PDB rendering based on 1ax8.
Symbols LEP; FLJ94114; OB; OBS
External IDs OMIM164160 MGI104663 HomoloGene193 GeneCards: LEP Gene
RNA expression pattern
PBB GE LEP 207092 at tn.png
More reference expression data
Species Human Mouse
Entrez 3952 16846
Ensembl ENSG00000174697 ENSMUSG00000059201
UniProt P41159 P41160
RefSeq (mRNA) NM_000230.2 NM_008493.3
RefSeq (protein) NP_000221.1 NP_032519.1
Location (UCSC) Chr 7:
127.88 – 127.9 Mb
Chr 6:
29.01 – 29.02 Mb
PubMed search [1] [2]
PDB 1ax8 EBI.jpg
Structure of the obese protein leptin-E100.[1]
Symbol Leptin
Pfam PF02024
Pfam clan CL0053
InterPro IPR000065
SCOP 1ax8

Leptin (Greek leptos meaning thin) is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones.[2] The Ob(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans.[3]



The effects of leptin were observed by studying mutant obese mice that arose at random within a mouse colony at the Jackson Laboratory in 1950.[4] 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 and colleagues at the Rockefeller University through the study of such mice.[5]


Human leptin is a protein of 167 amino acids. It is manufactured primarily in the adipocytes of white 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, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (lower part of fundic glands), mammary epithelial cells, bone marrow, pituitary and liver.[6]

Leptin has also been discovered to be synthesised from gastric chief cells and P/D1 cells in the stomach.[7]


Leptin acts on receptors in the hypothalamus of the brain where it inhibits appetite by (1) counteracting the effects of neuropeptide Y (a potent feeding stimulant secreted by cells in the gut and in the hypothalamus); (2) counteracting the effects of anandamide (another potent feeding stimulant that binds to the same receptors as THC), 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 (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 or following a very-low-calorie diet (VLCD) lowers leptin levels.[8] 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.[9] 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.[10][11]

There is some controversy regarding the regulation of leptin by melatonin during the night. One research group suggested that increased levels of melatonin caused a downregulation of leptin.[12] However, in 2004, Brazilian researchers found that melatonin increases leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping.[13]

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.[14]

Adiposity signal

To date, only leptin and insulin are known to act as an adiposity signal. In general,

  • Leptin circulates at levels proportional to body fat.
  • It enters the central nervous system (CNS) in proportion to its plasma 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[15]

Interaction with amylin

Co-administration of two neurohormones known to have a role in body weight control, amylin (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.[16]


Leptin binds to neuropeptide Y (NPY) neurons in the arcuate nucleus, 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.[17] 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.[18][19][20] Circulating leptin levels give the brain input regarding energy storage so it can regulate appetite and metabolism. Leptin works by inhibiting the activity of neurons that contain neuropeptide Y (NPY) and agouti-related peptide (AgRP), and by increasing the activity of neurons expressing α-melanocyte-stimulating hormone (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. On the converse, α-MSH is an important mediator of satiety, and differences in the gene for the receptor at which α-MSH acts in the brain are linked to obesity in humans.

Circulatory system

The role of leptin/leptin receptors in modulation of T cell 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.[21]

Leptin promotes angiogenesis by increasing vascular endothelial growth factor (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.[22][23]

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.[24]


In mice, leptin is also required for male and female fertility. 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.[25]

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.[26] 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.[27]

There is also evidence that leptin plays a role in hyperemesis gravidarum (severe morning sickness of pregnancy),[28] in polycystic ovary syndrome[29] and a 2007 research suggests that hypothalamic leptin is implicated in bone growth.[30]

Effects on bone

The fact that leptin, a hormone released from fat tissue, can regulate bone mass first came to prominence in 2000.[31] 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. 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.[32]

Bone metabolism is under direct control of the brain and thus nerve fibres are present in bone tissue.[33] 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.[33][34] 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 and bind to its receptors in the brain where it acts through the sympathetic nervous system to regulate bone metabolism.[35] 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.[36] 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.[37]
  • In the obese patients with obstructive sleep apnea (OSA), Leptin is increased, but decreases after administration of a CPAP.[38][39] 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.[40][41]
  • Increased by perceived emotional stress.[42]
  • Decreased by testosterone and increased by estrogen.[43]
  • Chronically affected by exercise training; it decreases leptin levels.[44]

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 response,[45][46][47] 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.[1][46][48] Circulating leptin seems to effect the HPA axis, suggesting a role for leptin in stress response.[49] Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.[50]

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. 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.[51] 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. [52]

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 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.[53] (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.)[54] Furthermore, plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis, concurrent hypocaloric dieting and weight loss notwithstanding.[55] 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.[56] 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 to the effects of insulin. 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 lectins[57] and fructose.[58]

A signal-to-noise ratio theory has been proposed to explain the phenomenon of leptin resistance.[36] In healthy individuals, baseline leptin levels are between 1-5 ng/dl in men and 7-13 ng/dl in women.[36] 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 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,[59][60] and that leptin resistance in overweight individuals is the standard feature of mammalian physiology, which possibly confers a survival advantage.[61]

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,[62] and it is reversed when these animals are put back on low energy-density chow.[63] 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." [64] 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 causes leptin resistance and elevated triglycerides 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.[65][66][67] 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.[68] Ob-Rb is the only receptor isoform that can signal intracellularly via the Jak-Stat and MAPK signal transduction pathways,[69] and is present in hypothalamic nuclei.[70]

It is unknown as to whether leptin can cross the blood-brain barrier to access receptor neurons, because the blood-brain barrier is attenuated in the area of the median eminence, close to where the NPY neurons of the arcuate nucleus are. It is generally thought that leptin might enter the brain at the choroid plexus, 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[citation needed]. 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.[6]


An analog of human leptin, metreleptin is under investigation for the treatment of diabetes and/or hypertriglyceridemia, in patients with rare forms of lipodystrophy, syndromes characterized by abnormalities in adipose tissue distribution, and severe metabolic abnormalities. Amylin Pharmaceuticals, 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).[71]

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 (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.[16]

The Juvenile Diabetes Research Foundation (JDRF) has also partnered with Amylin Pharmaceuticals 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.[72]

See also

  • Teleost leptins


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