Leptin

Leptin (from Greek λεπτός leptos, "thin"), the "satiety hormone," is a is_associated_with::hormone made by is_associated_with::adipose cells that helps to regulate energy balance by inhibiting hunger. Leptin is opposed by the actions of the hormone is_associated_with::ghrelin, the "hunger hormone". Both hormones act on receptors in the is_associated_with::arcuate nucleus of the is_associated_with::hypothalamus to regulate appetite to achieve is_associated_with::energy homeostasis. In obesity, a decreased sensitivity to leptin occurs, resulting in an inability to detect satiety despite high energy stores.

Although regulation of fat stores is deemed to be the primary function of leptin, it also plays a role in other physiological processes, as evidenced by its multiple sites of synthesis other than fat cells, and the multiple cell types beside hypothalamic cells that have leptin receptors. Many of these additional functions are yet to be defined.

Identification of the gene
In 1950, a non-obese mouse colony being studied at the is_associated_with::Jackson Laboratory produced a strain of obese offspring, suggesting that a mutation has occurred in a hormone regulating hunger and energy expenditure. Mice homozygous for the so-called ob mutation (ob/ob) ate voraciously and were massively obese. In the 1960s, a second mutation causing obesity and a similar phenotype was identified by Douglas Coleman, also at the Jackson Laboratory, and was named diabetes (db), as both ob/ob and db/db were obese. In 1990 is_associated_with::Rudolph Leibel and is_associated_with::Jeffrey M. Friedman reported mapping of the ob gene. Consistent with Coleman’s and Leibel's hypothesis, several subsequent studies from Leibel's and Friedman’s labs and other groups confirmed that the ob gene encoded a novel hormone that circulated in blood and that could suppress food intake and body weight in ob and wild type mice, but not in db mice. In 1994, Friedman's laboratory reported the identification of the gene. In 1995, is_associated_with::Jose F. Caro's laboratory provided evidence that the mutations in the mouse ob gene did not occur in humans. Furthermore since ob gene expression was increased, not decreased, in human obesity, it suggested resistance to leptin to be a possibility. At the suggestion of is_associated_with::Roger Guillemin, Friedman named this new hormone "leptin" from the Greek lepto meaning thin. Leptin was the first fat cell-derived hormone (is_associated_with::adipokine) to be discovered. Subsequent studies in 1995 confirmed that the db gene encodes the leptin receptor, and that it is expressed in the is_associated_with::hypothalamus, a region of the brain known to regulate the sensation of hunger and body weight.

Recognition of scientific advances
Coleman and Friedman have been awarded numerous prizes acknowledging their roles in discovery of leptin, including the is_associated_with::Gairdner Foundation International Award (2005), the is_associated_with::Shaw Prize (2009), the is_associated_with::Lasker Award, the is_associated_with::BBVA Foundation Frontiers of Knowledge Award and the is_associated_with::King Faisal International Prize, Leibel has not received the same level of recognition from the discovery because he was omitted as a co-author of a scientific paper published by Friedman that reported the discovery of the gene. The various theories surrounding Friedman’s omission of Leibel and others as co-authors of this paper have been presented in a number of publications, including is_associated_with::Ellen Ruppel Shell’s 2002 book is_associated_with::The Hungry Gene.

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

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

Mutations
A human mutant leptin was first described in 1997, and subsequently six additional mutations were described. All of those affected were from Eastern countries; and all had variants of leptin not detected by the standard immunoreactive technique, so leptin levels were low or undetectable. The most recently described eighth mutation reported in January 2015, in a child with Turkish parents, is unique in that it is detected by the standard immunoreactive technique, so leptin levels are elevated; but the leptin does not turn on the leptin receptor, so the patient has functional leptin deficiency. These eight mutations all cause extreme obesity in infancy, with is_associated_with::hyperphagia.

Nonsense
A is_associated_with::nonsense mutation in the leptin gene that results in a is_associated_with::stop codon and lack of leptin production was first observed in mice in 1950. In the mouse gene, arginine-105 is encoded by CGA and only requires one nucleotide change to create the stop codon TGA. The corresponding amino acid in humans is encoded by the sequence CGG and would require two nucleotides to be changed to produce a stop codon, which is much less likely to happen.

Frameshift
A recessive is_associated_with::frameshift mutation resulting in a reduction of leptin has been observed in two is_associated_with::consanguineous children with juvenile obesity.

Polymorphisms
A Human Genome Equivalent (HuGE) review in 2004 looked at studies of the connection between genetic mutations affecting leptin regulation and obesity. They reviewed a common polymorphism in the leptin gene (A19G; frequency 0.46), three mutations in the is_associated_with::leptin receptor gene (Q223R, K109R and K656N) and two mutations in the is_associated_with::PPARG gene (P12A and C161T). They found no association between any of the polymorphisms and obesity.

A 2006 study found a link between the common LEP-4548 G/A phenotype and morbid obesity in is_associated_with::Taiwanese aborigines, but a 2014 meta-analysis did not, however, this polymorphism has been associated with weight gain in patients taking antipsychotics.

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

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

Transversion
A single case of a homozygous is_associated_with::transversion mutation of the gene encoding for leptin was reported in January 2015. It leads to functional leptin deficiency with high leptin levels in circulation. The transversion of (c.298G → T) changed is_associated_with::aspartic acid to is_associated_with::tyrosine at position 100 (p.D100Y). The mutant leptin could neither bind to nor activate the leptin receptor in vitro, nor in leptin-deficient mice in vivo. It was found in a two-year-old boy with extreme obesity with recurrent ear and pulmonary infections. Treatment with metreleptin led to "rapid change in eating behavior, a reduction in daily energy intake, and substantial weight loss".

Sites of synthesis
Leptin is produced primarily in the adipocytes of is_associated_with::white adipose tissue. It also is produced by is_associated_with::brown adipose tissue, is_associated_with::placenta (syncytiotrophoblasts), is_associated_with::ovaries, is_associated_with::skeletal muscle, is_associated_with::stomach (the lower part of the is_associated_with::fundic glands), mammary is_associated_with::epithelial cells, is_associated_with::bone marrow, is_associated_with::gastric chief cells and is_associated_with::P/D1 cells.

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

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

In specific conditions
In humans, many instances are seen where leptin dissociates from the strict role of communicating nutritional status between body and brain and no longer correlates with body fat levels:
 * Leptin level is decreased after short-term is_associated_with::fasting (24–72 hours), even when changes in fat mass are not observed.
 * Leptin plays a critical role in the adaptive response to starvation.
 * In obese patients with is_associated_with::obstructive sleep apnea, leptin level is increased, but decreased after the administration of is_associated_with::continuous positive airway pressure. In non-obese individuals, however, restful sleep (i.e., 8–12 hours of unbroken sleep) can increase leptin to normal levels.
 * Serum level of leptin is reduced by is_associated_with::sleep deprivation.
 * Leptin level is increased by perceived is_associated_with::emotional stress.
 * Leptin level is decreased by increases in testosterone levels and increased by increases in estrogen levels.
 * Leptin level is chronically reduced by is_associated_with::physical exercise is_associated_with::training.
 * Leptin release is increased by is_associated_with::dexamethasone.
 * Leptin level is increased by is_associated_with::insulin.
 * Leptin levels are paradoxically increased in is_associated_with::obesity.

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

Central (hypothalamic)
It is important to recognize that the terms central, primary, and direct are not used interchangeably: Central vs peripheral refers to hypothalamic vs non-hypothalamic location of action of leptin; direct vs indirect refers to whether there is no intermediary, or there is an intermediary in the mode of action of leptin; and primary vs secondary is an arbitrary description of a particular function of leptin.

Leptin acts on receptors in the lateral hypothalamus to inhibit hunger and the medial hypothalamus to stimulate satiety. Thus, a lesion in the lateral hypothalamus causes anorexia (due to a lack of hunger signals) and a lesion in the medial hypothalamus causes excessive hunger (due to a lack of satiety signals). This appetite inhibition is long-term, in contrast to the rapid inhibition of hunger by is_associated_with::cholecystokinin (CCK) and the slower suppression of hunger between meals mediated by is_associated_with::PYY3-36. The absence of leptin (or its receptor) leads to uncontrolled hunger and resulting obesity. Fasting or following a very-low-calorie diet lowers leptin levels. Leptin levels change more when food intake decreases than when it increases. The dynamics of leptin due to an acute change in energy balance may be related to appetite and eventually, to food intake rather than fat stores.
 * In the lateral hypothalamus, leptin inhibits hunger by
 * counteracting the effects of is_associated_with::neuropeptide Y, a potent hunger promoter secreted by cells in the gut and in the hypothalamus
 * counteracting the effects of is_associated_with::anandamide, another potent hunger promoter that binds to the same receptors as is_associated_with::THC
 * In the medial hypothalamus, leptin stimulates satiety by
 * promoting the synthesis of is_associated_with::α-MSH, a hunger suppressant


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

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

Leptin receptor activation inhibits is_associated_with::neuropeptide Y (NPY) and is_associated_with::agouti-related peptide (AgRP), and activates is_associated_with::α-melanocyte-stimulating hormone (α-MSH). The NPY neurons are a key element in the regulation of hunger; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic. Conversely, α-MSH is an important mediator of satiety, and differences in the gene for the α-MSH receptor are linked to obesity in humans.

Leptin interacts with six types of receptors (Ob-Ra–Ob-Rf, or LepRa-LepRf), which in turn are encoded by a single gene, LEPR. Ob-Rb is the only receptor isoform that can signal is_associated_with::intracellularly via the Jak-Stat and is_associated_with::MAPK is_associated_with::signal transduction pathways, and is present in hypothalamic nuclei.

Generally, leptin is thought to enter the brain at the is_associated_with::choroid plexus, where the intense expression of a form of leptin receptor molecule 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 effect changes in gene expression, one of the main effects being the down-regulation of the expression of is_associated_with::endocannabinoids, responsible for increasing hunger. In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them.

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

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

Peripheral (non-hypothalamic)
Non-hypothalamic targets of leptin are referred to as peripheral targets, in contrast to the hypothalamic target which is the central target. Leptin receptors are found on a wide range of cell types. There is a different relative importance of central and peripheral leptin interactions under different physiologic states, and variations between species. In the periphery leptin is a modulator of energy expenditure, modulator between fetal and maternal metabolism, permissive factor in puberty, activator of immune cells, activator of beta islet cells, and a growth factor. Further, it interacts with other hormones and energy regulators: insulin, glucagon, insulin-like growth factor, growth hormone, glucocorticoids, cytokines, and metabolites.

Circulatory system
The role of leptin/leptin receptors in modulation of is_associated_with::T cell activity in the immune system was shown in experimentation with mice. It modulates the immune response to atherosclerosis, of which obesity is a predisposing factor.

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

Hyperleptinemia produced by infusion or adenoviral gene transfer decreases blood pressure in rats.

Leptin microinjections into the nucleus of the solitary tract (NTS) have been shown to elicit sympathoexcitatory responses, and potentiate the cardiovascular responses to activation of the chemoreflex.

Fetal lung
In is_associated_with::fetal lung, leptin is induced in the alveolar interstitial fibroblasts ("lipofibroblasts") by the action of is_associated_with::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.

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

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

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

Puberty
Leptin along with is_associated_with::kisspeptin controls the onset of puberty. High levels of leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche. This may eventually lead to shorter is_associated_with::stature as is_associated_with::oestrogen secretion starts during menarche and causes early closure of is_associated_with::epiphyses.

Bone
Leptin's ability to regulate bone mass was first recognized in 2000. Leptin can affect is_associated_with::bone metabolism via direct signalling from the brain. Leptin decreases is_associated_with::cancellous bone, but increases is_associated_with::cortical bone. This "cortical-cancellous dichotomy" may represent a mechanism for enlarging bone size, and thus bone resistance, to cope with increased body weight.

Bone metabolism can be regulated by central sympathetic outflow, since sympathetic pathways innervate bone tissue. A number of brain-signalling molecules (is_associated_with::neuropeptides and is_associated_with::neurotransmitters) have been found in bone, including is_associated_with::adrenaline, is_associated_with::noradrenaline, is_associated_with::serotonin, is_associated_with::calcitonin gene-related peptide, is_associated_with::vasoactive intestinal peptide and is_associated_with::neuropeptide Y. Leptin binds to its receptors in the hypothalamus, where it acts through the is_associated_with::sympathetic nervous system to regulate bone metabolism. Leptin may also act directly on bone metabolism via a balance between energy intake and the IGF-I pathway. There is a potential for treatment of diseases of bone formation - such as impaired fracture healing - with leptin.

Brain
Leptin receptors are expressed not only in the hypothalamus but also in other brain regions, particularly in the hippocampus. Thus some leptin receptors in the brain are classified as central (hypothalamic) and some as peripheral (non-hypothalamic).
 * Deficiency of leptin has been shown to alter brain proteins and neuronal functions of obese mice which can be restored by leptin injection.
 * In humans, low circulating plasma leptin has been associated with cognitive changes associated with anorexia, depression, and HIV.
 * Studies in transgenic mouse models of Alzheimer's disease have shown that chronic administration of leptin can ameliorate brain pathology and improve cognitive performance, by reducing b-amyloid and hyperphosphorylated Tau, two hallmarks of Alzheimer's pathology.

Immune system
Factors that acutely affect leptin levels are also factors that influence other markers of inflammation, e.g., testosterone, sleep, emotional stress, caloric restriction, and body fat levels. While it is well-established that leptin is involved in the regulation of the inflammatory response,  it has been further theorized that leptin's role as an inflammatory marker is to respond specifically to adipose-derived inflammatory is_associated_with::cytokines.

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

Similar to what is observed in chronic inflammation, chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including is_associated_with::hypertension, is_associated_with::metabolic syndrome, and is_associated_with::cardiovascular disease. While leptin is associated with body fat mass, however, the size of individual fat cells, and the act of overeating, it is interesting that it is not affected by exercise (for comparison, IL-6 is released in response to muscular contractions). Thus, it is speculated that leptin responds specifically to adipose-derived inflammation. Leptin is a pro-angiogenic, pro-inflammatory and mitogenic factor, the actions of which are reinforced through crosstalk with IL-1 family cytokines in cancer.

Taken as such, increases in leptin levels (in response to caloric intake) function as an acute pro-inflammatory response mechanism to prevent excessive cellular stress induced by overeating. When high caloric intake overtaxes the ability of fat cells to grow larger or increase in number in step with caloric intake, the ensuing stress response leads to inflammation at the cellular level and ectopic fat storage, i.e., the unhealthy storage of body fat within internal organs, arteries, and/or muscle. The insulin increase in response to the caloric load provokes a dose-dependent rise in leptin, an effect potentiated by high cortisol levels. (This insulin-leptin relationship is notably similar to insulin's effect on the increase of IL-6 gene expression and secretion from preadipocytes in a time- and dose-dependent manner.) Furthermore, plasma leptin concentrations have been observed to gradually increase when is_associated_with::acipimox is administered to prevent is_associated_with::lipolysis, concurrent hypocaloric dieting and weight loss notwithstanding. Such findings appear to demonstrate high caloric loads in excess of storage rate capacities of fat cells lead to stress responses that induce an increase in leptin, which then operates as an adipose-derived inflammation stopgap signaling for the cessation of food intake so as to prevent adipose-derived inflammation from reaching elevated levels. This response may then protect against the harmful process of ectopic fat storage, which perhaps explains the connection between chronically elevated leptin levels and ectopic fat storage in obese individuals.

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

Studies on leptin is_associated_with::cerebrospinal fluid (CSF) levels provide evidence for the reduction in leptin crossing the BBB and reaching obesity-relevant targets, such as the hypothalamus, in obese people In humans it has been observed that the ratio of leptin in the CSF compared to the blood is lower in obese people than in people of a normal weight. The reason for this may be high levels of is_associated_with::triglycerides affecting the transport of leptin across the BBB or due to the leptin transporter becoming saturated. Although deficits in the transfer of leptin from the plasma to the CSF is seen in obese people, they are still found to have 30% more leptin in their CSF than lean individuals. These higher CSF levels fail to prevent their obesity. Since the amount and quality of leptin receptors in the hypothalamus appears to be normal in the majority of obese humans (as judged from leptin-mRNA studies), it is likely that the leptin resistance in these individuals is due to a post leptin-receptor deficit, similar to the post-insulin receptor defect seen in type 2 diabetes.

When leptin binds with the leptin receptor, it activates a number of pathways. Leptin resistance may be caused by defects in one or more part of this process, particularly the JAK/STAT pathway. Mice with a mutation in the leptin receptor gene that prevents the activation of is_associated_with::STAT3 are obese and exhibit hyperphagia. The PI3K pathway may also be involved in leptin resistance, as has been demonstrated in mice by artificial blocking of PI3K signalling. The PI3K pathway also is activated by the insulin receptor and is therefore an important area where leptin and insulin act together as part of energy homeostasis. The insulin-pI3K pathway can cause is_associated_with::POMC neurons to become insensitive to leptin through hyperpolarization. The consumption of a high is_associated_with::fructose diet from birth has been associated with a reduction in leptin levels and reduced expression of leptin receptor mRNA in rats. Long-term consumption of fructose in rats has been shown to increase levels of triglycerides and trigger leptin and insulin resistance, however, another study found that leptin resistance only developed in the presence of both high fructose and high fat levels in the diet. A third study found that high fructose levels reversed leptin resistance in rats given a high fat diet. The contradictory results mean that it is uncertain whether leptin resistance is caused by high levels of carbohydrates or fats, or if an increase of both, is needed.

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

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

Response to weight loss
Dieters who lose weight, particularly those with an overabundance of fat cells, experience a drop in levels of circulating leptin. This drop causes reversible decreases in thyroid activity, sympathetic tone, and energy expenditure in skeletal muscle, and increases in muscle efficiency and parasympathetic tone. The result is that a person who has lost weight below their natural body fat set-point has a lower basal metabolic rate than an individual at the same weight who is of that natural weight; these changes are leptin-mediated, homeostatic responses meant to reduce energy expenditure and promote weight regain as a result of fat cells being shrunken below normal size. Many of these changes are reversed by peripheral administration of recombinant leptin to restore pre-diet levels.

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

Leptin
Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalised is_associated_with::lipodystrophy.

Analog metreleptin
An analog of human leptin is_associated_with::metreleptin (trade name Myalept) was first approved in Japan in 2013, and in the United States (U.S.) in February 2014. In the U.S. it is indicated as a treatment for complications of leptin deficiency, and for the diabetes and is_associated_with::hypertriglyceridemia associated with congenital or acquired generalized is_associated_with::lipodystrophy.