Week 2: Genetics of Obesity

Question 1

How does obesity result in CVD + diabetes

Answer 1

Once adipose tissue reaches maximum capacity, lipids “spill-over” into the circulation where free fatty acids enter other organs where it leads to inflammation + build up of harmful by-products of lipid metabolism + liver cirrhosis

Question 2

The 2 types of heritable obesity

Answer 2

• Monogenic
  + 1 gene affected
  + Can be syndromic or non-syndromic
  + Rare
• Polygenic
  + Multiple genes involved
  + Strong environmental influence

Question 3

Leptin gene

Answer 3

• Can cause severe obesity and is a product of the OB loci
• Leptin was released from adipose tissue, which was the first indication that adipose tissue was an endocrine organ
• Leptin can function to increase energy expenditure by raising body temperature apart from food intake

Question 4

Functional + Structural difference between brown + white adipocyte

Answer 4

• Brown adipose tissue produces heat + burn energy
• White adipose tissue functions to store energy
• Cold temperatures can increase brown adipose tissue thermogenesis activity in healthy lean individuals, but still unknown in obese people
• The process of browning recruits white adipose tissue into brown adipose tissue

Question 5

Leptin-melanovortin system mutations in Monogenic (non-syndromic) obesity

Answer 5

• LEP
• LEPR
• POMC
• MC4R
• PCSK1
• BDNF
• NTRK2
• SIM1
• All are involved in leptin-melanocortin pathway in hypothalamus
• These monogenic forms of obesity are all very rare + collectively account for only a small fraction of global cases of obesity

Question 6

Types of monogenic syndromic obesity

Answer 6

• Bardet-Biedl Syndrome
• Prader-Willi Syndrome
• Angelman’s Syndrome

Question 7

Bardet-Biedl Syndrome (BBS)

Answer 7

• Caused by several causal mutations at various loci
• Clilipopathic - Genetic multisystem disorder that affects ciliary structure + function
• Hypogonadism
• Early onset obesity
• Renal disease

Question 8

Prader-Willi Syndrome (PWS)

Answer 8

• Caused by paternal deletions of ch1511.2q12
• Affects 1/15000 births
• An imprinting disorder
• There is a deletion of the paternal allele of ch-15, resulting in no functional ch-15, can also result in 2 copies of maternal ch-15. Healthy individuals will normally have mother’s genes silenced
• Typical signs are:
  + Short stature, hyperphagia, cognitive deficits, mental, social + behavioural problems + severe obesity

Question 9

Angelman’s Syndrome

Answer 9

• SNRPN/SNURF genes affected
• Genetic disorder affecting the nervous system
• Manifests in childhood
• Distinct facial + behaviourial features + developmental + intellectual disability
• Imprinting disorder in the same region as PWS
• Heritability similar to PWS except that cause is often maternal deletion of ch-15, paternal genes are silenced
• Overlap in features with PWS but also distinct