The effects of Ghrelin and Leptin hormones in body weight

1. Ghrelin and Leptin
hormones
By:
Zeravan Ali

2. • Introduction.
• Ghrelin.
 Structure of ghrelin.
 Actions of Ghrelin.
 Biological functions of ghrelin.
 Ghrelin Diagnostic Test.
• Leptin.
 Biological functions of leptin.
 Leptin deficiency.
 Leptin resistance.
 Leptin Diagnostic Test
• References.
Contents:

3. Introduction:
• Ghrelin and leptin are two hormones which are of great
interest in appetite regulation.
• Leptin is commonly considered to be anorexigenic (i.e.
appetite inhibit) while ghrelin is orexigenic (i.e. appetite
stimulant).
• They are secreted in a reciprocal rhythm, influenced by the
neuropeptide Y (NPY) system in the hypothalamus which
is acted upon by these afferent hormones. This highly
specific system shows rhythmic secretion, imparting in turn
the same pattern to the expression of appetite and feeding
behavior.

4. Introduction:

5. Ghrelin:
• Ghrelin is a 28-amino-acid peptide hormone first described
in 1999 as the endogenous ligand of the growth hormone
secretagogue receptor (GHSR; ghrelin receptor).
• Endocrine cells lining the stomach and proximal small
intestine serve as the source of most of the ghrelin that
circulates in the blood.
• In the stomach, cells that
secrete ghrelin include the
P/D1 cells in the fundus or
upper part of the stomach.

6. • Ghrelin is one of the main hormones to stimulate hunger.
Ghrelin levels increase before meals and decrease after
meals, a mechanism that has its roots in the hypothalamus.
• If the lateral hypothalamus (LH) is removed, feeding
becomes less frequent leading to severe weight loss and
death. If the ventromedial hypothalamus (VMH) is
removed, feeding increases, leading to weight gain and
severe obesity.
Ghrelin:

7. • Approximately 60–70 % of circulating ghrelin is
secreted by the stomach, with most of the remainder
originating in the small intestine.
• Low-level ghrelin expression also occurs in several
tissues outside the gut, including hypothalamus
(arcuate nucleus and paraventricular nucleus),
pituitary, lung, adrenal cortex, kidney, bone, testis,
placenta and pancreatic islet cells.
Ghrelin:

8. Ghrelin:
• When you have not eaten in some time, your stomach
releases ghrelin. Ghrelin then acts on your stomach itself
and empties it further. Once your stomach is empty, it
signals your brain that now is the time to fill up your
stomach.
• Ghrelin is high before you eat and low after you eat. If
you want to lose weight you want less ghrelin, so you don’t
get hungry. If you want to gain weight, then you want more
ghrelin.
• Ghrelin stimulates food intake, exerts adipogenic activity
and is involved in the long-term regulation of body weight.

9. Ghrelin and appetite:

10. • Ghrelin is a 28-amino acid
peptide existing in two major
forms: n-octanoyl-modified
ghrelin, which possesses an
n-octanoyl modification on
serine-3.
• a second type of ghrelin
peptide has been purified
and identified as des-Gln14-
ghrelin Figure: Structure of human ghrelin and
the modification process of octanoic
acid by GOAT.
Structure of ghrelin:

11. Structure of ghrelin:
Amino acid residues: A, Ala; C, Cys; D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile;
K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val;
W, Trp; Y, Tyr.

12. acylated and unacylated ghrelin:
• Acylated ghrelin (AG), usually referred to as ghrelin, has
been considered the only active form of the peptide. It
recognizes the Gq-coupled growth hormone secretagogue
receptor type 1a, denoted as GHS-R1a, mediating its
growth hormone–releasing properties as well as other
significant neuroendocrine actions. In contrast, unacylated
ghrelin (UAG) does not bind the GHSR1a and is devoid of
growth hormone secretagogue activity.
• AG reduces insulin sensitivity and exerts orexigenic
activity, whereas UAG has opposite effects

13. Regulation of energy homeostasis:
• There are two systems that operate in the regulation of the
quantity of food intake:
1. Short-term regulation: is concerned primarily with preventing
overeating at each meal, Signals from gastrointestinal [GI] tract
and the liver are involved in short-term regulation of feeding.
2. Long-term regulation: is primarily related with the
maintenance of normal quantities of energy stores in the form of
fat in the body. Insulin and leptin are the two most important
long-term regulators of food intake and energy balance.

14. Ghrelin Synaptic Signaling:
• Ghrelin signaling is strongly linked to alterations in synaptic
function in circuits regulating homeostatic, hedonic and
cognitive aspects of feeding behavior.
• The regulation of feeding by the brain suggests that nutrients
and peripheral signals released in the blood, such as glucose,
free fatty acids, leptin, insulin and ghrelin can sense the energy
status and reach the brain, where they modulate the activity of
several neuronal circuits.
• Ghrelin is an orexigenic hormone affecting both energy
homeostasis and higher brain functions. Ghrelin affects feeding-
associated behaviors, which are accompanied by changes in
synaptic strength and in the modulation of neuronal circuit
function, a phenomenon termed synaptic plasticity.

15. Actions of Ghrelin:
• There are several notable actions that ghrelin has on a
human body:
1. It regulates the blood glucose levels through reduced insulin
secretion and by regulating the synthesis and breakdown of
glucose and glycogen.
2. It reduces heat production to conserve energy.
3. It reduces sympathetic activity.
4. It promotes the differentiation and fusion of muscle fibers.
5. It plays a role in regulating bone growth through osteoblast
differentiation and proliferation, a role in bone protection, and
has an opposing role to leptin in bone metabolism.
6. It is also highly expressed in metastatic cancer cells.

16. Biological functions of ghrelin:
• Regulation of energy expenditure.
• Regulation of appetite and energy homeostats.
• Regulation of gastric secretion and emptying.
• Regulation of glucose metabolism.
• Regulation of insulin secretion.
• Regulation of vascular tone in heart.
• Regulation of apoptosis and regulation of cell proliferation
and differentiation.
• Influences on gonadal axis.

17. Ghrelin Diagnostic Test:
• Serum ghrelin levels can be analyzed by enzyme-linked
immunosorbent assay (ELISA) technique, and urine ghrelin
levels can be studied by validation technique.
• Its levels increase during periods of low food intake, such
as during fasting, starvation, and anorexia. The levels are
decreased in obesity or hyperglycemia too.
Key features and details:
• One-wash 90 minute
protocol
• Range: 1.95 pg/ml - 125
pg/ml
• Sample type: Serum
• Detection method:
Colorimetric
• Assay type: Sandwich
(quantitative)

18. What are the Clinical Indications for
performing the Ghrelin Blood Test?
• Following are the clinical indications for performing the
Ghrelin Blood Test:
 Gastric bypass surgery.
 Monitoring obesity.
 Rapid weight loss or weight gain.
 Suspected anorexia nervosa
Ghrelin Diagnostic Test:

19. What is the Significance of the Ghrelin
Blood Test Result?
• A high value for the Ghrelin Blood Test (greater than 650
pg/mL) may indicate:
Fasting.
Cachexia.
Anorexia.
• Certain factors interfere with the results of the Ghrelin
Blood Test and it includes the recent consumption of a
meal.
Ghrelin Diagnostic Test:

20. Leptin:
• Leptin (from the Greek word leptos, meaning “thin”) is
derived from the lep gene, located on chromosome 7, which
transcribes a 167 amino acid peptide with a molecular
weight of 16 kilodalton (kD).
• Leptin, the protein hormone, was first discovered in 1994.
It is produced by fat cells-adipocytes , and it signals the
brain to tell you when to stop eating.
• When leptin is released, it is secreted into the blood,
whereby it travels to a region of the brain called the
hypothalamus. There then begins a cascade of events that is
meant to reduce food intake.

21. • Within your hypothalamus, leptin signals that you have
eaten enough and now is the time to stop. It also boosts
your metabolism and makes you burn more calories than
usual.
• Circulating leptin levels positively reflect adipose tissue
size, and communicate energy storage status to the brain.
Leptin expression and circulating levels show circadian
fluctuations, and also change with nutritional state.
• Fasting decreases circulating leptin levels, while feeding
or obesity increases leptin levels.
Leptin:

23. • Leptin expression and secretion are regulated by many
factors, e.g. inflammatory cytokines, glucocorticoids and
insulin.
• There is a direct link between the amount of body fat you
have and leptin levels. The bigger your fat stores; the
higher the levels of leptin in your body. Thus, the obese
people feel less hungry.
Leptin:

24. Biological functions of leptin:
• Leptin is best known for its long-term regulation of body
weight and as an adaptive response to fasting and
starvation.
• Loss-of-function mutations in the leptin or leptin receptor
(LEPR) genes (like the ob and db mutation) not only cause
severe obesity but also abnormalities in:
 Hematopoiesis.
 Immunity.
 Reproduction.
 Bone metabolism.
 Blood pressure

25. • So Leptin has been implicated in the regulation of
the immune system, autonomic and cardiovascular
regulation, reproductive function and bone
formation.
Biological functions of leptin:

26. Leptin deficiency:
• Leptin deficiency or resistance can result in profound
obesity, diabetes, and infertility in humans.
• Leptin deficiency is a clinical syndrome associated with
distinct phenotypes, which include a very small subset of
obesity (i.e. those from leptin-related gene mutations),
hypothalamic amenorrhea, and lipoatrophy.
• Leptin deficiency reduces the immune system response,
decreases sympathetic nervous system activity and blood
pressure, delays puberty and can lead to infertility, in
addition to reducing bone density.

27. Leptin resistance in obesity:
• When your brain doesn’t receive the leptin signal, it
incorrectly thinks that your body is starving — even though
it has more than enough energy stored.
• Leptin resistance is the failure of high levels of leptin in
obese individuals to suppress feeding and prevent or
mitigate obesity
• Obesity is associated with leptin resistance, a phenomenon
that is similar to insulin resistance in patients with type 2
diabetes mellitus.
• Leptin resistance is associated with elevated circulating
levels of leptin, as well as with the inability of exogenous
leptin to decrease food intake and body weight.

28. What Causes Leptin Resistance?
• Several potential mechanisms behind leptin resistance have
been identified. These include:
– Inflammation: Inflammatory signaling in your hypothalamus is
likely an important cause of leptin resistance in both animals and
humans.
– Free fatty acids: Having elevated free fatty acids in your
bloodstream may increase fat metabolites in your brain and
interfere with leptin signaling.
– Having high leptin: Having elevated levels of leptin in the first
place seems to cause leptin resistance.

29. Can Leptin Resistance Be Reversed?
• Some researchers believe that reducing diet-induced inflammation
may help reverse leptin resistance. There are several things you can
do:
 Avoid processed food: Highly processed foods may compromise
the integrity of your gut and drive inflammation.
 Eat soluble fiber: Eating soluble fiber can help improve your gut
health and may protect against obesity.
 Exercise: Physical activity may help reverse leptin resistance.
 Sleep: Poor sleep is implicated in problems with leptin.
 Lower your triglycerides: Having high triglycerides can prevent
the transport of leptin from your blood to your brain. The best way
to lower triglycerides is to reduce your carbohydrates intake.
 Eat protein: Eating plenty of protein can cause automatic weight
loss, which may result from an improvement in leptin sensitivity.

30. • Quantitative determination of leptin in human serum can be
done by an enzyme immunoassay (EIA) method such as
leptin ELISA test follows a typical two-step capture or
‘sandwich’ type assay.
• Specimen: Serum or plasma.
• Sample container: Red-top tube, gel-barrier tube, or
(EDTA) tube.
• Expected normal values: Women = 3.7-11.1 ng/mL,
Men = 2.0-5.6 ng/mL.
• Leptin values are approximately 2.5 times higher in women
than men Body Mass Index (BMI).
Leptin Diagnostic Test:

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Leptin resistance and obesity. Obesity, 14(S8), pp.254S-258S.
3. Kelesidis, T., Kelesidis, I., Chou, S. and Mantzoros, C.S., 2010.
Narrative review: the role of leptin in human physiology: emerging
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4. Myers, M.G., Cowley, M.A. and Münzberg, H., 2008. Mechanisms
of leptin action and leptin resistance. Annu. Rev. Physiol., 70,
pp.537-556.
References: