Week 7- Etiology and development of Obesity

Question 1

BMI definitions

Answer 1

BMI

Status

<18.5

Underweight

18.5-25

Normal

25-30

Overweight

30-40

Obese

>40

Morbidly obese

Question 2

is BMI a good population screening tool?

Answer 2

It is a good average population screening tool.

• Has its disadvantages however as people with muscle mass do thus have a higher BMI

Question 3

the trend in global prevalence of obesity and overweight status

Answer 3

The global prevalence of overweight and obesity is rapidly escalating irrespective of the amount of development a country has seen

• Has been escalating since 1975

Question 4

obesity is the — highest risk factor of death. what other factors that are linked to obesity and how are they ranked

Answer 4

5th

• Diet low in fruit ranked 10th also linked to obesity
• Diet low in nuts and seeds ranked 11^th also linekd to obesity
• Diet low in vegetables ranked 13^th also linekd to obesity

Question 5

is obesity a disease?

Answer 5

yes it is now

Question 6

for the first time in 2 centuries….

Answer 6

CHILDREN HAVE A SHORTER EXPECTED LIFE EXPECTANCY THAN THEIR PARENTS, WHICH CONTENDS THAT THE RAPID INCREASE IN CHILDHOOD OBESITY, IF LEFT UNCHECKED, COULD SHORTEN LIFE SPANS BY AS MUCH AS 5 YEARS.

Question 7

the effects of an increase in childhood obesity

Answer 7

• With this increase we are also seeing an increase metabolic syndrome in children
  
  • Metabolic dysfunction at a young age predisposes them to the development of metabolic disease when older.

Question 8

% of children in Aus between 2-4 who are overweight

Answer 8

30

Question 9

is obesity more common in one sex?

Answer 9

yes, more in males- we do see sexual dimorphism here event at a young age

Question 10

Factors that impact obesity prevalence?

Answer 10

• Genetics/Epigenetics
  
  • Largely contribute to weight conformation.
• Lifestyle eating/ exercise patterns
  
  • Interacts with genetics to create resistant/ susceptible phenotype
• Socioeconomic Status
  
  • Increased prevalence of obesity in lower socioeconomic area
    
    • Linked to fact food
• Psychological factors
• Cultural background
• Age
  
  • Endocrine changes occur as we get older make us more likely to gain weight
    
    • E.g. less estrogen because of menopausal transition
• Hormonal, metabolic, physiological factors
• Sleep disturbances
  
  • In shift workers there is an increased prevalence of metabolic diseases, this increases likelihood of gaining weight

Question 11

Body composition has been seen to be —% heritable

Answer 11

~70%

Question 12

is the determination of body compositon monogenic or polygenic ?

Answer 12

polygenic, more than 600 genes contribute

Question 13

How heritable is BMI?

Answer 13

Reltively high, 50-90% heritable

Question 14

Evidence seen in Genetic selectio studies for obesity

Answer 14

we do see a genetic linkage. can be seen through the creation of lineages for favourable cattle/livestock traits which shows heritbaility

Question 15

monogenic forms of obesity are…

Answer 15

relatively rare

Question 16

Prader-Willi Syndrome

Answer 16

• Most known monogenic cause of syndromic obesity
  
  • Due to lack of expression of 15q11-q13 genes on paternal chromosome
• Increased accumulation of adipose tissue in abdominal visceral area
• Truncal obesity is associated with metabolic dysfunction

Question 17

% genetic causes of PWS

Answer 17

• 65%-75% of cases are de novo
  
  • De novo microdeletion of 15q11-q13 genes on paternal chromosome
• 20%-30% are because of maternal uniparental disomy
  
  • 2 maternal chromosomes, none from father
  • Associated with advanced maternal age
• 2-5% are because of imprinting error

Question 18

Symptoms of PWS

Answer 18

• Hypotonia
  
  • Weak muscle tone and floppiness at birth( enough for diagnosis at birth)
• Hypogonadism
  
  • Immature dev of the sexual organs and other sexual characteristics
• Obesity
  
  • Because of hyperphagia AND decreased caloric requirement because of lower energy expenditure
• CNS and endocrine gland dysfucntion
  
  • Causing carrying degrees of learning disability
  • Short stature
  • Hyperphagia
  • Somnolence(excessive sleepiness)
  • Poor emotional and social development

Question 19

Ghrelin in PWS children

Answer 19

Children with Prader-Willi have increased ghrelin levels, significant findings.

• Ghrelin is the only bodily hormone that increases food intake

Question 20

Mutations in the ob gene lead to…

• lack of function leptin

Answer 20

lack of functional leptin.

• This causes…
  
  • Profound obesity
  • Glucose intolerance/ insulin resistance
    
    • T2DM
  • Infertility
  • Cold intolerance
    
    • Because leptin is involved in energy expenditure
  • Immune dysfunction
  • No circulating leptin levels

Question 21

Leptin

Answer 21

• 16kDa encoded by ob gene
• Produced by fat cells
• Directly proportional to the total amount of fat in the body
• Informs the brain how much fat is contained in the body

Question 22

Why is leptin not a good weight loss agent?

Answer 22

When individuals become obese, they lose the ability to respond to leptin and become resistant. This is why leptin is not an effective weight loss agent.

Question 24

Congenital leptin deficiency in humans( effects ans treatments)

Answer 24

• Leads to a rapid gain in body weight early in life
• Treatment: human recombinant leptin treatment.
  
  • Can restore body weight to normal with therapy

Question 25

The effects of a leptin deficiency

Answer 25

Without leptin the body believes it is constantly in a state of starvation or there is an absence of fat stores. This signals to the brain to increase food intake and reduce energy expenditure * No satiation leads to patients eating uncontrollably * Leads to profound morbid obesity * Body weight can be restored with leptin replacement

Question 26

Mutations in Leptin Receptor

Answer 26

Mutations in the LepR often result in early onset of obesity * Marked increase in body weight even in childhood * Treatment: can place on weight loss therapy * Works for a bit but very hard to sustain * Causes increasing levels of leptin * The brain continues to produce it despite not responding * Individuals DO NOT respond to exogenous leptin therapy

Question 27

What to do about patients with typical idiopathic obesity?

Answer 27

We think there is a gene and environemnt interaction that causes obesity * There is a bodily set point determined by our environemnt and genetics * it has been found that when we eat too little or too much there is compensatory chnages in energy expenditure which occur to remain at the set point * Eat too much: increase in EE, temporary * Eat too little: reduction in EE, lasts longer as we are wired to prevent weight loss

Question 28

is set point plastic?

Answer 28

Set point occurs in adults and cannot be changed in adulthood but it is not present in adolescents * In pre pubertal children we can re-establish and rest the set point

Question 29

How do we identify susceptibility genes?

Answer 29

* Through genome wide association studies/ GWAS * Examination of a genome wide set of genetic variants in different individuals to see if nay variant is associated with the trait * Primarily investigates SNPs and how they are related to the phenotype of obesity * From this the first gene known to contribute to common obesity was found(FTO)

Question 30

what is FTO and how was it found?

Answer 30

* FTO gene “fat mass and obesity associated gene” * First screening study was done in… * 4000 individuals * Identified FTO gene in all samples * A variant was found when a single nucleotide changes * When the individual has 2 copies of the variant FTO they were 1.67 x more likely to be obese

Question 31

Overexpression of FTO in mice lead to

Answer 31

* Increased body weight * Drastically increased fat mass * Increased food intake * Increased preference of higher calorie foods * Reduced physical activity and energy expenditure * Impaired browning of WAT

Question 32

Several different variants in FTO have been linked to...

Answer 32

obesity onset, ghrelin and impaired food-cure responsivity