1. when your jeans don’t fit?
Are your genes to blame
when your jeans don’t fit?
Giles Yeo
@GilesYeo

2. Getting lunch – it’s a jungle out there
Primal directives of life:
Find and eat food
Avoid becoming food
Reproduce
Repeat

3. Seven deadly sins

4. Adaptive Thermogenesis
Energy balance
Energy
Intake
Energy
Expenditure
Basal Metabolism
Physical Activity
Adaptive Thermogenesis
Food Intake

5. Scully, Nature, 508(7496):S50-1, 2014

6. Changing pattern of obesity
Frequency (%) 14 12 13 16 19 22 25 28 31 34 37 40 43 46 49 10 8 6 4 2 1
BMI (kg/m2)

7. Heritability of BODY WEIGHT = Heritability of HEIGHT
Twin studies
Heritability of BODY WEIGHT = Heritability of HEIGHT

8. The discovery of leptin
Zhang et al (1994). NATURE 372:

9. Brain control of food intake
Yeo and Heisler, 2012
Brain response
and translation
Genetic modifiers
Hormonal and
nutritional cues

10. Disruption of melanocortin signalling causes severe obesity
Mutation resulting
in obese human
in obese mouse

11. Human congenital leptin deficiency
Detailed phenotype of 5 leptin deficient subjects
normal birthweight
hyperphagia after weaning
no macronutrient preference
normal basal temperature
no defect in BMR or free-living energy
expenditure
increased fat mass (57%)
normal bone density and mineralisation
hyperinsulinaemia consistent with obesity
normal linear growth
no thyroid or adrenal dysfunction
hypogonadotropic hypogonadism
impaired T cell mediated immunity

12. Human congenital leptin deficiency
Daily leptin treatment
Human congenital leptin deficiency
3yr old weighing 42kg
7yr old weighing 32kg

14. Increased linear growth in MC4R deficiency
MC4R G.O.O.S.
Height sds in MC4R deficient subjects
P<
p<0.002
0.5 1
1.5 2
2.5

15. Genotype – phenotype correlation
Leptin
deficiency
Inactive Partial
MC4R mutations
treated
leptin
controls
*** 10 20 30 40 50 60 70
Mean ad libitum energy intake (kcal/kg lean mass)
inactive partial
BMI sds
Height sds
BMD z score
Insulin (mU/ml)

16. Monogenic vs Polygenic
Obesity

17. GWAS and common obesity
Loos, Best Prac& Res Clin Endo & Met, 2009

18. Willer et al, Nature Genetics, 2009

19. Locke et al, Nature 2015

20. Risk vs predicability

21. Your genes are like a hand of poker
You can’t do anything about the cards you have
But you can choose how to play them

22. There’s always time and (tummy) space for dessert

23. Are we all sinners?

24. Dr Giles Yeo gshy2@cam.ac.uk