CSAR 2014

Stephen O’Rahilly

Prevalence (%) estimates of diabetes (20-79 years), 2030

Source: IDF Diabetes Atlas 2009

Obesity Has Become More Common

1890

2000

Helmchen and Fulford Ann Hum Biol 2004 31:174-81

50-59 yr old White Northern US males

3.4%

35%

Less Energy Out More Energy In

Why Isn't Everybody Fat?

Evidence for Genetic Factors

1)1) Identical vs. non-identical twinsIdentical vs. non-identical twins

2) 2) Adoptees vs. biological and adoptive parentsAdoptees vs. biological and adoptive parents

3) 3) Identical twins reared apart Identical twins reared apart

Vol 322 No. 21 THE NEW ENGLAND JOURNAL OF MEDICINE 1483

THE BODY-MASS INDEX OF TWINS WHO HAVE BEEN REARED APART

ALBERT J. STUNKARD, M.D., JENNIFER R. HARRIS, PH.D., NANCY L. PEDERSEN, PH.D.,AND GERALD E. MCLEARN, PH.D.

Abstract to assess the relative importance of genetic and environmental effects on the body mass index (weight in kilograms divided by the square of the height in metres), we studied samples of identical and fraternal twins, reared apart or reared together. The samples consisted of 93 pairs of identical twins reared apart, 154 pairs of identical twins reared together, 218 pairs of fraternal twins reared apart, and 208 pairs of fraternal twins reared together.

The intrapair correlation coefficients of the values for body-mass index of identical twins reared apart were 0.70 for men and 0.66 for women. These are the most direct estimates of the relative importance of genetic influences (heritability) on the body-mass index, and they were only slightly lower that those for twins reared together in this and earlier studies

N Engl J Med 1990; 322:1483-7N Engl J Med 1990; 322:1483-7

Similar estimates were derived from maximum-likelihood model-fitting analyses – 0.74 for men and 0.69 for women. Nonadditive genetic variance made a significant contribution to the estimates of heritiability, particularly among men. Of the potential environmental influences, only those unique to the individual and not shared by family members were important, contributing about 30 percent of the variance. Sharing the same childhood environment did not contribute to the similarity of the body-mass index of twins later in life.

We conclude that genetic influences on body-mass index are substantial, whereas the childhood environment has little or no influence. These findings corroborate and extend the results of earlier studies of twins and adoptees.

Dizygotic Dizygotic TwinsTwins

Monozygotic Monozygotic TwinsTwins

Wardle J et al Am Clin Nutr 2008 Heritability of childhood BMI in UK – 75%

Heritability estimates

0.55-0.75

Stunkard et al The Body Mass Index of twins who have been raised apat NEJM 1990

Before Leptin Age 3 yr After Leptin Age 6 yr

Leptin replacement therapy is dramatically effective

There are inherent biological processes strongly influencing the amount of fat stored in animals, including ourselves

These processes work with varying efficiency between people

Inherited factors plays a major role in determining the variation in efficiency of those processes

Understanding the underlying biology of obesity will be important to its solution as a bio-medical problem

Energy Stored = Energy Intake - Energy Expended

Energy stored

Fat tissue

Non-Fat tissues

“Nutrient partitioning”

Cause of Obesity is Very Simple

CO2

Waste

Heat

Work

Exercise

42 TonsWater

3 TonsFat

3 Tons

Protein

8 Tons

Carbohydrates

10,000,000 LitresOxygen

Lifetime of Consumption

0.4 Tons Minerals

Fundamentals Fundamentals of Nutritionof Nutrition

<1 Kg. Carbohydrate<1 Kg. Carbohydrate

3.4 Kg. Minerals3.4 Kg. Minerals

10.2 Kg. Protein10.2 Kg. Protein

8.8 Kg. Fat8.8 Kg. Fat

48 Kg. Water48 Kg. Water

Kennedy 1950Kennedy 1950

StopStop

StopStop

StartStart

OverfeedingOverfeeding Normal growthNormal growth

UnderfeedingUnderfeeding

Frohlich et al.

Patients with tumoursin the hypothalamusdeveloped severe obesity

1880-1900

Lateral

Hypothalamus

Medial

Hypothalamus

1940s-50s Hypothalamic Lesioning Experiments 1940s-50s Hypothalamic Lesioning Experiments (Hetherington, Anand)(Hetherington, Anand)

G.R. Hervey, J. Physiol 1959 145, 336-352G.R. Hervey, J. Physiol 1959 145, 336-352

1959 Parabiosis Experiments of Hervey 1959 Parabiosis Experiments of Hervey

D.L. Coleman, Diabetologia 1973 4, 294-298D.L. Coleman, Diabetologia 1973 4, 294-298

Ob/Ob Normal Ob/Ob Normal

1973 Parabiosis experiments in ob/ob mice1973 Parabiosis experiments in ob/ob mice

Zhang et al. Nature 1994:372; 425-32Zhang et al. Nature 1994:372; 425-32

1994 Discovery of Leptin (Friedman)

Decrease food intakeDecrease food intake

Increase thermogenesisIncrease thermogenesis

Increase physical activityIncrease physical activity

Leptin, the central controller of the adipostatLeptin, the central controller of the adipostat

Increased fat Increased fat cell masscell mass

IncreaseIncreaseLeptinLeptin

Fat cell

Berthoud HR

Nature December 1994

Sadaf Farooqi

Human Leptin deficiency Nature June 1997

New Eng J Med 1995

First generalised disorder of prohormone processing in any species above yeast

Jackson et al, Nature Genetics 1997Jackson et al J Clin. Invest 2003Farooqi et al JCEM 2007

PCSK1 deficiency

Highly Penetrant Human Obesity Genes (1997-2004)Highly Penetrant Human Obesity Genes (1997-2004)

pomc

PC1

MC4R

TrkB

BDNF

leptin

Ob-R

1) Most genes highly expressed in brain, especially hypothalamus

2) Mutation carriers have objective evidence of hyperphagia

Sim1

SadafFarooqi

GilesYeo

Tony Coll

Froguel Zinn

Grueters

Before Leptin Age 3 yr After Leptin Age 6 yr

The Same Processes are Operating in Humans

foodfood non-foodnon-food

Leptin Influences Higher Brain Functions in Humans Leptin Influences Higher Brain Functions in Humans

Two congenitally leptin deficient adolescents (14 and 18 yrs old)Two congenitally leptin deficient adolescents (14 and 18 yrs old)

Pre- and 1 week post-leptin Rx (70% reduction in food intake)Pre- and 1 week post-leptin Rx (70% reduction in food intake)

Measured - neuronal activation using fMRI Measured - neuronal activation using fMRI liking ratings of food imagesliking ratings of food images

0

1

2

3

4

5

6

7

8

9

10

NAccumbens Putamen Amygdala Hippocampus

Pre

Post leptin

Regional parameter estimates

0

1

2

3

4

5

6

7

8

9

10

NAccumbens Putamen Amygdala Hippocampus

Pre

Post leptin

Regional parameter estimates

Paul Paul FletcherEd BullmoreEd Bullmore

Farooqi et al Science 2007317(5843):1355.

Sadaf Farooqi

SIM1 Ramachandrappa S et al J Clin Invest. 2013 1;123(7):3042-50 (Whitelaw)

MRAP2 Asai et al Science. 2013 19;341(6143):275-8 (Majzoub)

SH2B1 Bochukova E et al Nature. 2010 Feb 4;463(7281):666-70. Doche J Clin Invest. 2012;122(12):4732-6

KSR2 Pearce L et al Cell. 2013 Nov 7;155(4):765-77

More Human Obesity Genes!

Sadaf Farooqi

Ines Barroso

What Progress has been made in identifying the specific DNA variants underlying the heritability of Common Obesity ?

G ANTG ANTC O N S O R T I U MC O N S O R T I U M

New International Collaborative Cultural Ethos

Huge Numbers

Rigorous Independent Replication

MC4RFTO

TMEM18

NEGR1

SEC16B

ETV5

BDNF

FAIM2

SH2B1

KCTD15

GNPDA2

MTCH2

NRXN3TFAP2B

LYPLAL1*

Genetics of Adiposity vs Fat Distribution

BMI

Waist

Obesity

NPC1

MAFPTERMSRA

GPRC5B

RBJ

MAP2K5

FANCL

QPCTL

TNNI3K

FLJ35779SLC39A8

TMEM160

CADM2

PRKD1

LRP1B

MTIF3

ZNF608

RPL27A

NUDT3PTBP2

LRRN6C

RSPO3VEGFA

TBX15-WARS2

DNM3-PIGC

ITPR2-SSPN

LY86CPEB4

NISCH-STAB1

ZNRF3

GRB14NFE2L3

ADAMTS9

HOXC13

Heid al Nature Genetics 2010 Waist Hip Ratio Ruth Loos

1 Maintain Energy Balance

2 Safely store excess energy in fat

3 Maintain Insulin sensitivity of glucose metabolism

How to Avoid Type 2 Diabetes

4 Don’t exhaust your pancreatic beta cells

How do we get from obesity to insulin resistance in muscle and liver ?

Sustained Positive Energy balance

XS AdipocytokinesXS AdipocytokinesTNF,Il6, RBP4, resistin, visfatin etcTNF,Il6, RBP4, resistin, visfatin etc

Reduced adiponectinReduced adiponectin

Liver and Muscle Defective insulin signalling

Ectopic Fat

Human Lipodystrophies

DavidSavage

Adipocyte Unilocular Fat Droplet

The Adipocyte Triglyceride Droplet. A Highly Regulated Organelle

CIDEC

Tri-acylglycerol

Fasting Related Stimuli

Glycerol

Glycerol

Glycerol

Di-acylglycerol

Mono-acylglycerol

Free Fatty Acid

ATGL (droplet surface)

HSL (droplet surface)

MGL (cytosol)

Genetic Forms of lipodystrophy

Impaired Adipocyte DifferentiationPPAR gammaLamin A/C Seipin

Impaired Triacylglycerol Synthesis AGPAT2

Impaired Insulin Signalling AKT2

Impaired Nutrient UptakeCaveolin 1PTRF

David Savage, Corinne Vigoroux et al (N Engl J Med. 2011J Biol Chem 2011)

HSLATGL

CGI58

Perilipin

David Savage Oscar Rubio CabezasMike Czech (EMBO Mol Med. 2009)

A primary abnormality solely affecting the regulation of unilocular lipid droplet regulationcauses severe metabolic syndrome in humans

Homozygous nonsense mutation in CideC/FSP27

Human Perliipin Mutations

Mutations of Adipocyte Droplet Surface Proteins cause a “metabolic syndrome !

Does “Biology” have any Relevance to Tackling Obesity as a Public Health Problem?

Smoking?

Hypertension?

Information

Facilitation

Incentivisation

Coercion

Successful influence on individual and population behaviour through…

Pre 1940s- low salt diets e.g. “rice diet”

1940s Surgical Sympathectomy

1950s Drugs with severe side effects(ganglion blockers, reserpine)

Hypocaloric diets and exercise

Bariatric surgery

1970s onwards

Beta adrenergic receptor blockersCalcium AntagonistsAlpha-adrenergic receptor blockers ACE inhibitorsAT2R1 blockers

Drugs with limited effectand significant adverse effectse.g. Sibutramine, Orlistat, Rimonabant

1960s Drugs with limited effect/adverse effects (thiazide diuretics, methyldopa)

Major impact on hypertension

a) Policies to reduce salt intakeb) Screening c) Drugs (now generic, cheap and in combination)

Hypertension

(Higher end of BP distribution)

Obesity

(Higher end of an adiposity distribution)

The amelioration of the adverse population health impact of obesity, will, as has been the case for hypertension, ultimately require the combination of

a) Public health measures focused on prevention

AND

b) The selective use of cheap, effective and safe medications i) To correct energy imbalanceii) To promote the safe storage of excess calories

The design of such medicines will require a deeper understanding of the control of human energy balance and the links between obesity and its adverse outcomes

Tackling Obesity. A Multidisciplinary Approach

 Social and Economic Consequences of Overweight in Adolescence and Young Adulthood

Steven L. Gortmaker, Aviva Must, James M. Perrin, Arthur M. Sobol, and William H. Dietz

New England Journal of Medicine 1993 Sep 30;329(14):1008-12

From The Sunday Times February 10, 2008

Face it, fatty, your genes are innocentIndia Knight

Shouting abuse at fat people is not just fun. It’s socially useful

ROD LIDDLESpectator 08 JULY 2009

If you really wanted to turn a profit from the hordes of the morbidly obese, you would cull them humanely and render them down to make soap, or possibly biofuel. The thought that someone capable of turning themselves into a quivering 200Kg lump of immobile, ulcerated adiposity will suddenly become a productive member of the workforce when they lose a few stone after having their oesophagus stapled to their anus, or whatever the latest fashion is in bariatric surgery, strikes me as improbable.

Anti-gluttony (sorry, bariatric) surgery is nonsenseBy Dr Bob Bury – Hospital Doctor 12th September 2010

8:57pm

Thanks to…

Presentation of clinical images is with explicit,informed consent of patients, parents and/or guardians

Colleagues and Collaborators

Referring physicians

Funders

MRCWellcome TrustNIHREU Framework programme

Patients and Families

Fido and owners