Genetic Determinants of Obesity Flashcards
What is obesity?
A metabolic disorder which is consequence of an imbalance between energy intake and usage.
What is obesity a risk factor for?
Cardiovascular diseases
Type 2 Diabetes
Several cancers
What are some causes of obesity?
– Genetic
– Epigenetic
– Environmental
What are the obesity-related traits?
– ↑BMI (Body Mass Index)
– Unhealthy weight gain
– ↑waist circumference
– Excess of body fat
What is dylipidemia?
High cholesterol
What is hypertension?
High blood pressure
What is BMI?
mass (kg) / height (m2)
What is considered underweight?
Less than 18.5
What is considered a healthy BMI?
18.5-25
What is considered an overweight BMI?
25-30
What is considered an obese BMI?
More than 30.
What is the correlation between BMI and obesity?
A high BMI increases cancer risk.
How is obesity an adaptive response?
An adaptive response to famine, analogous to fat storage observed in other animals in preparation for periods of food scarcity.
How was obesity proved to most probably not be positive selection?
In Western world despite plenty food supply, ~70% population not obese.
What is the evidence for genetic contribution for obesity?
Inter-individual variation on BMI and body fatness
Animal model: ob/ob mice
What kind of people were used in Inter-individual variation on BMI and body fatness tests?
Twins, adoptees and
family.
What percentage of obesity was proved to be down to genetics through inter-individual variation?
25-40%
What percentage of obesity was proved to be down to non-hereditary factors through inter-individual variation?
60 – 75%
What was the major breakthrough found through the use of animal models on obesity?
Mutation of the ob (obese) gene results in severe obesity and type 2 diabetes.
What is the ob gene?
Leptin
What is the role of leptin?
Decreases appetite, body fat stores & insulin production.
What is Leptin?
Satiety hormone.
Where is Leptin produced?
Adipose tissue.
Where is the adipose tissue?
Body Fat
What are the 2 main types of obesity?
Monogenic
Polygenic
What is monogenic obesity?
Mendelian obesity, is inherited through a gene mutation.
What is polygenic obesity?
Common obesity.
How common is monogenic obesity?
Rare
When does monogenic obesity start?
Early onset (childhood)
When does polygenic obesity start?
Later onset
What causes polygenic obesity?
Environment and slightly SNPs.
How do monogenic mutations lead to obesity?
Defect in the satiety centres in the brain
Defect in the appetite control centres in the brain
What does a defect in the satiety centres in the brain lead to?
Loss of Leptin signalling.
What is Congenital Leptin Deficiency?
Extremely rare mutations in the LEP gene– no leptin.
What is Leptin Receptor deficiency?
Rare mutations in LEPR gene – no response to leptin
What kind of inheritance do monogenic obesity diseases follow?
Autosomal recessive.
What is the consequence of Loss of Leptin signalling?
Excessive hunger leads to severe obesity
Decrease in the production of hormones directing sexual development and reproductive function
Hyperinsulinemia
What is Hyperinsulinemia?
Insulin Resistance
What do monogenic mutations that lead to a defect in the brain appetite control centres?
POMC pathway defects.
What is the POMC pathway?
The melanocortin pathway
The fed state is signalled by the abundance of circulating hormones such as leptin and insulin
Bind to receptors expressed at the surface of pro-opiomelanocortin (POMC) neurons to promote the processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH).
What is ACTH?
Adrenocorticotropic hormone
What is the role of ACTH?
Stimulates cortisol release by adrenal glands
What are α-MSH and β-MSH?
Melanocyte-stimulating hormone
What is the role of α-MSH and β-MSH?
Weight regulation & energy balance maintenance
Skin pigmentation (melanin production)
What are β-endorphin?
Endogenous opiates
What are Met-encephalin?
Endogenous opiates
What is POMC?
Proopiomelano cortin
What is the role of POMC?
Extensively cleave into multiple peptide hormones
What happens when mutations occur in POMC?
Damaged versions or absence of POMC
Decreased levels (or loss) of ACTH, α-MSH, and β-MSH
Dysregulation of body’s energy balance
Excessive hunger→ excessive feeding & severe
obesity
What happens when an individual has POMC deficiency?
An autosomal recessive disorder causing severe obesity, red hair and pale skin.
What are POMC-neurons activated by?
Leptin and Insulin
What is the role POMC-neurones produce?
Produce α-MSH which activates melanocortin (MC4R & MC3R) receptors & increase the satiety signal.
What is the role of Neurons (NPY /AGRP)?
Express NPY & AGRP
Inhibit MC4R and POMC neurons signalling resulting in an increased appetite.
What is NPY?
Neuropeptide Y
What is AGRP?
Agouti-related protein
What are Neurons (NPY/AGRP) activated by?
Ghrelin (‘hunger hormone’)
How is leptin affected in mendelian obesity?
Mutations reduce signalling
Obesity Leptin gene affected and there’s a decrease in circulating leptin
LEPR gene which is resistance to leptin
How is Leptin affected in common/polygenic obesity?
High circulating concentrations of leptin and are ‘leptin resistant’.
This means there is an issue with access to the brain or of downstream signalling
pathway.
What genetics association in common obesity?
Genetic associations exist between candidate genes and obesity-related phenotypes.
What SNPs involved in the leptin/melanocortin pathway have a positive genetic association with the risk of obesity?
- AGRP
- LEPR
- MC4R
- NPY
- POMC
What is the fat mass and obesity-associated protein?
mRNA demethylase
Where is the FTO?
Highly expressed in hypothalamus
What is the SNP(rs9939609) in FTO gene, risk allele linked to?
Decrease in Satiety
Increase in food intake
Increase Ghrelin expression and leptin resistance
What is an Odds ratio?
Relative probabilities of the occurrence of the outcome given a particular genotype for an SNP.
