when your jeans don’t fit? Are your genes to blame when your jeans don’t fit? Giles Yeo gshy2@cam.ac.uk @GilesYeo

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

Seven deadly sins

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

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

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)

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

The discovery of leptin Zhang et al (1994). NATURE 372: 425-432

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

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

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

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

Increased linear growth in MC4R deficiency MC4R G.O.O.S. Height sds in MC4R deficient subjects P< 0.0002 p<0.002 0.5 1 1.5 2 2.5

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 3.9 2.3 Height sds 1.9 0.4 BMD z score 1.9 1.3 Insulin (mU/ml) 27 24

Monogenic vs Polygenic Obesity

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

Willer et al, Nature Genetics, 2009

Locke et al, Nature 2015

Risk vs predicability

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

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

Are we all sinners?

Dr Giles Yeo gshy2@cam.ac.uk