatment of obesity. Co-administration of amylin
Amylin
Amylin, or Islet Amyloid Polypeptide , is a 37-residue peptide hormone secreted by pancreatic β-cells at the same time as insulin .-Clinical significance:...

 (produced by beta cells in the pancreas) and leptin (produced by fat cells), results in sustained, fat-specific weight loss in a leptin-resistant animal model of obesity.

The Juvenile Diabetes Research Foundation
Juvenile Diabetes Research Foundation
JDRF is the leading global organization focused on type 1 diabetes research. Driven by volunteers connected to children, adolescents, and adults with this disease, JDRF is the largest charitable supporter of T1D research...

 (JDRF) has also partnered with Amylin Pharmaceuticals
Amylin Pharmaceuticals
Amylin Pharmaceuticals is a biopharmaceutical company based in San Diego, CA, that was founded in 1987. The company is engaged in the discovery, development and commercialization of drug candidates for the treatment of diabetes, obesity and other diseases. Currently, Amylin produces two drugs,...

 and researchers at the The University of Texas (UT) Southwestern Medical Center to study whether metreleptin can be used to improve the treatment of type 1 diabetes.

External links