Leptin wikipedia.docx

7/27/2019 Leptin wikipedia.docx

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2.1 Leptin

Leptin (from the Greekleptos, meaning thin) is a protein hormone with important effects

in regulating body weight, metabolism and reproductive function. The protein is approximately

16 kDa in mass and encoded by the obese (ob) genE.1 Leptin, discovered through positional

cloning 15 years ago is an adipocyte-secreted hormone with a key role in energy homeostasis.2

2.1.1 Biosynthesis

Leptin is a 167 amino acid protein which belongs to the cytokine family.3

Human leptin

gene is located on chromosome 7.4

It is manufactured primarily in the adipocytes of white

adipose tissue, and the level of circulating leptin is directly proportional to the total amount of fat

in the body. In addition to white adipose tissue, the major source of leptin, it can also be

produced by brown adipose tissue,placenta (syncytiotrophoblasts), ovaries, skeletal muscle,

stomach (lower part of fundic glands), mammary epithelial cells,bone marrow,pituitary and

liver.Leptin play key role in food intake, energy balance, and adiposity as well as in immune and

endocrine system. It acts as feedback loop to maintain the constant store of body fat.5

Leptin levels are pulsatile and follow a circadian rhythm, with highest levels between

midnight and early morning and lowest levels in the early- to mid- afternoon . Specifically, the

concentration of circulating leptin may be up to 75.6% higher during the night as compared to

afternoon trough levels. The pulsatile characteristics of leptin secretion are similar in obese and

lean individuals, except the obese have higher pulse amplitudes. Leptin concentration reflects the

amount of energy stored in body fat. Circulating leptin levels are directly proportional to the

amount of body fat and fluctuate with acute changes in caloric intake. This system is especially

sensitive to energy deprivation. Women tend to have higher leptin levels than men, although

women experience a significant decline in the amount of circulating leptin after menopause. This

sexual dimorphism is largely independent of body mass index (BMI), and is due in part to

differences in sex hormones, fat mass, and body fat distribution. Women tend to accumulate

body fat peripherally whereas men are prone to an abdominal or android distribution of fat.

Subcutaneous fat expresses more leptin mRNA than omental fat, and this may partially explain
http://en.wikipedia.org/wiki/White_adipose_tissuehttp://en.wikipedia.org/wiki/White_adipose_tissuehttp://en.wikipedia.org/wiki/Brown_adipose_tissuehttp://en.wikipedia.org/wiki/Placentahttp://en.wikipedia.org/wiki/Ovarieshttp://en.wikipedia.org/wiki/Skeletal_musclehttp://en.wikipedia.org/wiki/Stomachhttp://en.wikipedia.org/w/index.php?title=Mammary_epithelial_cells&action=edit&redlink=1http://en.wikipedia.org/wiki/Bone_marrowhttp://en.wikipedia.org/wiki/Pituitaryhttp://en.wikipedia.org/wiki/Liverhttp://en.wikipedia.org/wiki/Liverhttp://en.wikipedia.org/wiki/Pituitaryhttp://en.wikipedia.org/wiki/Bone_marrowhttp://en.wikipedia.org/w/index.php?title=Mammary_epithelial_cells&action=edit&redlink=1http://en.wikipedia.org/wiki/Stomachhttp://en.wikipedia.org/wiki/Skeletal_musclehttp://en.wikipedia.org/wiki/Ovarieshttp://en.wikipedia.org/wiki/Placentahttp://en.wikipedia.org/wiki/Brown_adipose_tissuehttp://en.wikipedia.org/wiki/White_adipose_tissuehttp://en.wikipedia.org/wiki/White_adipose_tissue


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the higher leptin concentrations in women compared to men. Hormones and cytokines other than

sex steroids also affect leptin secretion but to a smaller degree (Table 1).6

Table 1 Factors that regulate circulating leptin levels6

Factors promoting leptin secretion

Excess energy stored as fat (obesity)

Overfeeding

Glucose

Insulin

Glucocorticoids

Estrogens

Inflammatory cytokines, including Tumor Necrosis Factor- and Interleukin-6

(acute effect)

Factors inhibiting leptin secretion

Low energy states with decreased fat stores (leanness)

Fasting

Catecholamines and adrenergic agonists

Thyroid hormones

Androgens

Peroxisome Proliferator-activated Receptor- (PPAR) agonists

Inflammatory cytokines, including Tumor Necrosis Factor- (prolonged effect)

2.1.2 Mechanism of action

Leptin binds to leptin receptors (ObRs) located throughout the central nervous system and

several peripheral tissues. At least six variations or isoforms of the leptin receptor have been

identified (ObRa, ObRb, ObRc, ObRd, ObRe, and ObRf). These isoforms have homologous

extracellular domains but distinct intracellular domains, which vary by length and sequence due
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to alternative mRNA splicing. The short isoforms ObRa and ObRc are thought to play important

roles in transporting leptin across the bloodbrain barrier (BBB). The long leptin receptor

isoform ObRb is primarily responsible for leptin signaling.5

The long leptin receptor isoform is

expressed abundantly in the hypothalamus and activates the Janus kinase signal transducer and

activator of trascription (JAK-STAT) system to alter the expression of hypothalamic

neuropeptides.This functional leptin receptor ObRb, expressed in several organs, is strongly

expressed throughout the central nervous system but particularly in the hypothalamus, where it

regulates energy homeostasis and neuroendocrine function described further below. In the db/db

mouse model, the ObRb is dysfunctional, resulting in obesity and the metabolic syndrome.6

Figure 1 Leptin's action in the brain during states of energy excess and energy deficiency. 6

During states of leptin and energy excess, leptin's access to the hypothalamus and other brain

areas is impaired and leptin's action is blunted. In states of leptin and energy deficiency,

neuropeptides that are normally inhibited by leptin are elevated (+) and neuropeptides stimulated

by leptin are suppressed (-). A change in the concentrations of these neuropeptides leads to


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alterations in neuroendocrine function and energy homeostasis. Alterations in leptin levels may

also affect the hedonic aspects of feeding behavior. The role of leptin in the brain is discussed in

greater detail in the text.

Abbreviations: ACTH, adrenocorticotropic hormone; AgRP, agouti-related peptide; ARC,

arcuate nucleus; BDNF, brain-derived neurotrophic factor; CART, cocaine- and amphetamine-

regulated transcript; CCK, cholecystokinin; CRH, corticotropin-releasing hormone; FSH,

follicle-stimulating hormone; GH, growth hormone; GLP-1, glucagon-like peptide 1; GnRH,

gonadotropin-releasing hormone; IGF-1, insulin-like growth factor 1; LH, luteinizing hormone;

LHA, lateral hypothalamic area; MCH, melanin-concentrating hormone; NPY, neuropeptide Y;

NST, nucleus of the solitary tract; PO, preoptic area; POMC, proopiomelanocortin; PVN,

paraventricular nucleus; SN, substantia nigra; TRH, thyrotropin-releasing hormone; TSH,

thyrotropin-stimulating hormone; VMH, ventromedial hypothalamus; VTA, ventral tegmental

area.

Activation ofObRb sets off a cascade of several signal transduction pathways (Table 2),

of which the best studied pathway is the Janus kinase 2/signal transducer and activator of

transcription 3 (JAK2/STAT3) pathway. STAT3 has been shown to mediate the transcription of

several genes that affect a number of cellular processes. Leptin controls energy homeostasis and

body weight primarily by activating ObRb in the hypothalamus. The ObRb activate numerous

JAK2/STAT3-dependent and -independent signaling pathways that act in coordination as a

network to fully mediate leptin's action. The activation of individual pathways in the leptin

signaling network appears to be differentially regulated in discrete subpopulations of ObRb-

expressing neurons. These pathways are also likely to be regulated by various other hormonal,

neuronal, and metabolic signals that cross-talk with leptin. Hence, it is important to fully

determine whether and how positive and negative regulators ofObRb signaling, metabolic state,

and/or neuronal activity regulate leptin signaling networks in a cell/tissue type-specific manner

and how activation of these signaling pathways mediates leptin's effects in humans.6
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Table 2 Leptin Signaling6

Signaling

Pathway

Primary Site of

Action

Known Mechanisms of

Action

Clinical Results

JAK-STAT3 Hypothalamus Stimulates transcription ofPOMC and suppresses

transcription of NPY

Regulates appetite and,thus, body weight

May also contribute toneuroendocrine function

as neural-specific STAT3

deletion results in

decreased linear growth

and infertility

P13K Hypothalamus Stimulates POMC neurons

Inhibits FOXO1, an

inhibitor of POMC

transcription, to increase

POMC expression

Regulates appetite andbody weight.

May contribute to leptinresistance in obesity,

given the overlapping

pathway with insulin

May mediate thestimulation of

sympathetic outflow

MAPK Hypothalamus, liver,

pancreas, adipose

tissue, and myocytes

Stimulates POMC neurons

and inhibits AgRP/NPY

neurons

Regulates appetite andbody weight

Increases sympatheticactivity to brown adipose

tissue

Increases fatty acidoxidation in peripheral

tissues

Promotes cardiomyocyte


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Signaling

Pathway

Primary Site of

Action

Known Mechanisms of

Action

Clinical Results

hypertrophy

AMPK Hypothalamus,

muscle

Stimulates ACC activity in

the hypothalamus to

regulate food intake and

weight

Inhibits ACC activity in

muscle

Regulates appetite andweight

Stimulates fatty-acidoxidation in muscle and

may sensitize muscle toinsulin

mTOR Hypothalamus Induces phosphorylation of

S6K1 to regulate protein

synthesis

Regulates appetite andweight

Abbreviations: ACC, acetyl coenzyme A carboxylase; AMPK, 5'adenosine monophosphate-

activated protein kinase; ATP, adenosine triphosphate; FOXO1, forkhead box O1; JAK-STAT3,

janus kinase-signal transducers and activator of transcription 3; K+, potassium; MAPK, mitogen-

activated protein kinase; mTOR, mammalian target of rapamycin; NPY, neuropeptide Y;

POMC, pro-opiomelanocortin; P13K, phosphatidylinositol 3-kinase; S6K1, S6 Kinase 1.

2.1.3 Effects in organs

Leptin acts on receptors in the hypothalamus of the brain where it inhibits appetite by (1)

counteracting the effects ofneuropeptide Y (a potent feeding stimulant secreted by cells in the

gut and in the hypothalamus); (2) counteracting the effects of anandamide (another potent

feeding stimulant that binds to the same receptors as THC), and (3) promoting the synthesis of-

MSH, an appetite suppressant. This inhibition is long-term, in contrast to the rapid inhibition of

eating by cholecystokinin (CCK) and the slower suppression of hunger between meals mediated

by PYY3-36.7 The absence of leptin (or its receptor) leads to uncontrolled food intake and

resulting obesity. Several studies have shown that fasting or following a very-low-calorie diet

(VLCD) lowers leptin levels. It might be that, in the short-term, leptin is an indicator of energy
http://en.wikipedia.org/wiki/Neuropeptide_Yhttp://en.wikipedia.org/wiki/Anandamidehttp://en.wikipedia.org/wiki/THChttp://en.wikipedia.org/wiki/%CE%91-MSHhttp://en.wikipedia.org/wiki/%CE%91-MSHhttp://en.wikipedia.org/wiki/%CE%91-MSHhttp://en.wikipedia.org/wiki/%CE%91-MSHhttp://en.wikipedia.org/wiki/Cholecystokininhttp://en.wikipedia.org/wiki/PYY3-36http://en.wikipedia.org/wiki/Fastinghttp://en.wikipedia.org/wiki/Very-low-calorie_diethttp://en.wikipedia.org/wiki/Very-low-calorie_diethttp://en.wikipedia.org/wiki/Fastinghttp://en.wikipedia.org/wiki/PYY3-36http://en.wikipedia.org/wiki/Cholecystokininhttp://en.wikipedia.org/wiki/%CE%91-MSHhttp://en.wikipedia.org/wiki/%CE%91-MSHhttp://en.wikipedia.org/wiki/THChttp://en.wikipedia.org/wiki/Anandamidehttp://en.wikipedia.org/wiki/Neuropeptide_Y


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balance. This system is more sensitive to starvation than to overfeeding; leptin levels change

more when food intake decreases than when it increases.8

There is some controversy regarding the regulation of leptin by melatonin during the

night. One research group suggested that increased levels of melatonin caused a downregulation

of leptin.9However, in 2004, Brazilian researchers found that melatonin increases leptin levels in

the presence ofinsulin, therefore causing a decrease in appetite during sleeping.10

2.1.3.1 Clinical significance

Leptin has traditionally been regarded as a link between fat mass, food intake, and energy

expenditure. This link originally arose from animal research findings, but its application to

describing human systems has since been challenged.11 In humans, there are many instances

where leptin dissociates from the strict role of communicating nutritional status between body

and brain and no longer correlates with body fat levels:

Leptin levels decrease after short-term fasting (2472 hours), even when changes in fatmass are not observed.

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In the obese patients with obstructive sleep apnea (OSA), Leptin is increased, butdecreases after administration of a CPAP.

13In non-obese individuals, however, restful

sleep (i.e., 812 hours of unbroken sleep) can increase leptin within normal ranges.

Serum levels of Leptin are reduced by sleep deprivation.14 Increased by perceived emotional stress.15 Decreased by testosterone and increased by estrogen.16 Chronically affected by exercise training; it decreases leptin levels.16

2.1.3.2 Adiposity signal

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

circulates at levels proportional to body fat. It enters the central nervous system (CNS) in

proportion to its plasma concentration. Its receptors are found in brain neurons involved in

regulating energy intake and expenditure. It controls food intake and energy expenditure by

acting on receptors in the mediobasal hypothalamus. 17
http://en.wikipedia.org/wiki/Melatoninhttp://en.wikipedia.org/wiki/Melatoninhttp://en.wikipedia.org/wiki/Insulinhttp://en.wikipedia.org/wiki/CPAPhttp://en.wikipedia.org/wiki/Insulinhttp://en.wikipedia.org/wiki/Adiposityhttp://en.wikipedia.org/wiki/Adipose_tissuehttp://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Blood_plasmahttp://en.wikipedia.org/wiki/Hypothalamushttp://en.wikipedia.org/wiki/Hypothalamushttp://en.wikipedia.org/wiki/Hypothalamushttp://en.wikipedia.org/wiki/Blood_plasmahttp://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Adipose_tissuehttp://en.wikipedia.org/wiki/Adiposityhttp://en.wikipedia.org/wiki/Insulinhttp://en.wikipedia.org/wiki/CPAPhttp://en.wikipedia.org/wiki/Insulinhttp://en.wikipedia.org/wiki/Melatoninhttp://en.wikipedia.org/wiki/Melatonin


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2.1.3.3 Interaction with amylin

Co-administration of two neurohormones known to have a role in body weight control,

amylin (produced by beta cells in the pancreas) and leptin (produced by fat cells), results in

sustained, fat-specific weight loss in a leptin-resistant animal model of obesity. 18

2.1.3.4 Satiety

Leptin binds to neuropeptide Y (NPY) neurons in the arcuate nucleus, in such a way that

decreases the activity of these neurons. Leptin signals to the brain that the body has had enough

to eat, producing a feeling of satiety. A very small group of humans possess homozygous

mutations for the leptin gene that leads to a constant desire for food, resulting in severe obesity.

This condition can be treated somewhat successfully by the administration of recombinant

human leptin.However, extensive clinical trials using recombinant human leptin as a therapeutic

agent for treating obesity in humans have been inconclusive because only the most obese

subjects who were given the highest doses of exogenous leptin produced statistically significant

weight loss. It was concluded that large and frequent doses are needed to provide only modest

benefit because of leptins low circulating half-life, low potency, and poor solubility. Circulating

leptin levels give the brain input regarding energy storage so it can regulate appetite and

metabolism. Leptin works by inhibiting the activity of neurons that contain neuropeptide Y(NPY) and agouti-related peptide (AgRP), and by increasing the activity ofneurons expressing

-melanocyte-stimulating hormone (-MSH). The NPY neurons are a key element in the

regulation of appetite; small doses of NPY injected into the brains of experimental animals

stimulates feeding, while selective destruction of the NPY neurons in mice causes them to

become anorexic. On the converse, -MSH is an important mediator of satiety, and differences in

the gene for the receptor at which -MSH acts in the brain are linked to obesity in humans.19

2.1.3.5 Circulatory system

The role of leptin/leptin receptors in modulation ofT cell activity in immune system was

shown in experimentation with mice. It modulates the immune response to atherosclerosis, which

is a predisposing factor in patients with obesity.20
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In some epidemiological studies, hyperleptinemia is considered as a risk factor. However,

recently a handful of animal experiments demonstrated that systemic hyperleptinemia produced

by infusion or adenoviral gene transfer decreases blood pressure in rats.21,22

2.1.3.6 Lung surfactant activity

In fetal lung, leptin is induced in the alveolar interstitial fibroblasts ("lipofibroblasts") by

the action of PTHrP secreted by formative alveolar epithelium (endoderm) under moderate

stretch. The leptin from the mesenchyme, in turn, acts back on the epithelium at the leptin

receptor carried in the alveolar type II pneumocytes and induces surfactant expression, which is

one of the main functions of these type II pneumocytes.23

2.1.3.7 Reproduction

In mice, leptin is also required for male and female fertility. Leptin has a lesser effect in

humans. In mammals such as humans, ovulatory cycles in females are linked to energy balance

(positive or negative depending on whether a female is losing or gaining weight) and energy flux

(how much energy is consumed and expended) much more than energy status (fat levels). When

energy balance is highly negative (meaning that a woman is starving) or energy flux is very high

(meaning that a woman is exercising at extreme levels, but still consuming enough calories), the

ovarian cycle stops and females stop menstruating. Only if a female has an extremely low body

fat percentage does energy status affect menstruation. Some studies have indicated that leptin

levels outside an ideal range can have a negative effect on egg quality and outcome during IVF.24

The body's fat cells, under normal conditions, are responsible for the constant production and

release of leptin. This can also be produced by the placenta.25

Leptin levels rise during pregnancy

and fall after parturition (childbirth). Leptin is also expressed in fetal membranes and the uterine

tissue. Uterine contractions are inhibited by leptin.26

2.1.3.8 Effects on bone

It is now well established that leptin can affect bone metabolism via direct signalling

from the brain and that although leptin acts to reduce cancellous bone, it conversely increases

cortical bone. A number of theories suggesting that increased leptin during obesity may represent
http://en.wikipedia.org/wiki/Fetalhttp://en.wikipedia.org/wiki/PTHrPhttp://en.wikipedia.org/wiki/Fertilityhttp://en.wikipedia.org/wiki/Mammalshttp://en.wikipedia.org/wiki/Placentahttp://en.wikipedia.org/wiki/Bone_metabolismhttp://en.wikipedia.org/wiki/Cancellous_bonehttp://en.wikipedia.org/wiki/Cortical_bonehttp://en.wikipedia.org/wiki/Cortical_bonehttp://en.wikipedia.org/wiki/Cancellous_bonehttp://en.wikipedia.org/wiki/Bone_metabolismhttp://en.wikipedia.org/wiki/Placentahttp://en.wikipedia.org/wiki/Mammalshttp://en.wikipedia.org/wiki/Fertilityhttp://en.wikipedia.org/wiki/PTHrPhttp://en.wikipedia.org/wiki/Fetal


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a mechanism for enlarging bone size and thus bone resistance to cope with increased body

weight.27

Bone metabolism is under direct control of the brain and thus nerve fibres are present in

bone tissue. A number of brain signalling molecules (neuropeptides and neurotransmitters) have

been found in bone including adrenaline, noradrenaline, serotonin, calcitonin gene-related

peptide, vasoactive intestinal peptide and neuropeptide Y. This evidence supports a direct

signalling system between the brain and bone with accumulating evidence suggesting that these

molecules are directly involved in the regulation of bone metabolism. Leptin, once released from

fat tissue, can cross the blood-brain barrierand bind to its receptors in the brain where it acts

through the sympathetic nervous system to regulate bone metabolism. It is also possible that, in

addition to its effects through the brain, leptin may act directly on cells in the bone to regulatebone metabolism. In reality, leptin probably signals to bone on multiple levels, with local and

systemic checks and balances impacting the final outcome. As a result, the clinical utility of

leptin for treatment of bone diseases remains open but ongoing research may yet provide much

needed therapies for stimulating bone formation.28

2.1.3.9 Inflammatory marker

Factors that acutely affect leptin levels are also factors that influence other markers ofinflammation, 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.29

In terms of both structure and function,

leptin resembles IL-6 and is a member of the cytokine superfamily. Circulating leptin seems to

effect the HPA axis, suggesting a role for leptin in stress response. Elevated leptin concentrations

are associated with elevated white blood cell counts in both men and women.30

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
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interesting that it is not affected by exercise (for comparison, IL-6 is released in response to

muscular contractions).31

2.1.4.0 Obesity and leptin resistance

Although leptin is a circulating signal that reduces appetite, obese individuals generally

exhibit an unusually high circulating concentration of leptin.These people are said to be resistant

to the effects of leptin, in much the same way that people with type 2 diabetes are resistant to the

effects ofinsulin. 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.

A signal-to-noise ratio theory has been proposed to explain the phenomenon of leptin

resistance. In healthy individuals, baseline leptin levels are between 1-5 ng/dl in men and 7-

13 ng/dl in women. A large intake of calories triggers a leptin response that reduces hunger,

thereby preventing an overload of the inflammatory response induced by caloric intake. It has

been theorized that, in obese individuals, the leptin response to caloric intake is blunted due to

chronic, low-grade hyperleptinemia depressing the signal-to-noise ratio such that acute leptin

responses have less of a physiological effect on the body.

The mere fact that leptin resistance is extremely common in obese individuals suggests

that it may simply be an adaptation to excess body weight. It has been suggested that the major

physiological role of leptin is not as a satiety signal to prevent obesity in times of energy

excess, but as a starvation signal to maintain adequate fat stores for survival during times of

energy deficit, and that leptin resistance in overweight individuals is the standard feature of

mammalian physiology, which possibly confers a survival advantage.31

Daftar Pustaka

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http://en.wikipedia.org/wiki/Inflammation#Post-inflammatory_muscle_growth_and_repairhttp://en.wikipedia.org/wiki/Inflammation#Post-inflammatory_muscle_growth_and_repairhttp://en.wikipedia.org/wiki/Type_2_diabeteshttp://en.wikipedia.org/wiki/Insulin_resistancehttp://en.wikipedia.org/wiki/Insulinhttp://en.wikipedia.org/wiki/Signal-to-noise_ratiohttp://en.wikipedia.org/wiki/Signal-to-noise_ratiohttp://en.wikipedia.org/wiki/Insulinhttp://en.wikipedia.org/wiki/Insulin_resistancehttp://en.wikipedia.org/wiki/Type_2_diabeteshttp://en.wikipedia.org/wiki/Inflammation#Post-inflammatory_muscle_growth_and_repairhttp://en.wikipedia.org/wiki/Inflammation#Post-inflammatory_muscle_growth_and_repair


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