Lecture 26; Obesity and Genetics Flashcards
What is Obesity?
The excess accumulation of fat mass.
This lecture focuses on why this occurs
What causes obesity?
Obesity results from the complex interaction of environmental factors that act on genetic background that determine the susceptibility to obesity.
What did the genetics study regarding adopted children show?
Genetics plays a powerful role in obesity, its not all about will power
- This study showed that weight of a child had stronger correlation with the biological parents and even strong with biological sibling that adoptee parents and family
- Estimated that 70% of obesity is genetic
What happened when they studied twins and obesity?
Univariate analyses showed that genetic influences a high heritability for height and weight and moderate heritability for metabolic rate.
“Twin studies suggest a heritability of fat mass of between 40 and 70% with a concordance of 0.7-0.9 between monozygotic twins compared with 0.35 -0.45 between dizygotic twins.”
What is the heritability of obese genes?
Strong evidence of genetic influence on human obesity has been obtained from studies on twins and adoptees. These studies provide compelling evidence that the resemblance of adult family members in body mass index is due more to shared genes than to shared rearing environment.
What are the possible models of spontaneous obesity mutations?
Five known, four regulate the Melanocortin leptin axis;
1) Ob/Ob - No leptin produced
2) db/db mice and Fa/fa rats = defective leptin receptor
3) Agouti - Antagonist ectopic MSH
4) Fat/fat = Enzyme (cpe) Modifies post translational peptides esp. imp. in prohormones
Not on the MLA;
5) Tub/Tub = GPCR - gene transcription
How did the ob/ob mouse model impact out understanding of obesity?
It was shown that it caused obesity when the mutation caused no leptin production.
BUT useless as only 2-3 families in the world have this
Describe what happened to the 2-3 families with the ob/ob mutaiton;
= Congenital Leptin Deficiency
Three unrelated probands (ages 2,3 and 9 yr) with undetectable plasma leptin
All have severe early-onset obesity, hyperphagia
All are consanguineous offspring of parents of Pakistani origin
All homozygous for Δ133G frameshift
What is the agouti mouse model?
Ectopic production of agouti protein antagonises α-MSH -
• in skin to give a yellow coat colour
• in brain at the MC4R to give obesity
Is agouti produced in humans?
Homology search for proteins similar to agouti protein identified Agouti- related peptide known as AgRP
AgRP is a natural antagonist for MC4R and MC3R in the brain
Therefore what did the agouti mouse model tell us?
That MC4R is important in body weight regulation
The Melanocortin System plays a pivotal role in energy homeostasis.
What did the agouti mouse models lead researchers to do?
Knockout more receptors in the melanocortin pathway.
Produced lots of obese mice however… in reality there are very few mutations in receptor genes in humans, so what about that pathways?
How many morbidly obese children have mutation in the MC4R?
~5% morbidly obese children have point mutations in one allele
What did POMC gene defects do to mice?
- Obese
- Hyperphagic
- Pigmentation
- Glucocorticoid deficient
- Not diabetic
- No glucose produced in response to hypoglycemia
What did POMC gene defects do to humans?
• Obese • Hyperphagic • Pigmentation (fair) • Glucocorticoid deficient - monogenetic (rare)
very rare, meant no ACTH production thus all must be treated with glucocorticoids to survive
