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Leptin
Structure of the obese protein leptin-E100.
Identifiers
Symbol	Leptin
Pfam	PF02024
Pfam clan	CL0053
InterPro	IPR000065
SCOP2	1ax8 / SCOPe / SUPFAM
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary PDB 1ax8​

Leptin (from Greek λεπτός leptos, "thin") is a hormone made by fat cells which regulates total body fat by regulating both the sensation of hunger in the brain (central effect), and thermogenesis in cells throughout the body (Hwa 1996)(peripheral effect). When the total fat stores reach a certain level, leptin is secreted by fat cells, and circulating leptin triggers receptors on hypothalamic nerve cells which leads to decreased hunger (satiety) and thus decreased food-seeking behavior as well as increased energy expenditure in peripheral cells. Although regulation of fat stores is deemed to be the primary function of leptin, it also plays a role in many other physiological processes, as evidenced by its multiple sites of synthesis other than fat cells, and the multiple cell types other than hypothalamic cells which have leptin receptors. Many of these ancillary funtions are yet to be defined.

Discovery of the gene

The existence of a hormone regulating hunger and energy expenditure was hypothesized based on studies of mutant obese mice that arose at random within a mouse colony at the Jackson Laboratory in 1950. Mice homozygous for the 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. Rudolph Leibel and Jeffrey M. Friedman reported the mapping of the ob gene in 1990. 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, with the ob gene isolated, Friedman reported the discovery of the gene. At the suggestion of Roger Guillemin, Friedman named this new hormone leptin from the Greek lepto meaning thin. Leptin was the first fat cell-derived hormone to be discovered. Subsequent studies confirmed that the db gene encodes the leptin receptor and that it is expressed in the hypothalamus, a region of the brain known to regulate the sensation of hunger and body weight.

Recognition of scientific advances

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

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

Structure of hormone and location of gene

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

Sites of synthesis

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

Variations in blood levels

Leptin circulates in blood in free form and bound to proteins. Serum leptin levels are higher between midnight and early morning which could have an effect in suppressing appetite during the night while sleeping. The diurnal rhythm of plasma leptin can be modified by meal-timing indicating that plasma leptin is entrained to meal timing.

Mechanisms of action

Central (Hypothalamic) effects

Leptin acts on receptors in the hypothalamus, where it inhibits hunger by

1. counteracting the effects of neuropeptide Y, a potent hunger promoter secreted by cells in the gut and in the hypothalamus.
2. counteracting the effects of anandamide, another potent huger promoter that binds to the same receptors as THC.
3. promoting the synthesis of α-MSH, a hunger suppressant.

This appetite inhibition is long-term, in contrast to the rapid inhibition of hunger by cholecystokinin (CCK) and the slower suppression of hunger between meals mediated by PYY3-36. The absence of leptin (or its receptor) leads to uncontrolled hunger and resulting obesity. Fasting or following a very-low-calorie diet lowers leptin levels. Lleptin levels change more when food intake decreases than when it increases. The dynamics of leptin due to an acute change in energy balance may be related to appetite and eventually to food intake rather than fat stores.

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

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

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

Receptors and intracellular signaling

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 intracellularly via the Jak-Stat and MAPK signal transduction pathways, and is present in hypothalamic nuclei.

Leptin is generally thought to enter the brain at the choroid plexus, where the intense expression of a form of leptin receptor molecule could act as a transport mechanism.

Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to effect changes in gene expression, One of the main effects being the down-regulation of the expression of endocannabinoids, responsible for increasing hunger. In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them.

Regulation by melatonin

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

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

Peripheral effects

Peripheral effects may be mediated centrally or peripherally.

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, 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 T cell activity in 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 angiogenesis by increasing vascular endothelial growth factor levels.

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

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

Fetal lung

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

Reproductive system

Ovulatory cycle

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

Pregnancy

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

Lactation

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

Puberty

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

Bone

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

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

Brain

Leptin receptors are expressed not only in the hypothalamus but also in other brain regions, particularly in the hippocampus.

• 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. At the cellular level, the mechanism of leptin action involves 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 cytokines.

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

Similar to what is observed in chronic inflammation, chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including hypertension, metabolic syndrome, and cardiovascular disease. 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 or increase in number in step with caloric intake, the ensuing stress response leads to inflammation at the cellular level and ectopic fat storage, i.e., the unhealthy storage of body fat within internal organs, arteries, and/or muscle. The insulin increase in response to the caloric load provokes a dose-dependent rise in leptin, an effect potentiated by high cortisol levels. (This insulin-leptin relationship is notably similar to insulin's effect on the increase of IL-6 gene expression and secretion from preadipocytes in a time- and dose-dependent manner.) Furthermore, plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis, concurrent hypocaloric dieting and weight loss notwithstanding. Such findings appear to demonstrate high caloric loads in excess of 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.

Levels 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 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 obstructive sleep apnea, leptin level is increased, but decreased after the administration of continuous positive airway pressure. In non-obese individuals, however, restful sleep (i.e., 8–12 hours of unbroken sleep) can increase leptin to normal levels.
• Serum level of leptin is reduced by sleep deprivation. However, a recent study showed that sleep deprivation was linked with higher levels of leptin.
• Leptin level is increased by perceived emotional stress.
• Leptin level is decreased or increased by increases in testosterone or estrogen level, respectively.
• Leptin level is chronically reduced by physical exercise training.
• Leptin level is increased by dexamethasone.
• Leptin level is increased by insulin.
• Leptin levels are paradoxically increased in obesity.

Genetic mutations

A nonsense mutation in the leptin gene that results in a stop codon and lack of leptin production was first observed in mice in 1950. No homologous mutation has been found in humans. 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 in order to produce a stop codon, which is much less likely to happen.

Lepin over-expression in adipose tissue has been observed in a number of individuals with morbid obesity. However, the association between leptin mutations and obesity in humans is less clear than in mice. A Human Genome Equivalent (HuGE) review of previous studies looking at the connection between genetic mutations affecting leptin regulation and obesity was published in 2004. As well as looking at a common polymorphism in the leptin gene (A19G; frequency 0.46), they also reviewed 3 mutations in the leptin receptor gene (Q223R, K109R and K656N) and 2 mutations in the PPARG gene (P12A and C161T). They found no association between any of the polymorphisms and obesity.

A meta-analysis published in 2014 found no association between the common LEP-2548 G/A mutation and obesity in the overall results but did find a significant link between obesity and the GG phenotype in the American population. A previous study has found a similar link between the GG phenotype and morbid obesity in Taiwanese aborigines. The -2548A/G polymorphism has been associated with weight gain patients taking antipsychotics. This polymorphism has also been linked with an increased risk of prostate cancer, gestational diabetes and osteoporosis.

A recessive frameshift mutation resulting in a reduction of leptin has been observed in two consanguineous children with juvenile obesity. Other rare polymorphisms have been found but their association with obesity are not consistent. This may be due to the fact that obesity is a complex problem involving multiple genes as well as environmental influences.

Obesity

Leptin resistance

Although leptin reduces appetite as a circulating signal, 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 to the effects of insulin. The sustained high concentrations of leptin from the enlarged adipose stores implies 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.

The main target of leptin action is the leptin receptor that is located in the hypothalamus. In order for circulating leptin to reach its receptor in the hypothalamus, it must first cross the blood-brain barrier. Studies on leptin CSF levels in humans have provided untowardly evidence for leptin obesity-relevant targets being located in brain structures such as the hypothalamus, but the subject remains controversial. For example, in humans leptin in the CSF correlates with BMI but the ratio of CSF to serum leptin decreased with increasing BMI. Also the efficiency of leptin uptake(measured as the CSF:plasma leptin ratio) was lower in human subjects in the highest as compared with the lowest plasma leptin quintile (5.4-fold difference).

Although showing a sluggish leptin-transfer function from plasma to CSF, obese subjects with very high plasma leptin values (300% higher than normal) have 30% more leptin in the CSF than lean individuals, but such abnornally high leptin concentrations in CSF have not prevented their obesity. Since the amount and quality of leptin receptors in hypothalamus of obese humans appear normal (as judged from leptin-mRNA studies), it is inevitable to conclude that leptin resistance in obese individuals is likely to be due to a post leptin-receptor defect, similar to the case of type 2 diabetes, where insulin resistance is due to a post-insulin receptor defect.

Some researchers attempted to explain the failure of leptin to prevent obesity in humans as a metabolic disorder, possibly caused by a specific nutrient or a combination of nutrients not present or uncommon in the prehistoric diet. Some proposed "villain" nutrients include lectins and fructose.

A signal-to-noise ratio theory has been proposed to explain the phenomenon of leptin resistance. In healthy individuals with a normal BMI, serum leptin levels have been observed as being between 6.6 and 7.2ng/ml in men and 13.9 and 16.5ng/ml 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. In obese individuals, the leptin response to caloric intake is theorized to be 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 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 it may simply be an adaptation to excess body weight. The major physiological role of leptin is suggested to be 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 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.

Although the notion of obesity as a state of 'leptin resistance' has become ingrained in the minds of many researchers, some observations do not directly support this contention. For example, the work of Rudolph Leibel at Columbia University has shown that, in both obese and lean individuals, leptin injections do not reduce body mass. Despite the lack of response in obese and lean subjects, there is little argument that lean subjects are also leptin-resistant; hence, whether obese subjects are in fact resistant to leptin remains to be empirically demonstrated. This finding also underscores the notion that the brain is not designed to respond to increased leptin by decreasing food intake; rather, as discussed above, lack of leptin acts as a signal to increase food intake. Indeed, Leibel's work has shown that the decreases in serum leptin that occur post-weight-loss constitute a state of leptin deficiency, which drives increased appetite. As such, leptin injections in weight-reduced patients can prevent the increases in appetite and thereby allow patients to maintain weight loss. These studies therefore demonstrate that leptin treatment may be a useful strategy to treat obesity in humans, if not by driving weight loss directly then by allowing weight loss (as a result of diet and exercise) to be more readily maintained.

The consumption of high amounts of fructose is suggested to cause 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. 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 indices (soda, candy, and other foods with easily liberated sugar).

Leptin interacts with amylin: coadministration of two neurohormones known to have a role in body weight control, amylin (nutrient/glucose appearance inhibitor roduced by β cells in the pancreas) and leptin , results in sustained, fat-specific weight loss in a leptin-resistant animal model of obesity.

Weight loss

Dieters who lose weight 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 has a lower basal metabolic rate than an individual at the same weight who has never lost weight; these changes are leptin-mediated, homeostatic responses meant to reduce energy expenditure and promote weight regain. 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.

Therapeutic use

Leptin

Leptin has not been approved for any therapeutic use.

Analogs

An analog of human leptin, metreleptin, has been approved in Japan for metabolic disorders including lipodystrophy. In the United States it is approved as replacement therapy to treat the complications of leptin deficiency in patients with congenital zed or acquired generalized lipodystrophy. Metreleptin is currently being investigated for the treatment of diabetes and hypertriglyceridemia, in patients with rare forms of lipodystrophy, syndromes characterized by abnormalities in adipose tissue distribution, and severe metabolic abnormalities.

See also

• Ghrelin
• NAPEs
• Teleost leptins

References

1. ^ Zhang F, Basinski MB, Beals JM, Briggs SL, Churgay LM, Clawson DK, DiMarchi RD, Furman TC, Hale JE, Hsiung HM, Schoner BE, Smith DP, Zhang XY, Wery JP, Schevitz RW (May 1997). "Crystal structure of the obese protein leptin-E100". Nature. 387 (6629): 206–9. doi:10.1038/387206a0. PMID 9144295.{{cite journal}}: CS1 maint: multiple names: authors list (link)
2. Brennan AM, Mantzoros CS (2006). "Drug Insight: the role of leptin in human physiology and pathophysiology--emerging clinical applications". Nat Clin Pract Endocrinol Metab. 2 (6): 318–27. doi:10.1038/ncpendmet0196. PMID 16932309.
3. ^ Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM (July 1995). "Weight-reducing effects of the plasma protein encoded by the obese gene". Science. 269 (5223): 543–6. doi:10.1126/science.7624777. PMID 7624777.{{cite journal}}: CS1 maint: multiple names: authors list (link)
4. ^ Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P (July 1995). "Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks". Science. 269 (5223): 546–9. doi:10.1126/science.7624778. PMID 7624778.{{cite journal}}: CS1 maint: multiple names: authors list (link)
5. ^ Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F (July 1995). "Effects of the obese gene product on body weight regulation in ob/ob mice". Science. 269 (5223): 540–3. doi:10.1126/science.7624776. PMID 7624776.{{cite journal}}: CS1 maint: multiple names: authors list (link)
6. ^ Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S (November 1995). "Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects". Nat. Med. 1 (11): 1155–61. doi:10.1038/nm1195-1155. PMID 7584987.{{cite journal}}: CS1 maint: multiple names: authors list (link)
7. ^ Considine RV, Considine EL, Williams CJ, Nyce MR, Magosin SA, Bauer TL, Rosato EL, Colberg J, Caro JF (June 1995). "Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity". J. Clin. Invest. 95 (6): 2986–8. doi:10.1172/JCI118007. PMC 295988. PMID 7769141.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid7769141" was defined multiple times with different content (see the help page).
8. ^ Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF (February 1996). "Serum immunoreactive-leptin concentrations in normal-weight and obese humans". N. Engl. J. Med. 334 (5): 292–5. doi:10.1056/NEJM199602013340503. PMID 8532024.{{cite journal}}: CS1 maint: multiple names: authors list (link)
9. Dickie MM, Lane PW (1957). "Plus letter to Roy Robinson 7/7/70". Mouse News Lett. (17): 52.
10. Bahary N, Siegel DA, Walsh J, Zhang Y, Leopold L, Leibel R, Proenca R, Friedman JM (September 1993). "Microdissection of proximal mouse chromosome 6: identification of RFLPs tightly linked to the ob mutation". Mamm. Genome. 4 (9): 511–5. doi:10.1007/BF00364786. PMID 7906968.{{cite journal}}: CS1 maint: multiple names: authors list (link)
11. Friedman JM, Leibel RL, Siegel DS, Walsh J, Bahary N (December 1991). "Molecular mapping of the mouse ob mutation". Genomics. 11 (4): 1054–62. doi:10.1016/0888-7543(91)90032-A. PMID 1686014.{{cite journal}}: CS1 maint: multiple names: authors list (link)
12. ^ Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (December 1994). "Positional cloning of the mouse obese gene and its human homologue". Nature. 372 (6505): 425–32. doi:10.1038/372425a0. PMID 7984236.{{cite journal}}: CS1 maint: multiple names: authors list (link)
13. Leibel RL, Bahary N, Friedman JM, (January 1990). "Genetic variation and nutrition in obesity: approaches to the molecular genetics of obesity". World Rev Nutr Diet. 63 (1): 90–101. PMID 1973864.{{cite journal}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
14. Bahary N, Leibel RL, Joseph L, Friedman JM (November 1990). "Molecular mapping of the mouse db mutation". Proc Natl Acad Sci U S A. 87 (21): 8642–6. Bibcode:1990PNAS...87.8642B. doi:10.1073/pnas.87.21.8642. PMC 55013. PMID 1978328.{{cite journal}}: CS1 maint: multiple names: authors list (link)
15. Leibel RL, Bahary N, Friedman JM (January 1993). "Strategies for the molecular genetic analysis of obesity in humans". Crit Rev Food Sci Nutr. 33 (4–5): 351–58. doi:10.1080/10408399309527632. PMID 8357496.{{cite journal}}: CS1 maint: multiple names: authors list (link)
16. Neill US (1 October 2010). "Leaping for leptin: the 2010 Albert Lasker Basic Medical Research Award goes to Douglas Coleman and Jeffrey M. Friedman". Journal of Clinical Investigation. 120 (10): 3413–3418. doi:10.1172/JCI45094.
17. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI (December 1995). "Identification and expression cloning of a leptin receptor, OB-R". Cell. 83 (7): 1263–71. doi:10.1016/0092-8674(95)90151-5. PMID 8548812.{{cite journal}}: CS1 maint: multiple names: authors list (link)
18. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP (February 1996). "Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice". Cell. 84 (3): 491–5. doi:10.1016/S0092-8674(00)81294-5. PMID 8608603.{{cite journal}}: CS1 maint: multiple names: authors list (link)
19. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM (February 1996). "Abnormal splicing of the leptin receptor in diabetic mice". Nature. 379 (6566): 632–5. doi:10.1038/379632a0. PMID 8628397.{{cite journal}}: CS1 maint: multiple names: authors list (link)
20. Chua SC, Chung WK, Wu-Peng XS, Zhang Y, Liu SM, Tartaglia L, Leibel RL (February 1996). "Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor". Science. 271 (5251): 994–6. Bibcode:1996Sci...271..994C. doi:10.1126/science.271.5251.994. PMID 8584938.{{cite journal}}: CS1 maint: multiple names: authors list (link)
21. Bonner J (2005). "Jeffrey Friedman, discoverer of leptin, receives Gairdner, Passano awards". Newswire. The Rockefeller University.
22. News-Medical "Jeffrey Friedman receives Shaw Prize for discovery of leptin". News-Medical.net. 2009. {{cite web}}: Check |url= value (help)
23. "The Lasker Foundation – 2010 Awards". Lasker Foundation. 2010.
24. "BBVA Foundation Frontiers of Knowledge Awards". BBVA Foundation. 2012.
25. "KFF – KFIP – Winners 2013 – Medicine". King Faisal Foundation. 2013.
26. Shell E (January 1, 2002). "On the Cutting Edge". The Hungry Gene: The Inside Story of the Obesity Industry. Atlantic Monthly Press. ISBN 978-1-4223-5243-4.
27. Shell E (2002). "Hunger". The Hungry Gene: The Inside Story of the Obesity Industry. Atlantic Monthly Press. ISBN 978-1-4223-5243-4.
28. Pool R (2001). Fat: fighting the obesity epidemic. New York: Oxford University Press. ISBN 978-0-19-511853-7.
29. Kolata GB (2007). Rethinking thin: the new science of weight loss—and the myths and realities of dietin. New York: Farrar. ISBN 978-0-374-10398-9.
30. Castracane VD, Henson MC (2006). "The Obese (ob/ob) Mouse and the Discovery of Leptin". In Castracane VD, Henson MC (ed.). Leptin. Endocrine Updates. Vol. 25. pp. 1–9. doi:10.1007/978-0-387-31416-7_1. ISBN 978-0-387-31415-0. {{cite book}}: External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help)
31. GreGreen ED, Maffei M, Braden VV, Proenca R, DeSilva U, Zhang Y, Chua SC Jr, Leibel RL, Weissenbach J, Friedman JM (August 1995). "The human obese (OB) gene: RNA expression pattern and mapping on the physical, cytogenetic, and genetic maps of chromosome 7". Genome Res. 5 (1): 5–12. doi:10.1101/gr.5.1.5. PMID 8717050.{{cite journal}}: CS1 maint: multiple names: authors list (link)
32. ^ Margetic S, Gazzola C, Pegg GG, Hill RA (2002). "Leptin: a review of its peripheral actions and interactions". Int. J. Obes. Relat. Metab. Disord. 26 (11): 1407–1433. doi:10.1038/sj.ijo.0802142. PMID 12439643.{{cite journal}}: CS1 maint: multiple names: authors list (link)
33. Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, Moizo L, Lehy T, Guerre-Millo M, Le Marchand-Brustel Y, Lewin MJ (August 1998). "The stomach is a source of leptin". Nature. 394 (6695): 790–793. doi:10.1038/29547. PMID 9723619.{{cite journal}}: CS1 maint: multiple names: authors list (link)
34. Sinha MK, Opentanova I, Ohannesian JP, Kolaczynski JW, Heiman ML, Hale J, Becker GW, Bowsher RR, Stephens TW, Caro JF (September 1996). "Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting". J. Clin. Invest. 98 (6): 1277–82. doi:10.1172/JCI118913. PMC 507552. PMID 8823291.{{cite journal}}: CS1 maint: multiple names: authors list (link)
35. Sinha MK, Ohannesian JP, Heiman ML, Kriauciunas A, Stephens TW, Magosin S, Marco C, Caro JF (March 1996). "Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects". J. Clin. Invest. 97 (5): 1344–7. doi:10.1172/JCI118551. PMC 507189. PMID 8636448.{{cite journal}}: CS1 maint: multiple names: authors list (link)
36. Schoeller DA, Cella LK, Sinha MK, Caro JF (October 1997). "Entrainment of the diurnal rhythm of plasma leptin to meal timing". J. Clin. Invest. 100 (7): 1882–7. doi:10.1172/JCI119717. PMC 508375. PMID 9312190.{{cite journal}}: CS1 maint: multiple names: authors list (link)
37. Dubuc G, Phinney S, Stern J, Havel P (1998). "Changes of serum leptin and endocrine and metabolic parameters after 7 days of energy restriction in men and women". Metab. Clin. Exp. 47 (4): 429–34. doi:10.1016/S0026-0495(98)90055-5. PMID 9550541.{{cite journal}}: CS1 maint: multiple names: authors list (link)
38. Pratley R, Nicolson M, Bogardus C, Ravussin E (1997). "Plasma leptin responses to fasting in Pima Indians". Am. J. Physiol. 273 (3 Pt 1): E644–9. PMID 9316457.{{cite journal}}: CS1 maint: multiple names: authors list (link)
39. Weigle DS, Duell PB, Connor WE, Steiner RA, Soules MR, Kuijper JL (February 1997). "Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels". J. Clin. Endocrinol. Metab. 82 (2): 561–5. doi:10.1210/jc.82.2.561. PMID 9024254.{{cite journal}}: CS1 maint: multiple names: authors list (link)
40. Wadden TA, Considine RV, Foster GD, Anderson DA, Sarwer DB, Caro JS (January 1998). "Short- and long-term changes in serum leptin dieting obese women: effects of caloric restriction and weight loss". J. Clin. Endocrinol. Metab. 83 (1): 214–8. doi:10.1210/jc.83.1.214. PMID 9435444.{{cite journal}}: CS1 maint: multiple names: authors list (link)
41. Chin-Chance C, Polonsky K, Schoeller D (2000). "Twenty-four-hour leptin levels respond to cumulative short-term energy imbalance and predict subsequent intake". J. Clin. Endocrinol. Metab. 85 (8): 2685–2691. doi:10.1210/jc.85.8.2685. PMID 10946866.{{cite journal}}: CS1 maint: multiple names: authors list (link)
42. Keim N, Stern J, Havel P (1998). "Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women". Am. J. Clin. Nutr. 68 (4): 794–801. PMID 9771856.{{cite journal}}: CS1 maint: multiple names: authors list (link)
43. Mars M, de Graaf C, de Groot C, van Rossum C, Kok F (2006). "Fasting leptin and appetite responses induced by a 4-day 65%-energy-restricted diet". International journal of obesity (Lond). 30 (1): 122–128. doi:10.1038/sj.ijo.0803070. PMID 16158086.{{cite journal}}: CS1 maint: multiple names: authors list (link)
44. Williams KW, Scott MM, Elmquist JK (March 2009). "From observation to experimentation: leptin action in the mediobasal hypothalamus". Am. J. Clin. Nutr. 89 (3): 985S – 990S. doi:10.3945/ajcn.2008.26788D. PMC 2667659. PMID 19176744.{{cite journal}}: CS1 maint: multiple names: authors list (link)
45. Baicy K, London ED, Monterosso J, Wong ML, Delibasi T, Sharma A, Licinio J (November 2007). "Leptin replacement alters brain response to food cues in genetically leptin-deficient adults". Proc. Natl. Acad. Sci. U.S.A. 104 (46): 18276–9. doi:10.1073/pnas.0706481104. PMC 2084333. PMID 17986612. {{cite journal}}: Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help)CS1 maint: multiple names: authors list (link)
46. Wang MY, Zhou YT, Newgard CB, Unger RH (August 1996). "A novel leptin receptor isoform in rat". FEBS Lett. 392 (2): 87–90. doi:10.1016/0014-5793(96)00790-9. PMID 8772180.{{cite journal}}: CS1 maint: multiple names: authors list (link)
47. Malendowicz W, Rucinski M, Macchi C, Spinazzi R, Ziolkowska A, Nussdorfer GG, Kwias Z (October 2006). "Leptin and leptin receptors in the prostate and seminal vesicles of the adult rat". Int. J. Mol. Med. 18 (4): 615–8. doi:10.3892/ijmm.18.4.615. PMID 16964413.{{cite journal}}: CS1 maint: multiple names: authors list (link)
48. "LepRb antibody (commercial site)".
49. Lynn RB, Cao GY, Considine RV, Hyde TM, Caro JF (February 1996). "Autoradiographic localization of leptin binding in the choroid plexus of ob/ob and db/db mice". Biochem. Biophys. Res. Commun. 219 (3): 884–9. doi:10.1006/bbrc.1996.0328. PMID 8645274.{{cite journal}}: CS1 maint: multiple names: authors list (link)
50. Di Marzo V (2008). "The endocannabinoid system in obesity and type 2 diabetes". Diabetologia. 51 (8): 1356–67. doi:10.1007/s00125-008-1048-2. PMID 18563385.
51. Kus I, Sarsilmaz M, Colakoglu N, Kukne A, Ozen OA, Yilmaz B, Kelestimur H (2004). "Pinealectomy increases and exogenous melatonin decreases leptin production in rat anterior pituitary cells: an immunohistochemical study". Physiol Res. 53 (4): 403–8. PMID 15311999.{{cite journal}}: CS1 maint: multiple names: authors list (link)
52. Alonso-Vale MI, Andreotti S, Peres SB, Anhê GF, das Neves Borges-Silva C, Neto JC, Lima FB (April 2005). "Melatonin enhances leptin expression by rat adipocytes in the presence of insulin". Am. J. Physiol. Endocrinol. Metab. 288 (4): E805 – E812. doi:10.1152/ajpendo.00478.2004. PMID 15572654.{{cite journal}}: CS1 maint: multiple names: authors list (link)
53. Copinschi G (2005). "Metabolic and endocrine effects of sleep deprivation". Essential psychopharmacology. 6 (6): 341–7. PMID 16459757.
54. Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, Wenner BR, Bain JR, Charron MJ, Newgard CB, Unger RH (March 2010). "Leptin therapy in insulin-deficient type I diabetes". Proc. Natl. Acad. Sci. U.S.A. 107 (11): 4813–4819. doi:10.1073/pnas.0909422107. PMC 2841945. PMID 20194735. {{cite journal}}: Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help)CS1 maint: multiple names: authors list (link)
55. Taleb S, Herbin O, Ait-Oufella H, Verreth W, Gourdy P, Barateau V, Merval R, Esposito B, Clément K, Holvoet P, Tedgui A, Mallat Z. (2007). "Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis". Arterioscler Thromb Vasc Biol. 27 (12): 2691–2698. doi:10.1161/ATVBAHA.107.149567. PMID 17690315.{{cite journal}}: CS1 maint: multiple names: authors list (link)
56. Zhang W, Telemaque S, Augustyniak R, Anderson P, Thomas G, An J, Wang Z, Newgard C, Victor R. (2010). "Adenovirus-mediated leptin expression normalises hypertension associated with diet-induced obesity". J Neuroendocrinol. 22 (3): 175–180. doi:10.1111/j.1365-2826.2010.01953.x. PMID 20059648.{{cite journal}}: CS1 maint: multiple names: authors list (link)
57. Knight W, Seth R, Boron J, Overton J. (2009). "Short-term physiological hyperleptinemia decreases arterial blood pressure". Regul Pept. 154 (1–3): 60–68. doi:10.1016/j.regpep.2009.02.001. PMID 19323984.{{cite journal}}: CS1 maint: multiple names: authors list (link)
58. Ciriello J, Moreau JM (November 2012). "Systemic administration of leptin potentiates the response of neurons in the nucleus of the solitary tract to chemoreceptor activation in the rat". J. Neuroscience. 229: 88–99. doi:10.1016/j.neuroscience.2012.10.065. PMID 23159310.
59. Torday JS, Rehan VK (October 2006). "Up-regulation of fetal rat lung parathyroid hormone-related protein gene regulatory network down-regulates the Sonic Hedgehog/Wnt/beta-catenin gene regulatory network". Pediatr. Res. 60 (4): 382–8. doi:10.1203/01.pdr.0000238326.42590.03. PMID 16940239.
60. Anifandis G, Koutselini E, Louridas K, Liakopoulos V, Leivaditis K, Mantzavinos T, Sioutopoulou D, Vamvakopoulos N (April 2005). "Estradiol and leptin as conditional prognostic IVF markers". Reproduction. 129 (4): 531–534. doi:10.1530/rep.1.00567. PMID 15798029.{{cite journal}}: CS1 maint: multiple names: authors list (link)
61. Comninos AN, Jayasena CN, Dhillo WS (2014). "The relationship between gut and adipose hormones, and reproduction". Hum. Reprod. Update. 20 (2): 153–74. doi:10.1093/humupd/dmt033. PMID 24173881.{{cite journal}}: CS1 maint: multiple names: authors list (link)
62. Zhao J, Townsend KL, Schulz LC, Kunz TH, Li C, Widmaier EP (2004). "Leptin receptor expression increases in placenta, but not hypothalamus, during gestation in Mus musculus and Myotis lucifugus". Placenta. 25 (8–9): 712–722. doi:10.1016/j.placenta.2004.01.017. PMID 15450389.{{cite journal}}: CS1 maint: multiple names: authors list (link)
63. Moynihan AT, Hehir MP, Glavey SV, Smith TJ, Morrison JJ (2006). "Inhibitory effect of leptin on human uterine contractility in vitro". Am. J. Obstet. Gynecol. 195 (2): 504–509. doi:10.1016/j.ajog.2006.01.106. PMID 16647683.{{cite journal}}: CS1 maint: multiple names: authors list (link)
64. Aka N, Atalay S, Sayharman S, Kiliç D, Köse G, Küçüközkan T (2006). "Leptin and leptin receptor levels in pregnant women with hyperemesis gravidarum". The Australian & New Zealand journal of obstetrics & gynaecology. 46 (4): 274–277. doi:10.1111/j.1479-828X.2006.00590.x. PMID 16866785.{{cite journal}}: CS1 maint: multiple names: authors list (link)
65. Cervero A, Domínguez F, Horcajadas JA, Quiñonero A, Pellicer A, Simón C (2006). "The role of the leptin in reproduction". Current Opinion in Obstetrics and Gynecology. 18 (3): 297–303. doi:10.1097/01.gco.0000193004.35287.89. PMID 16735830.{{cite journal}}: CS1 maint: multiple names: authors list (link)
66. Iwaniec UT, Boghossian S, Lapke PD, Turner RT, Kalra SP (2007). "Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice". Peptides. 28 (5): 1012–1019. doi:10.1016/j.peptides.2007.02.001. PMC 1986832. PMID 17346852.{{cite journal}}: CS1 maint: multiple names: authors list (link)
67. Casabiell X, Piñeiro V, Tomé MA, Peinó R, Diéguez C, Casanueva FF (1997). "Presence of leptin in colostrum and/or breast milk from lactating mothers: a potential role in the regulation of neonatal food intake". J. Clin. Endocrinol. Metab. 82 (12): 4270–3. doi:10.1210/jcem.82.12.4590. PMID 9398752.{{cite journal}}: CS1 maint: multiple names: authors list (link)
68. Sanchez-Garrido MA, Tena-Sempere M (2013). "Metabolic control of puberty: roles of leptin and kisspeptins". Horm Behav. 64 (2): 187–94. doi:10.1016/j.yhbeh.2013.01.014. PMID 23998663.
69. Matkovic V, Ilich JZ, Skugor M, Badenhop NE, Goel P, Clairmont A, Klisovic D, Nahhas RW, Landoll JD (October 1997). "Leptin is inversely related to age at menarche in human females". J. Clin. Endocrinol. Metab. 82 (10): 3239–45. doi:10.1210/jc.82.10.3239. PMID 9329346.{{cite journal}}: CS1 maint: multiple names: authors list (link)
70. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G (January 2000). "Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass". Cell. 100 (2): 197–207. doi:10.1016/S0092-8674(00)81558-5. PMID 10660043.{{cite journal}}: CS1 maint: multiple names: authors list (link)
71. ^ Hamrick MW, Ferrari SL (July 2008). "Leptin and the sympathetic connection of fat to bone". Osteoporos Int. 19 (7): 905–912. doi:10.1007/s00198-007-0487-9. PMID 17924050.
72. ^ Allison SJ, Herzog H (2006). "NPY and bone". EXS (95): 171–82. PMID 16383006.
73. Gordeladze JO, Reseland JE (March 2003). "A unified model for the action of leptin on bone turnover". J. Cell. Biochem. 88 (4): 706–712. doi:10.1002/jcb.10385. PMID 12577304.
74. Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G (November 2002). "Leptin regulates bone formation via the sympathetic nervous system". Cell. 111 (3): 305–317. doi:10.1016/S0092-8674(02)01049-8. PMID 12419242.{{cite journal}}: CS1 maint: multiple names: authors list (link)
75. Martin A, David V, Malaval L, Lafage-Proust MH, Vico L, Thomas T (2007). "Opposite effects of leptin on bone metabolism: a dose-dependent balance related to energy intake and insulin-like growth factor-I pathway". Endocrinology. 148 (7): 3419–25. doi:10.1210/en.2006-1541. PMID 17431002.{{cite journal}}: CS1 maint: multiple names: authors list (link)
76. Farr SA, Banks WA, Morley JE (June 2006). "Effects of leptin on memory processing". Peptides. 27 (6): 1420–5. doi:10.1016/j.peptides.2005.10.006. PMID 16293343.{{cite journal}}: CS1 maint: multiple names: authors list (link)
77. Casanueva FF, Dieguez C, Popovic V, Peino R, Considine RV, Caro JF (April 1997). "Serum immunoreactive leptin concentrations in patients with anorexia nervosa before and after partial weight recovery". Biochem. Mol. Med. 60 (2): 116–20. doi:10.1006/bmme.1996.2564. PMID 9169091.{{cite journal}}: CS1 maint: multiple names: authors list (link)
78. Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, DeCarli C, Wolf PA, Seshadri S (December 2009). "Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging". JAMA. 302 (23): 2565–72. doi:10.1001/jama.2009.1836. PMC 2838501. PMID 20009056.{{cite journal}}: CS1 maint: multiple names: authors list (link)
79. Greco SJ, Bryan KJ, Sarkar S, Zhu X, Smith MA, Ashford JW, Johnston JM, Tezapsidis N, Casadesus G (2010). "Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer's disease". J. Alzheimers Dis. 19 (4): 1155–67. doi:10.3233/JAD-2010-1308. PMC 2862270. PMID 20308782.{{cite journal}}: CS1 maint: multiple names: authors list (link)
80. Doherty GH, Beccano-Kelly D, Yan SD, Gunn-Moore FJ, Harvey J (January 2013). "Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β". Neurobiol. Aging. 34 (1): 226–37. doi:10.1016/j.neurobiolaging.2012.08.003. PMID 22921154.{{cite journal}}: CS1 maint: multiple names: authors list (link)
81. Greco SJ, Sarkar S, Johnston JM, Tezapsidis N (February 2009). "Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells". Biochem. Biophys. Res. Commun. 380 (1): 98–104. doi:10.1016/j.bbrc.2009.01.041. PMC 2657956. PMID 19166821.{{cite journal}}: CS1 maint: multiple names: authors list (link)
82. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI (August 1998). "Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression". Nature. 394 (6696): 897–901. doi:10.1038/29795. PMID 9732873.{{cite journal}}: CS1 maint: multiple names: authors list (link)
83. ^ Fantuzzi G, Faggioni R (October 2000). "Leptin in the regulation of immunity, inflammation, and hematopoiesis". J. Leukoc. Biol. 68 (4): 437–46. PMID 11037963.
84. Caldefie-Chezet F, Poulin A, Tridon A, Sion B, Vasson MP (March 2001). "Leptin: a potential regulator of polymorphonuclear neutrophil bactericidal action?". J. Leukoc. Biol. 69 (3): 414–8. PMID 11261788.{{cite journal}}: CS1 maint: multiple names: authors list (link)
85. Madej T, Boguski MS, Bryant SH (October 1995). "Threading analysis suggests that the obese gene product may be a helical cytokine". FEBS Lett. 373 (1): 13–18. doi:10.1016/0014-5793(95)00977-H. PMID 7589424.{{cite journal}}: CS1 maint: multiple names: authors list (link)
86. Heiman ML, Ahima RS, Craft LS, Schoner B, Stephens TW, Flier JS (September 1997). "Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress". Endocrinology. 138 (9): 3859–3863. doi:10.1210/en.138.9.3859. PMID 9275075.{{cite journal}}: CS1 maint: multiple names: authors list (link)
87. Mabuchi T, Yatsuya H, Tamakoshi K, Otsuka R, Nagasawa N, Zhang H, Murata C, Wada K, Ishikawa M, Hori Y, Kondo T, Hashimoto S, Toyoshima H (2005). "Association between serum leptin concentration and white blood cell count in middle-aged Japanese men and women". Diabetes Metab. Res. Rev. 21 (5): 441–447. doi:10.1002/dmrr.540. PMID 15724240.{{cite journal}}: CS1 maint: multiple names: authors list (link)
88. Hamilton BS, Paglia D, Kwan AY, Deitel M (September 1995). "Increased obese mRNA expression in omental fat cells from massively obese humans". Nat. Med. 1 (9): 953–956. doi:10.1038/nm0995-953. PMID 7585224.{{cite journal}}: CS1 maint: multiple names: authors list (link)
89. Perrier S, Caldefie-Chézet F, Vasson MP (January 2009). "IL-1 family in breast cancer: potential interplay with leptin and other adipocytokines". FEBS Lett. 583 (2): 259–65. doi:10.1016/j.febslet.2008.12.030. PMID 19111549.{{cite journal}}: CS1 maint: multiple names: authors list (link)
90. Wabitsch M, Jensen PB, Blum WF, Christoffersen CT, Englaro P, Heinze E, Rascher W, Teller W, Tornqvist H, Hauner H (October 1996). "Insulin and cortisol promote leptin production in cultured human fat cells". Diabetes. 45 (10): 1435–1438. doi:10.2337/diabetes.45.10.1435. PMID 8826983.{{cite journal}}: CS1 maint: multiple names: authors list (link)
91. LaPensee CR, Hugo ER, Ben-Jonathan N (November 2008). "Insulin stimulates interleukin-6 expression and release in LS14 human adipocytes through multiple signaling pathways". Endocrinology. 149 (11): 5415–5422. doi:10.1210/en.2008-0549. PMC 2584585. PMID 18617614.{{cite journal}}: CS1 maint: multiple names: authors list (link)
92. Worm D, Vinten J, Vaag A, Henriksen JE, Beck-Nielsen H (September 2000). "The nicotinic acid analogue acipimox increases plasma leptin and decreases free fatty acids in type 2 diabetic patients". Eur. J. Endocrinol. 143 (3): 389–395. doi:10.1530/eje.0.1430389. PMID 11022182.{{cite journal}}: CS1 maint: multiple names: authors list (link)
93. Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS (May 2003). "The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men". J. Clin. Invest. 111 (9): 1409–1421. doi:10.1172/JCI17490. PMC 154448. PMID 12727933.{{cite journal}}: CS1 maint: multiple names: authors list (link)
94. Kolaczynski JW, Considine RV, Ohannesian J, Marco C, Opentanova I, Nyce MR, Myint M, Caro JF (November 1996). "Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves". Diabetes. 45 (11): 1511–5. doi:10.2337/diab.45.11.1511. PMID 8866554.{{cite journal}}: CS1 maint: multiple names: authors list (link)
95. Kolaczynski JW, Ohannesian JP, Considine RV, Marco CC, Caro JF (November 1996). "Response of leptin to short-term and prolonged overfeeding in humans". J. Clin. Endocrinol. Metab. 81 (11): 4162–5. doi:10.1210/jc.81.11.4162. PMID 8923877.{{cite journal}}: CS1 maint: multiple names: authors list (link)
96. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS (July 1996). "Role of leptin in the neuroendocrine response to fasting". Nature. 382 (6588): 250–2. doi:10.1038/382250a0. PMID 8717038.{{cite journal}}: CS1 maint: multiple names: authors list (link)
97. Friedman JM (March 2009). "Leptin at 14 y of age: an ongoing story". Am. J. Clin. Nutr. 89 (3): 973S – 979S. doi:10.3945/ajcn.2008.26788B. PMC 2667654. PMID 19190071.
98. Zirlik S, Hauck T, Fuchs FS, Neurath MF, Konturek PC, Harsch IA (February 2011). "Leptin, Obestatin and Apelin levels in patients with obstructive sleep apnoea syndrome". Med. Sci. Monit. 17 (3): CR159–64. doi:10.12659/MSM.881450. PMC 3524733. PMID 21358603.{{cite journal}}: CS1 maint: multiple names: authors list (link)
99. Harsch IA, Konturek PC, Koebnick C, Kuehnlein PP, Fuchs FS, Pour Schahin S, Wiest GH, Hahn EG, Lohmann T, Ficker JH (August 2003). "Leptin and ghrelin levels in patients with obstructive sleep apnoea: effect of CPAP treatment". Eur. Respir. J. 22 (2): 251–257. doi:10.1183/09031936.03.00010103. PMID 12952256.{{cite journal}}: CS1 maint: multiple names: authors list (link)
100. Seaborg E (2007). "Growing evidence links too little sleep to obesity and diabetes". Endocrine News: 14–15.
101. Knutson KL, Spiegel K, Penev P, Van Cauter E (June 2007). "The metabolic consequences of sleep deprivation". Sleep Med Rev. 11 (3): 163–178. doi:10.1016/j.smrv.2007.01.002. PMC 1991337. PMID 17442599.{{cite journal}}: CS1 maint: multiple names: authors list (link)
102. Otsuka R, Yatsuya H, Tamakoshi K, Matsushita K, Wada K, Toyoshima H (October 2006). "Perceived psychological stress and serum leptin concentrations in Japanese men". Obesity (Silver Spring). 14 (10): 1832–1838. doi:10.1038/oby.2006.211. PMID 17062814.{{cite journal}}: CS1 maint: multiple names: authors list (link)
103. Ahima RS, Flier JS (2000). "Leptin". Annu. Rev. Physiol. 62: 413–437. doi:10.1146/annurev.physiol.62.1.413. PMID 10845097.
104. de Salles BF, Simão R, Fleck SJ, Dias I, Kraemer-Aguiar LG, Bouskela E (July 2010). "Effects of resistance training on cytokines". Int J Sports Med. 31 (7): 441–450. doi:10.1055/s-0030-1251994. PMID 20432196.{{cite journal}}: CS1 maint: multiple names: authors list (link)
105. Hickey MS, Considine RV, Israel RG, Mahar TL, McCammon MR, Tyndall GL, Houmard JA, Caro JF (November 1996). "Leptin is related to body fat content in male distance runners". Am. J. Physiol. 271 (5 Pt 1): E938–40. PMID 8944684.{{cite journal}}: CS1 maint: multiple names: authors list (link)
106. Hickey MS, Houmard JA, Considine RV, Tyndall GL, Midgette JB, Gavigan KE, Weidner ML, McCammon MR, Israel RG, Caro JF (April 1997). "Gender-dependent effects of exercise training on serum leptin levels in humans". Am. J. Physiol. 272 (4 Pt 1): E562–6. PMID 9142875.{{cite journal}}: CS1 maint: multiple names: authors list (link)
107. Considine RV, Nyce MR, Kolaczynski JW, Zhang PL, Ohannesian JP, Moore JH, Fox JW, Caro JF (May 1997). "Dexamethasone stimulates leptin release from human adipocytes: unexpected inhibition by insulin". J. Cell. Biochem. 65 (2): 254–8. doi:10.1002/(SICI)1097-4644(199705)65:2<254::AID-JCB10>3.0.CO;2-I. PMID 9136082.{{cite journal}}: CS1 maint: multiple names: authors list (link)
108. Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, Mudaliar SR, Olefsky J, Caro JF (May 1996). "Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro". Diabetes. 45 (5): 699–701. doi:10.2337/diabetes.45.5.699. PMID 8621027.{{cite journal}}: CS1 maint: multiple names: authors list (link)
109. ^ Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV (November 1996). "Leptin: the tale of an obesity gene". Diabetes. 45 (11): 1455–62. doi:10.2337/diab.45.11.1455. PMID 8866547.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid8866547" was defined multiple times with different content (see the help page).
110. ^ Paracchini, V; Pedotti, P; Taioli, E. (2005). "Genetics of Leptin and Obesity: A HuGE Review". Am. J. Epidemiol. 162 (2): 101–114. doi:10.1093/aje/kwi174. PMID 15972940. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
111. Zhang L, Lu M, Yuan L, Lai W, Wang Y. (2014). "Association of leptin gene-2548 G/A polymorphism with obesity: a meta-analysis". Wei Sheng Yan Jiu. 43 (1): 128–32. PMID 24564125. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
112. Wang, T; et al. (2006). "G-2548A Polymorphism of the Leptin Gene Is Correlated with Extreme Obesity in Taiwanese Aborigines". Obesity. 14 (2): 183–187. doi:10.1038/oby.2006.23. PMID 16571841. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)
113. Templeman LA, Reynolds GP, Arranz B, San L. (2005). "Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis". Pharmacogenet Genomics. 15 (4): 195–200. PMID 15864111. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
114. Kang SG; et al. (2008). "Possible association between the -2548A/G polymorphism of the leptin gene and olanzapine-induced weight gain". Prog Neuropsychopharmacol Biol Psychiatry. 32 (1): 160–3. PMID 17804136. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)
115. Wu R; et al. (2011). "Genetic predictors of antipsychotic-induced weight gain: a case-matched multi-gene study". Zhong Nan Da Xue Xue Bao Yi Xue Ban. 36 (8): 720–3. doi:10.3969/j.issn.1672-7347.2011.08.003.. PMID 21937795. {{cite journal}}: Check |doi= value (help); Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)
116. Ribeiro R; et al. (2004). "Overexpressing leptin genetic polymorphism (-2548 G/A) is associated with susceptibility to prostate cancer and risk of advanced disease". Prostate. 59 (3): 268–74. PMID 15042602. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)
117. Vaskú JA, Vaskú A, Dostálová Z, Bienert P. (2006). "Association of leptin genetic polymorphism -2548 G/A with gestational diabetes mellitus". Genes Nutr. 1 (2): 117–23. doi:10.1007/BF02829953.. PMID 18850205. {{cite journal}}: Check |doi= value (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
118. Ye XL, Lu CF (2013). "Association of polymorphisms in the leptin and leptin receptor genes with inflammatory mediators in patients with osteoporosis". Endocrine. 44 (2): 481–8. doi:10.1007/s12020-013-9899-9.. PMID 23460508. {{cite journal}}: Check |doi= value (help); Unknown parameter |month= ignored (help)
119. Caro JF, Ittoop O, Pories WJ, Meelheim D, Flickinger EG, Thomas F, Jenquin M, Silverman JF, Khazanie PG, Sinha MK (July 1986). "Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity". J. Clin. Invest. 78 (1): 249–58. doi:10.1172/JCI112558. PMC 329556. PMID 3522628.{{cite journal}}: CS1 maint: multiple names: authors list (link)
120. ^ Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV (July 1996). "Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance". Lancet. 348 (9021): 159–61. doi:10.1016/S0140-6736(96)03173-X. PMID 8684156.{{cite journal}}: CS1 maint: multiple names: authors list (link)
121. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D (May 1996). "Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans". Nat. Med. 2 (5): 589–93. doi:10.1038/nm0596-589. PMID 8616722.{{cite journal}}: CS1 maint: multiple names: authors list (link)
122. Considine RV, Considine EL, Williams CJ, Hyde TM, Caro JF (July 1996). "The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations". Diabetes. 45 (7): 992–4. doi:10.2337/diabetes.45.7.992. PMID 8666155.{{cite journal}}: CS1 maint: multiple names: authors list (link)
123. Considine RV, Caro JF (November 1997). "Leptin and the regulation of body weight". Int. J. Biochem. Cell Biol. 29 (11): 1255–72. doi:10.1016/S1357-2725(97)00050-2. PMID 9451823.
124. Jönsson T, Olsson S, Ahrén B, Bøg-Hansen TC, Dole A, Lindeberg S (2005). "Agrarian diet and diseases of affluence—do evolutionary novel dietary lectins cause leptin resistance?". BMC Endocr Disord. 5: 10. doi:10.1186/1472-6823-5-10. PMC 1326203. PMID 16336696.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
125. ^ Shapiro A, Mu W, Roncal C, Cheng KY, Johnson RJ, Scarpace PJ (November 2008). "Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding". Am. J. Physiol. Regul. Integr. Comp. Physiol. 295 (5): R1370–5. doi:10.1152/ajpregu.00195.2008. PMC 2584858. PMID 18703413.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid18703413" was defined multiple times with different content (see the help page).
126. Pilon B. "Leptin and Inflammation | Inflammation Theory". Press75.com. Retrieved 2011-04-19.
127. Hickey, Matthew S.; et al. (1996). "Gender Differences in Serum Leptin Levels in Humans". Biochem Mol Med. 59 (1): 1–6. doi:10.1006/bmme.1996.0056. PMID 8902186. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)
128. Oswal A, Yeo G (February 2010). "Leptin and the control of body weight: a review of its diverse central targets, signaling mechanisms, and role in the pathogenesis of obesity". Obesity (Silver Spring). 18 (2): 221–9. doi:10.1038/oby.2009.228. PMID 19644451.
129. Banks WA, Farr SA, Morley JE (June 2006). "The effects of high fat diets on the blood-brain barrier transport of leptin: failure or adaptation?". Physiol. Behav. 88 (3): 244–8. doi:10.1016/j.physbeh.2006.05.037. PMID 16781741.{{cite journal}}: CS1 maint: multiple names: authors list (link)
130. Myers MG, Cowley MA, Münzberg H (2008). "Mechanisms of leptin action and leptin resistance". Annu. Rev. Physiol. 70: 537–556. doi:10.1146/annurev.physiol.70.113006.100707. PMID 17937601.{{cite journal}}: CS1 maint: multiple names: authors list (link)
131. Wang J, Obici S, Morgan K, Barzilai N, Feng Z, Rossetti L (December 2001). "Overfeeding rapidly induces leptin and insulin resistance". Diabetes. 50 (12): 2786–2791. doi:10.2337/diabetes.50.12.2786. PMID 11723062.{{cite journal}}: CS1 maint: multiple names: authors list (link)
132. Enriori PJ, Evans AE, Sinnayah P, Jobst EE, Tonelli-Lemos L, Billes SK, Glavas MM, Grayson BE, Perello M, Nillni EA, Grove KL, Cowley MA (March 2007). "Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons". Cell Metab. 5 (3): 181–194. doi:10.1016/j.cmet.2007.02.004. PMID 17339026.{{cite journal}}: CS1 maint: multiple names: authors list (link)
133. Obici S, Rossetti L (December 2003). "Minireview: nutrient sensing and the regulation of insulin action and energy balance". Endocrinology. 144 (12): 5172–8. doi:10.1210/en.2003-0999. PMID 12970158.
134. "Fructose Sets Table For Weight Gain Without Warning". Science News. Science Daily. 2008-10-19. Retrieved 2008-11-15.
135. Vasselli JR (November 2008). "Fructose-induced leptin resistance: discovery of an unsuspected form of the phenomenon and its significance. Focus on "Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding," by Shapiro et al". Am. J. Physiol. Regul. Integr. Comp. Physiol. 295 (5): R1365 – R1369. doi:10.1152/ajpregu.90674.2008. PMID 18784330.
136. Roth JD, Roland BL, Cole RL, Trevaskis JL, Weyer C, Koda JE, Anderson CM, Parkes DG, Baron AD (May 2008). "Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies". Proc. Natl. Acad. Sci. U.S.A. 105 (20): 7257–7262. doi:10.1073/pnas.0706473105. PMC 2438237. PMID 18458326.{{cite journal}}: CS1 maint: multiple names: authors list (link)
137. ^ Ahima RS (July 2008). "Revisiting leptin's role in obesity and weight loss". J. Clin. Invest. 118 (7): 2380–3. doi:10.1172/JCI36284. PMC 2430504. PMID 18568083.
138. Chou K, Perry CM (2013). "Metreleptin: first global approval". Drugs. 73 (9): 989–997. doi:10.1007/s40265-013-0074-7. PMID 23740412.
139. "Amylin Seeks FDA Approval for Metreleptin". diabetesincontrol.com. 11 April 2012.

External links

• Leptin: Your brain, appetite and obesity by the British Society of Neuroendocrinology

• Leptin by Colorado State University - nice illustrations, but last updated 1998
• Leptin at 3Dchem.com, description and structure diagrams

• Peptide hormones
• Mutated genes
• Obesity