Leptin&Ghrelin

8/9/2019 Leptin&Ghrelin

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In addition to white adipose tissue 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 has also been discovered to be synthesized from Gastric Chief Cells and P cells in

the stomach .Leptin receptors are located in the hypothalamus.

It is one of the most important adipose derived hormones

(4)l

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Ghrelin is synthesized as a preprohormone, then proteolytically processed to yield a 28-

amino acid peptide.

The predominant source of circulating ghrelin is the gastrointestinal tract, primarily from

the stomach, but also in smaller amounts from the intestine. The hypothalamus in the

brain is another significant source of ghrelin; smaller amounts are produced in the

placenta, kidney, and pituitary gland.

Ghrelin receptor was known well before ghrelin was discovered. Cells within theanterior pituitary bear a receptor that, when activated, potently stimulates secretion of

growth hormone - that receptor was named the growth hormone secretagogues receptor

Ghrelin levels increase before meals and decrease after meals(GHS-R). (5)

Mechanism of action:

Hunger is the feeling experienced when one has a desire to eat. Satiety is the absence of

hunger.

The fluctuation of leptin and ghrelin hormone levels results in the motivation of a person

to consume food. When he eats, adipocytes trigger the release of leptin into the body.

Increasing levels of leptin results in a reduction of one's motivation to eat. After hours of

non-consumption, leptin levels drop significantly. These low levels of leptin cause the

release of secondary hormone, ghrelin, which in turn reinitiates the feeling of hunger.

Some studies have suggested that an increased production of ghrelin may enhance

appetite evoked by the sight of food, while an increase in stress may also influence the

hormone's production. These findings may help to explain why hunger can prevail even

in stressful situations. (6)

Ghrelin's activity in modulating feeding behavior and energy balance are best explained

by the presence of ghrelin receptors in areas of the hypothalamus long known to be

involved in appetite regulation. Receptors are also found concentrated in other areas of

the brain, including the hippocampus and regions which may also be related to this

hormone's effects on appetite. Ghrelin-responsiveness of these neurones is both leptin-



and insulin-sensitive. (6)

Function of leptin:

Leptin acts on receptors in the hypothalamus of the brain where it inhibits appetite by:

(1) counteracting the effects of neuropeptide Y (a potent feeding stimulant secreted by

cells in the gut and in the hypothalamus);

2) counteracting the effects of anandamide (another potent feeding stimulant that

binds to the same receptors as THC, the active ingredient of marijuana)

3) promoting the synthesis of α-MSH, an appetite suppressant(.melanocyte stimulating

hormone). (7)

Roles of leptin:

1) 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 (8)

.

2)Leptin & melatonin regulation:

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 down

regulation of leptin. However, in 2004, Brazilian researchers found that in the presence

of insulin, "melatonin interacts with insulin and up-regulates insulin-stimulated leptin

expression", therefore causing a decrease in appetite whilst sleeping. (9)

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. (10)

4)Satiety: appetite control:

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, or 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(under trials).

Large and frequent doses were needed to only provide modest benefit because of leptin’s

low circulating half-life, low potency, and poor solubility

(11)

5) Circulatory system:

The role of Leptin/Leptin receptors in modulation of T cell activity in immune system

was shown in experimentation with mice. It modulates the immune response to

atherosclerosis, which is a predisposing factor in patients with obesity (12)

Leptin promotes angiogenesis by increasing vascular endothelial growth factor (VEGF)

levels.

Leptin influences blood pressure regulation by several mechanisms: activation of the

sympathetic nervous system and the pituitary-adrenal axis; influence on the water-

electrolyte balance; modulation of endothelial cell function; and influence on vascular

remodeling. (13)

6) Lung surfactant activity:

In fetal lung leptin is induced in the alveolar interstitial fibroblasts and induces

surfactant expression.

7) Reproduction:

-Some studies have indicated that leptin levels outside an ideal range(meaning a woman

is exercising at extreme levels, but still consuming enough calories or /starving) canhave a negative effect on egg quality and outcome during IVF.

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.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.

-There is also evidence that leptin plays a role in hyperemesis gravidarum (severe

morning sickness) and in polycystic ovary syndrome.

8) Bone growth:

-In 2007 research suggests that hypothalamic leptin is implicated in bone growth. (14)

9) Leptin resistance and obesity -leptin&insulin:

Although leptin is a circulating signal that reduces appetite, in general, obese people

have 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 high sustained concentrations of leptin from



the enlarged adipose stores result in leptin desensitization. The pathway of leptin control

in obese people might be flawed at some point so the body doesn't adequately receive

the satiety feeling subsequent to eating. The absence of a 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.

This system is more sensitive to starvation than to overfeeding. That is, leptin levels donot rise extensively after overfeeding. (15)

In March 2010, researchers reported that mice with type 1 diabetes treated with leptin

alone or in conjunction with insulin did better (blood sugar didn't fluctuate as much,

cholesterol levels went down and they didn't form as much body fat) than mice with type

1 diabetes treated with insulin alone, raising the prospect of a new treatment for

diabetes. (16)

10) Role in disease:

High leptin expression was associated with an increased intratumour MVD (microvessel

density) and thus may be associated with HCC (hepatocellular carcinoma)development.

In addition, high leptin expression was a predictor for improved survival of patients with

HCC, treated postoperatively with MPA (medroxyprogesteron acetate). (17)

Function of ghrelin:

1) Stimulation of growth hormone secretion: control the timing and magnitude of growth

hormone secretion (the growth hormone secretagogues).

2) Regulation of energy balance: ghrelin functions to increase hunger , suppress fat

utilization in adipose tissue.

3) Is essential for cognitive adaptation to changing environments and the process of

learning.

4) Other effects of ghrelin include stimulating gastric emptying and having a variety of

positive effects on cardiovascular function (e.g. increased cardiac output). It is not

totally clear whether the cardiovascular effects are a direct effect of ghrelin or represent

an indirect effect of ghrelin's ability to stimulate growth hormone secretion.

5) known to be involved in reward systems (e.g. tegmental area); indeed, ghrelin appearsto activate some of the same circuits that are involved in drug reward.(18)

http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/gh.html






Blood concentrations of ghrelin are

lowest shortly after consumption of a

meal, then rise during the fast just prior to the next meal. The figure to

the right shows this pattern based onassays of plasma ghrelin in 10

humans during the course of a day.

Roles of Ghrelin:

1) Lung Development:In fetuses, it seems that ghrelin is early produced by the lung and promotes growth.

2) Learning and Memory:

Ghrelin may enter the hippocampus from the bloodstream, altering nerve-cell

connections, and so enhancing learning and memory. It is suggested that learning may

be best during the day and when the stomach is empty, since ghrelin levels are higher at

these times, and is essential for cognitive adaptation to changing environments and the

process of learning.

3) Stress-Induced Depression:

A study appearing in the journal Nature Neuroscience (June 15, 2008 online) suggests

that the hormone might help defend against symptoms of stress-induced depression and

anxiety.

4) Sleep-Duration:

That short sleep duration is associated with high levels of ghrelin and obesity; ghrelin

appears to be a factor contributing to the short sleep duration and obesity.

as the hours of sleep increase, ghrelin concentrations were considerably lower, thereby

potentially reducing appetite and avoiding potential obesity.

5) Role in Disease:

-Ghrelin levels in the plasma of obese individuals are lower than those in leaner

individuals.

-Those suffering from the eating disorder anorexia nervosa have high plasma level of

ghrelin compared to both the constitutionally thin and normal-weight controls.

-These findings suggest that ghrelin plays a role in both anorexia and obesity. Increased



levels of ghrelin boost production of dopamine, a neurotransmitter implicated in the

reward system associated with addictive behavior (Jerlhag et al., 2006). (19)

Inhibition of nicotinic receptors by injecting nicotinic acetylcholine antagonists would

decrease the effects of ghrelin. Similar to its involvement in other addictive behaviors,

ghrelin may be involved in compulsive eating via neurotransmitter and hormonal

pathways of the reward system (Jerlhag et al., 2006). Thus, it is proposed that psychopharmaceutical and clinical treatments might be developed to treat BN as an

addiction and target symptoms when ghrelin is more clearly understood.

-Ghrelin levels are also high in patients that have cancer-induced cachexia.

-Prader-Willi syndrome is also characterized by high fasting levels of ghrelin; here the

ghrelin levels are associated with high food intake.

-At least one study found that gastric bypass surgery not only reduces the gut's capacity

for food but also dramatically lowers ghrelin levels compared to both lean controls and

those that lost weight through dieting alone. (20)

All in all, both hunger hormone and satiety hormone are needed within our bodies, but

there must be found a balance in the amounts in which they are produced by the cells.Because when the levels of ghrelin are higher than common, it leads to obesity, but

when the levels of this troubling hunger hormone are lower than usual, it inhibits growth

and memory abilities.

- Ghrelin also appears to promote gastrointestinal and pancreatic malignancy. (21)

-Ghrelin may find application in slowing down the onset of Parkinson's disease. (22)

5) Role in the gastrointestinal tract:

-Suppresses the pro-inflammatory mechanisms and augments anti-inflammatory

mechanisms-.Ghrelin also enhances the motility of gastrointestinal tract.

-It has also been shown to have regenerative capacity and is beneficial in case of

mucosal injury to the stomach. (23)

Anti-obesity vaccine:

Recently, Scripps research scientists have developed an anti-obesity vaccine directed

against the hormone ghrelin(24).The antibodies prevents ghrelin from reaching the central

nervous system, thus producing a desired reduction in weight gain(under trial). (25)

Also, administration of recombinant human leptin (under trials).

Conclusion:-

-Logically, medical experts have linked ghrelin hormone to obesity and eating

disorders and the leptin hormone to lack of appetite disorders such as anorexia or other

diseases in which patients do not manifest any urge to eat, like when suffering from



various types of cancer, AIDS etc. That is why they thought that the treatment for the

two types of eating problems - eating too much or too less - should consists of

reversing the functions of the appetite hormones. Consequently, ghrelin should be used

to enhance hunger in those that are too skinny and lack the physiological need of

eating, while leptin should be used for making obese people eating less.

-All in all, both hunger hormone and satiety hormone are needed within our bodies, but

there must be found a balance in the amounts in which they are produced by the cells.

Because when the levels of ghrelin are higher than common, it leads to obesity, but

when the levels of this troubling hunger hormone are lower than usual, it inhibits growth

and memory abilities.

-More recent researches have provided us with even more surprising news: it seems

that, besides leptin, there is a second appetite-blocking hormone called obestatin.

Obestatin is another hormone found in our bodies that regulates hunger and, if found in

high levels, stops hunger sensation and transmits satiety signals to the brain. But the

novelty really consists in the fact that obestatin and ghrelin - the two completely

opposed hormones - are produced by the same kind of cells.

Anti- obesity vaccine still under trial.



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http://en.wikipedia.org/wiki/Leptin


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http://en.wikipedia.org/wiki/Leptin


http://content.nejm.org/cgi/content/short/346/21/1623



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UNIVERSITY OF ALEXANDRIA

HIGH INSTITUTE OF PUBLIC HEALTH

DEPARTMENT OF NUTRITION

ROLE OF LEPTIN AND GHRELIN IN NUTRITION

BY Samah Nafis

2009-2010

SUPERVISED BY :Dr/Dalia Tayel

Lecturer of nutrition

Leptin&Ghrelin

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