Al Ain university of science and technology

College of pharmacy
Biochemistry
First semester 2018-2019

Leptin Hormone

Done By: Marah Almahameed 201710180

Aya Adnan 201710174
Under Supervision of : Dr. Rose Ghemrawi &
Dr. Nezar ABataineh
 Introduction
• For patients struggling with obesity and weight,
hormones often affect their overall health. Excess
body fat can cause problems with weight and
hormonal issues. Leptin is one of the hormones
directly connected to body fat and obesity.
 What is Leptin?
• Leptin is a hormone secreted from fat cells located in the adipose tissue, that helps
to regulate body weight.
• It is often referred to as the "satiety hormone" or the "starvation hormone.“
• Leptin's primary target is in the brain, particularly an area called the
hypothalamus.
• The name leptin is derived from the Greek word 'leptos' meaning thin. It is
sometimes referred to as the 'Fat Controller'.

• Because it comes from fat cells, leptin amounts are directly connected to
an individual’s amount of body fat.
• If the individual adds body fat, leptin levels will increase.
• If an individual lowers body fat percentages, the leptin will decrease as
well.
 Leptin structure
• Leptin is made up of 4 alpha helices that are connected by loops.
• The AB Loop connects the A and B helices, BC loop connects the B and C helices and the CD loop connects the
C and D helices.
• The AB loop is an extended loop, which passes in front of the D helix, that allows the B helix to run in the same
direction as the A helix.
• The BC loop is short and allows for the BC stack of helices to be anti parallel.
• The CD loop is another extended loop that allows the C and D helices to extend in the downward direction. The
CD loop also contains helix E, a short and distorted helix.
 What types of hormones leptin is?
• Hormones can be grouped into three main types:
1. amines, these are simple molecules.
2. proteins and peptides which are made from chains of amino acids.
3. steroids which are derived from cholesterol.

• Leptin is a peptide hormone from adipocytes.

• The peptide leptin, secreted into blood, consists of 145 amino acid
residues and results from the cleavage of a signal peptide off the ob
protein.
• Leptin was obtained by genetic engineering methods.
 Leptin signaling pathways

• The binding of leptin to the long isoform of leptin receptor (LepRb) results in its dimerization, leading to
the formation of the LepRb/Janus kinase 2 (JAK2) complex. The activated JAK2 phosphorylates itself and
also Tyr-985genes, which mediate leptin's anorexigenic effect. Suppressor of cytokine signaling 3 (SOCS3), a
target gene of STAT3, inhibits the JAK2/STAT3 pathway by interacting with phospho-Tyr985 or JAK2 and
acting as a feedback inhibitor of leptin signaling. Protein tyrosine phosphatase 1B (PTP1B) also inhibits
leptin signaling through dephosphorylation of JAK2. After JAK2 activation, SH2-containing protein
tyrosine phosphatase 2 (SHP2) binds to phospho-Tyr985 in the LepRb and recruits the adaptor protein
growth factor receptor-bound protein 2 (Grb2), leading to activation of the mitogen-activated protein
kinase (MAPK) signaling cascade. Leptin activates MAPK independent of SHP2 and also regulates
phosphatidylinositol 3 kinase (PI3K) signaling through insulin receptor substrate (IRS) phosphorylation.
Forkhead box O1 (FoxO1), mammalian target of rapamycin (mTOR), and phosphodiesterase 3B (PDE3B)
are important downstream targets of PI3K in the leptin signaling pathway. Leptin regulates feeding and
metabolism through 5' adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA
carboxylase (ACC) in the brain and peripheral organs.
 How does leptin hormone works?

• This hormone is produced by the body's fat cells. The more body fat
they carry, the more leptin they produce.
• Leptin is carried by the bloodstream and into the brain, where it sends
a signal to the hypothalamus, the brain area that controls when and
how much we eat.
• The fat cells use leptin to "tell" the brain how much body fat they carry.
Lots of leptin tells the brain that we have plenty of fat stored, while low
levels of leptin tell the brain that fat stores are low and that we are at
risk of starvation.
 Leptin Resistance
• May Be The Main Biological Abnormality in Obesity, People who are obese
have a lot of body fat in their fat cells.
• Because fat cells produce leptin in proportion to their size, obese people also
have very high levels of leptin.
• Given the way leptin is supposed to work, these people shouldn't be eating
more, their brain should know that they have plenty of energy stored.
• However, the problem is that the leptin signal isn't working, there’s a whole
ton of leptin floating around, but the brain doesn't "see" that it is there.
• This condition is known as leptin resistance. It is now believed to be the
main biological abnormality in human obesity.
• When the brain doesn't receive the leptin signal, it erroneously thinks that
the body is starving, even though it has more than enough energy stored.
• This makes the brain change our physiology and behavior in order to regain
the fat that the brain thinks we're missing.
• Eating more: The brain thinks that we MUST eat so that we don't starve to
death.
• Reduced energy expenditure: The brain thinks we need to conserve energy, so
it makes us feel lazier and makes us burn fewer calories at rest.
• In this way, eating more and exercising less is not the cause of weight gain, it
is the consequence of leptin resistance, a hormonal defect.
• Losing Weight Reduces Leptin, so The Brain Tries to Gain The
Weight Back
• Most "diets" don't provide good long-term results. This is a well
known problem in weight loss studies
• Losing weight reduces fat mass, When leptin goes down, this leads
to hunger, increased appetite, reduced motivation to exercise and
decreased amount of calories burned at rest.
• Basically, the reduced leptin makes the brain think it is starving, so
it initiates all sorts of powerful mechanisms to regain that lost body
fat, erroneously thinking that it is protecting us from starvation.
• This is the main reason so many people "yo-yo" diet, they
lose a significant amount of weight, only to gain it back
(and then some).
 What Causes Leptin Resistance?
 1. Inflammation: Inflammatory signaling in the hypothalamus is likely an
important cause of leptin resistance in both animals and humans.
 2. Free fatty acids: Having elevated free fatty acids in the bloodstream may
increase fat metabolites in the brain.
 3. Having high leptin: Having elevated levels of leptin in the first place seems to
cause leptin resistance.
 Leptin signaling and Alzheimer's disease
• Epidemiological studies have demonstrated that higher circulating leptin
levels are associated with lower risk of dementia including Alzheimer's
disease, and lower circulating levels of leptin have been reported in
patients with Alzheimer's disease.
• Hippocampus, is a major component of the brain of humans and
other vertebrates.
• In Alzheimer's disease (and other forms of dementia), the hippocampus is
one of the first regions of the brain to suffer damage; short-term memory
loss and disorientation are included among the early symptoms. Damage
to the hippocampus can also result from oxygen starvation (hypoxia),
encephalitis. People with extensive, bilateral hippocampal damage may
experience anterograde amnesia (the inability to form and retain new
memories).
• Alzheimer's disease (AD) is the most common cause of progressive dementia
in the elderly population.
• AD is histologically characterized by accumulation of amyloid-β protein (Aβ)
on extracellular plaques and deposition of hyperphosphorylated tau protein.
• excess Aβ causes dysfunction in hypothalamic arcuate NPY neurons and
possibly other leptin-responsive neurons to disrupt the efferent signal
regulating body weight. This ultimately results in decreased adiposity and a
state of pathologically low levels which may decrease leptin's potential
procognitive and neuroprotective effects against Aβ toxicity in the cortex and
hippocampusof plasma leptin.
 Leptin and cardiovascular disease

• Obesity and excess of adipose tissue are associated with

the development of cardiovascular risk factors such as
diabetes, hypertension, and hyperlipidemia.
• Abundant evidence shows that obesity is associated with
structural and functional changes in the heart
characterized by left ventricular (LV) hypertrophy, left
atrial enlargement, and impairment of LV systolic and
diastolic functions, which are believed to be precursors
to more overt forms of cardiac dysfunction and heart
failure.
 How to regulate your leptin levels?
1. Say no to sugar.
2. Get enough protein and fat.
3. Get regular sleep.
4. Spend time in nature.
5. DON'T SNACK!!!
6. Don't workout at first.
7. Change how you exercise.
8. Detox.
9. Increase omega-3, lower omega-6.
 Conclusion
• Obesity is not caused by greed, laziness or a lack of willpower.
• There are strong biochemical forces at play, which are mostly
driven by changes in the environment, and particularly
the Western diet.
• The truth is everywhere this diet goes, obesity and chronic disease
follows.
• Not because this diet turns people into gluttons and sloths, but
because it alters our biology in a way that changes our behavior.
• Although the causes of obesity are complicated and diverse, leptin
resistance is the main reason people gain weight and have such a
hard time losing it.