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Studies on leptin [[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<ref name="pmid24039946">{{cite journal | author = Veyrat-Durebex C, Poher AL, Caillon A, Somm E, Vallet P, Charnay Y, Rohner-Jeanrenaud F | title = Improved leptin sensitivity as a potential candidate responsible for the spontaneous food restriction of the Lou/C rat | journal = PLoS ONE | volume = 8 | issue = 9 | pages = e73452 | year = 2013 | pmid = 24039946 | pmc = 3765307 | doi = 10.1371/journal.pone.0073452 }}</ref> In humans it has been observed that the ratio of leptin in the blood compared to the CSF is lower in obese people than in people of a normal weight.<ref name="pmid8684156">{{cite journal | author = Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV | title = Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance | journal = Lancet | volume = 348 | issue = 9021 | pages = 159–61 | month = July | pmid = 8684156 | doi = 10.1016/S0140-6736(96)03173-X }}</ref> The reason for this may be high levels of [[triglycerides]] affecting the transport of leptin across the BBB or due to the leptin transporter becoming saturated.<ref name="pmid24039946"/> 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.<ref name="pmid8684156"/> 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),<ref name="pmid8666155">{{cite journal | author = Considine RV, Considine EL, Williams CJ, Hyde TM, Caro JF | title = The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations | journal = Diabetes | volume = 45 | issue = 7 | pages = 992–4 | year = 1996 | pmid = 8666155 | doi = 10.2337/diabetes.45.7.992 }}</ref> 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.<ref name="pmid9451823">{{cite journal | author = Considine RV, Caro JF | title = Leptin and the regulation of body weight | journal = Int. J. Biochem. Cell Biol. | volume = 29 | issue = 11 | pages = 1255–72 | date = November 1997 | pmid = 9451823 | doi = 10.1016/S1357-2725(97)00050-2 }}</ref>
Studies on leptin [[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<ref name="pmid24039946">{{cite journal | author = Veyrat-Durebex C, Poher AL, Caillon A, Somm E, Vallet P, Charnay Y, Rohner-Jeanrenaud F | title = Improved leptin sensitivity as a potential candidate responsible for the spontaneous food restriction of the Lou/C rat | journal = PLoS ONE | volume = 8 | issue = 9 | pages = e73452 | year = 2013 | pmid = 24039946 | pmc = 3765307 | doi = 10.1371/journal.pone.0073452 }}</ref> In humans it has been observed that the ratio of leptin in the blood compared to the CSF is lower in obese people than in people of a normal weight.<ref name="pmid8684156">{{cite journal | author = Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV | title = Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance | journal = Lancet | volume = 348 | issue = 9021 | pages = 159–61 | month = July | pmid = 8684156 | doi = 10.1016/S0140-6736(96)03173-X }}</ref> The reason for this may be high levels of [[triglycerides]] affecting the transport of leptin across the BBB or due to the leptin transporter becoming saturated.<ref name="pmid24039946"/> 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.<ref name="pmid8684156"/> 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),<ref name="pmid8666155">{{cite journal | author = Considine RV, Considine EL, Williams CJ, Hyde TM, Caro JF | title = The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations | journal = Diabetes | volume = 45 | issue = 7 | pages = 992–4 | year = 1996 | pmid = 8666155 | doi = 10.2337/diabetes.45.7.992 }}</ref> 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.<ref name="pmid9451823">{{cite journal | author = Considine RV, Caro JF | title = Leptin and the regulation of body weight | journal = Int. J. Biochem. Cell Biol. | volume = 29 | issue = 11 | pages = 1255–72 | date = November 1997 | pmid = 9451823 | doi = 10.1016/S1357-2725(97)00050-2 }}</ref>


When leptin binds with the leptin receptor it activated a number of pathways. Leptin resistance may be caused by defects in one or more part of this process, particularly the [[Janus kinase 1|JAK]]/[[STAT protein|STAT]] pathway. Mice with a mutation in the leptin receptor gene which prevents the activation of [[STAT3]] are obese and exhibit hyperphagia. The [[Phosphoinositide 3-kinase|PI3K]] pathway may also be involved in leptin resistance, as has been demonstarated in mice by artifical blocking of PI3K signalling. The PI3K pathway is also 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 [[POMC]] neurons to become insensitive to leptin through [[Hyperpolarization (biology)|hyperpolarization]].<ref name="pmid19644451"/>
The consumption of a high [[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.<ref name="pmid18703413">{{cite journal | author = Shapiro A, Mu W, Roncal C, Cheng KY, Johnson RJ, Scarpace PJ | title = Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding | journal = Am. J. Physiol. Regul. Integr. Comp. Physiol. | volume = 295 | issue = 5 | pages = R1370–R1375 | date = November 2008 | pmid = 18703413 | doi = 10.1152/ajpregu.00195.2008 | url = | pmc = 2584858 }}</ref><ref name="pmid18784330">{{cite journal | author = Vasselli JR | title = 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 | journal = Am. J. Physiol. Regul. Integr. Comp. Physiol. | volume = 295 | issue = 5 | pages = R1365–R1369 | date = November 2008 | pmid = 18784330 | doi = 10.1152/ajpregu.90674.2008 }}</ref> 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 is uncertain if leptin resistance is caused by high levels of carbohydrates or fats, or if an increase or both is needed. <ref name="pmid22496363">{{cite journal | author = Harris RB, Apolzan JW. | title = Changes in glucose tolerance and leptin responsiveness of rats offered a choice of lard, sucrose, and chow.| journal = Am J Physiol Regul Integr Comp Physiol. | volume = 302 | issue =11 | pages = R1327-39| date =Jun 2012 | pmid = 22496363| pmc =3378343| doi =10.1152/ajpregu.00477.2011. }}</ref>
The consumption of a high [[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.<ref name="pmid18703413">{{cite journal | author = Shapiro A, Mu W, Roncal C, Cheng KY, Johnson RJ, Scarpace PJ | title = Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding | journal = Am. J. Physiol. Regul. Integr. Comp. Physiol. | volume = 295 | issue = 5 | pages = R1370–R1375 | date = November 2008 | pmid = 18703413 | doi = 10.1152/ajpregu.00195.2008 | url = | pmc = 2584858 }}</ref><ref name="pmid18784330">{{cite journal | author = Vasselli JR | title = 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 | journal = Am. J. Physiol. Regul. Integr. Comp. Physiol. | volume = 295 | issue = 5 | pages = R1365–R1369 | date = November 2008 | pmid = 18784330 | doi = 10.1152/ajpregu.90674.2008 }}</ref> 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 is uncertain if leptin resistance is caused by high levels of carbohydrates or fats, or if an increase or both is needed. <ref name="pmid22496363">{{cite journal | author = Harris RB, Apolzan JW. | title = Changes in glucose tolerance and leptin responsiveness of rats offered a choice of lard, sucrose, and chow.| journal = Am J Physiol Regul Integr Comp Physiol. | volume = 302 | issue =11 | pages = R1327-39| date =Jun 2012 | pmid = 22496363| pmc =3378343| doi =10.1152/ajpregu.00477.2011. }}</ref>


Revision as of 15:14, 1 May 2014

Not to be confused with Lectin or Lecithin.

Template:PBB

Leptin
Structure of the obese protein leptin-E100.[1]
Identifiers
SymbolLeptin
PfamPF02024
Pfam clanCL0053
InterProIPR000065
SCOP21ax8 / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1ax8​

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 energy expenditure 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[2][3][4][5][6][7][8] 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 secondary functions are yet to be defined.

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.[9]

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.[10] 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.[11][12][13] Rudolph Leibel and Jeffrey M. Friedman reported the mapping of the ob gene in 1990.[14][15][16] 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.[3][4][5][6] In 1994, with the ob gene isolated, Friedman reported the discovery of the gene.[13] At the suggestion of Roger Guillemin, Friedman named this new hormone leptin from the Greek lepto meaning thin.[3][17] 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.[18][19][20][21]

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),[22] the Shaw Prize (2009),[23] the Lasker Award,[24] the BBVA Prize[25] and the King Faisal International Prize,[26] 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.[27][28]

The discovery of leptin is also documented in a series of books including Fat: Fighting the Obesity Epidemic by Robert Pool,[29] 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.[30][31] 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.[32]

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.,[33]gastric chief cells and P/D1 cells.[34]

Regulation of blood levels

Leptin circulates in blood in free form and bound to proteins.[35] Leptin levels vary exponentially, not linearly, with fat mass.[36][37][full citation needed] Leptin levels in blood are higher between midnight and early morning, which could have an effect in suppressing appetite during the night while sleeping.[38] The diurnal rhythm of blood leptin levels can be modified by meal-timing indicating that these levels are entrained to meal timing.[39]

Mechanisms of action

Central (Hypothalamic) effects

Two white mice both with similar sized ears, black eyes, and pink noses: The body of the mouse on the left, however, is about three times the width of the normal-sized mouse on the right.
A comparison of a mouse unable to produce leptin, resulting in obesity (left), and a normal mouse (right)

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.[40][41][42][43] Lleptin levels change more when food intake decreases than when it increases.[44] 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.[45][46]

  • It controls food intake and energy expenditure by acting on receptors in the mediobasal hypothalamus.[47]

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.[48]

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.[49] Ob-Rb is the only receptor isoform that can signal intracellularly via the Jak-Stat and MAPK signal transduction pathways,[50] and is present in hypothalamic nuclei.[51]

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.[52]

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.[53] 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.[54] However melatonin also appears to increase leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping.[55] Partial sleep deprivation has also been associated with decreased leptin levels.[56]

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.[57]

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.[33] 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.[33]

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.[58]

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.[59][60]

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.[61]

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.[62]

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.[63] Leptin is involved in reproduction by stimulating gonadotropin-releasing hormone from the hypothalamus.[64]

Pregnancy

The placenta produces leptin.[65] 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.[66] Leptin plays a role in hyperemesis gravidarum (severe morning sickness of pregnancy),[67] in polycystic ovary syndrome[68] and hypothalamic leptin is implicated in bone growth in mice.[69]

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.[70]

Puberty

Leptin along with kisspeptin controls the onset of puberty.[71] High levels of leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche.[72] 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.[73] 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.[74]


Bone metabolism can be regulated by central sympathetic outflow, since sympathetic pathways innervate bone tissue.[75] 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.[75][76] Leptin binds to its receptors in the hypothalamus, where it acts through the sympathetic nervous system to regulate bone metabolism.[77] Leptin may also act directly on bone metabolism via a balance between energy intake and the IGF-I pathway.[74][78] 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. 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.[79]
  • In humans, low circulating plasma leptin has been associated with cognitive changes associated with anorexia,[80] depression, and HIV.[81]
  • Studies in transgenic mouse models of Alzheimer's disease have shown that chronic administration of leptin can ameliorate brain pathology and improve cognitive performance[82] by reducing b-amyloid and hyperphosphorylated Tau,[83][84] 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,[85][86][87] it has been further theorized that leptin's role as an inflammatory marker is to respond specifically to adipose-derived inflammatory cytokines.

In terms of both structure and function, leptin resembles IL-6 and is a member of the cytokine superfamily.[1][86][88] Circulating leptin seems to affect the HPA axis, suggesting a role for leptin in stress response.[89] Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.[90]

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.[91] 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.[92]

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.[93] (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.)[94] Furthermore, plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis, concurrent hypocaloric dieting and weight loss notwithstanding.[95] 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:

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.[7]

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.[113]

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.[114] A previous study has found a similar link between the GG phenotype and morbid obesity in Taiwanese aborigines.[115] The -2548A/G polymorphism has been associated with weight gain patients taking antipsychotics.[116][117][118] This polymorphism has also been linked with an increased risk of prostate cancer,[119] gestational diabetes[120] and osteoporosis.[121]

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.[113]

Obesity

Leptin resistance

Although leptin reduces appetite as a circulating signal, obese individuals generally exhibit an higher circulating concentration of leptin than normal weight individuals due to their higher percentage body fat.[8] These people show resistance to leptin, similar to resistance of insulin in 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 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. [122]

Studies on leptin 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[123] In humans it has been observed that the ratio of leptin in the blood compared to the CSF is lower in obese people than in people of a normal weight.[124] The reason for this may be high levels of triglycerides affecting the transport of leptin across the BBB or due to the leptin transporter becoming saturated.[123] 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.[124] 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),[125] 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.[126]

When leptin binds with the leptin receptor it activated 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 which prevents the activation of STAT3 are obese and exhibit hyperphagia. The PI3K pathway may also be involved in leptin resistance, as has been demonstarated in mice by artifical blocking of PI3K signalling. The PI3K pathway is also 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 POMC neurons to become insensitive to leptin through hyperpolarization.[127]

The consumption of a high 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.[128][129] 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 is uncertain if leptin resistance is caused by high levels of carbohydrates or fats, or if an increase or both is needed. [130]

Leptin is known to interact with amylin, a hormone involved 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.[131]

It has been suggested that the main role of leptin is not as to act as a signal to help maintain fat stores during times of starvation, not as a signal to prevent overeating.[127][132] This would mean that leptin resistance in obese people is a normal part of mammalian physiology and could possibly confer a survival advantage.[122] 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.[133] This effect is reversed when the animals are put back on a low energy diet.[134] This may also have an evolutionary advantage; allowing energy to be stored efficiently when food is plentiful would be advantageous in populations where food can frequently be scarce.[135]

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.[136]

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.[136]

Therapeutic use

Leptin

Leptin has not been approved for any therapeutic use.

Analog

Main article: Metreleptin

An analog of human leptin, metreleptin (trade name Myalept), has been approved in Japan for metabolic disorders including lipodystrophy. In the United States it is approved as a treatment for complications of leptin deficiency, including diabetes and hypertriglyceridemia, in people with congenital generalized or acquired generalized lipodystrophy.[137][138]

See also

References

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