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CSAR 2014 Stephen O’Rahilly

CSAR 2014 Stephen O’Rahilly. Prevalence (%) estimates of diabetes (20-79 years), 2030. Source: IDF Diabetes Atlas 2009. Obesity Has Become More Common. 50-59 yr old White Northern US males. 1890. 2000. 35%. Helmchen and Fulford Ann Hum Biol 2004 31:174-81. 3.4%. Less Energy Out.

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CSAR 2014 Stephen O’Rahilly

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  1. CSAR 2014 Stephen O’Rahilly

  2. Prevalence (%) estimates of diabetes (20-79 years), 2030 Source: IDF Diabetes Atlas 2009

  3. Obesity Has Become More Common 50-59 yr old White Northern US males 1890 2000 35% Helmchen and Fulford Ann Hum Biol 2004 31:174-81 3.4%

  4. Less Energy Out More Energy In

  5. Why Isn't Everybody Fat?

  6. Evidence for Genetic Factors • Identical vs. non-identical twins • 2) Adoptees vs. biological and adoptive parents • 3) Identical twins reared apart

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

  8. Dizygotic Twins Heritability estimates 0.55-0.75 Monozygotic Twins Stunkard et al The Body Mass Index of twins who have been raised apat NEJM 1990 Wardle J et al Am Clin Nutr 2008 Heritability of childhood BMI in UK – 75%

  9. Before Leptin Age 3 yr After Leptin Age 6 yr Leptin replacement therapy is dramatically effective

  10. 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

  11. Cause of Obesity is Very Simple Energy Stored = Energy Intake - Energy Expended Fat tissue Energy stored “Nutrient partitioning” Non-Fat tissues

  12. Fundamentals of Nutrition 0.4 Tons Minerals 10,000,000 Litres Oxygen Lifetime of Consumption 8 Tons Carbohydrates 3 Tons Protein 3 Tons Fat 42 Tons Water CO2 Waste Heat Work Exercise <1 Kg. Carbohydrate 3.4 Kg. Minerals 10.2 Kg. Protein 8.8 Kg. Fat 48 Kg. Water

  13. Normal growth Kennedy 1950 Stop Overfeeding Start Underfeeding Stop

  14. 1880-1900 Frohlich et al. Patients with tumours in the hypothalamus developed severe obesity

  15. Medial Hypothalamus Lateral Hypothalamus 1940s-50s Hypothalamic Lesioning Experiments (Hetherington, Anand)

  16. 1959 Parabiosis Experiments of Hervey G.R. Hervey, J. Physiol 1959 145, 336-352

  17. Ob/Ob Normal 1973 Parabiosis experiments in ob/ob mice Ob/Ob Normal D.L. Coleman, Diabetologia 1973 4, 294-298

  18. 1994 Discovery of Leptin (Friedman) Zhang et al. Nature 1994:372; 425-32

  19. Leptin, the central controller of the adipostat Decrease food intake Increase thermogenesis Increase physical activity Increase Leptin Increased fat cell mass Fat cell

  20. Berthoud HR

  21. Nature December 1994 First generalised disorder of prohormone processing in any species above yeast New Eng J Med 1995 PCSK1 deficiency Jackson et al, Nature Genetics 1997 Jackson et al J Clin. Invest 2003 Farooqi et al JCEM 2007 Sadaf Farooqi Human Leptin deficiency Nature June 1997

  22. BDNF Giles Yeo TrkB Ob-R Tony Coll leptin Highly Penetrant Human Obesity Genes (1997-2004) Sadaf Farooqi MC4R Sim1 PC1 pomc Zinn Froguel Grueters • Most genes highly expressed in brain, especially hypothalamus 2) Mutation carriers have objective evidence of hyperphagia

  23. Before Leptin Age 3 yr The Same Processes are Operating in Humans After Leptin Age 6 yr

  24. food non-food Leptin Influences Higher Brain Functions in Humans Two congenitally leptin deficient adolescents (14 and 18 yrs old) Pre- and 1 week post-leptin Rx (70% reduction in food intake) Measured - neuronal activation using fMRI liking ratings of food images Sadaf Farooqi Paul Fletcher Ed Bullmore Farooqi et al Science 2007317(5843):1355.

  25. Sadaf Farooqi More Human Obesity Genes! SIM1Ramachandrappa 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 Ines Barroso

  26. C O N S O R T I U M What Progress has been made in identifying the specific DNA variants underlying the heritability of Common Obesity ? New International Collaborative Cultural Ethos Huge Numbers Rigorous Independent Replication

  27. Genetics of Adiposity vs Fat Distribution BMI Heidal Nature Genetics 2010 Waist Hip Ratio RSPO3 Ruth Loos VEGFA TBX15-WARS2 Obesity NFE2L3 DNM3-PIGC GRB14 ADAMTS9 Waist ITPR2-SSPN ZNRF3 NPC1 LY86 HOXC13 LYPLAL1* MAF CPEB4 MSRA PTER NISCH-STAB1 TFAP2B NRXN3 PTBP2 NUDT3 GPRC5B MTIF3 MC4R CADM2 FAIM2 FTO GNPDA2 MAP2K5 SEC16B LRP1B TMEM18 TNNI3K KCTD15 MTCH2 NEGR1 ETV5 RPL27A SH2B1 PRKD1 BDNF RBJ FANCL FLJ35779 SLC39A8 ZNF608 LRRN6C TMEM160 QPCTL

  28. How to Avoid Type 2 Diabetes 1 Maintain Energy Balance 3 Maintain Insulin sensitivity of glucose metabolism 4 Don’t exhaust your pancreatic beta cells 2 Safely store excess energy in fat

  29. XS Adipocytokines TNF,Il6, RBP4, resistin, visfatin etc Reduced adiponectin Ectopic Fat Liver and Muscle Defective insulin signalling How do we get from obesity to insulin resistance in muscle and liver ? Sustained Positive Energy balance

  30. David Savage Human Lipodystrophies

  31. Adipocyte Unilocular Fat Droplet

  32. Fasting Related Stimuli Tri-acylglycerol ATGL (droplet surface) Glycerol Di-acylglycerol CIDEC HSL (droplet surface) Glycerol Mono-acylglycerol MGL (cytosol) Glycerol Free Fatty Acid The Adipocyte Triglyceride Droplet. A Highly Regulated Organelle

  33. Genetic Forms of lipodystrophy Impaired Adipocyte Differentiation PPAR gamma Lamin A/C Seipin Impaired Triacylglycerol Synthesis AGPAT2 Impaired Insulin Signalling AKT2 Impaired Nutrient Uptake Caveolin 1 PTRF

  34. ATGL HSL CGI58 Perilipin Mutations of Adipocyte Droplet Surface Proteins cause a “metabolic syndrome ! Human Perliipin Mutations David Savage, Corinne Vigoroux et al (N Engl J Med. 2011J Biol Chem 2011) Homozygous nonsense mutation in CideC/FSP27 David Savage Oscar Rubio Cabezas Mike Czech (EMBO Mol Med. 2009) A primary abnormality solely affecting the regulation of unilocular lipid droplet regulation causes severe metabolic syndrome in humans

  35. Successful influence on individual and population behaviour through… Does “Biology” have any Relevance to Tackling Obesity as a Public Health Problem? Smoking? Information Facilitation Incentivisation Coercion Hypertension?

  36. Hypertension Obesity (Higher end of BP distribution) (Higher end of an adiposity distribution) Pre 1940s- low salt diets e.g. “rice diet” Hypocaloric diets and exercise 1940s Surgical Sympathectomy Bariatric surgery 1950s Drugs with severe side effects (ganglion blockers, reserpine) Drugs with limited effect and significant adverse effects e.g. Sibutramine, Orlistat, Rimonabant 1960s Drugs with limited effect/adverse effects (thiazide diuretics, methyldopa) 1970s onwards Beta adrenergic receptor blockers Calcium Antagonists Alpha-adrenergic receptor blockers ACE inhibitors AT2R1 blockers Major impact on hypertension a) Policies to reduce salt intake b) Screening c) Drugs (now generic, cheap and in combination)

  37. Tackling Obesity. A Multidisciplinary Approach • The amelioration of the adverse population health impact of obesity, • will, as has been the case for hypertension, ultimately require the combination of • Public health measures focused on prevention • AND • b) The selective use of cheap, effective and safe medications • i) To correct energy imbalance • ii) 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

  38. Social and Economic Consequences of Overweight in Adolescence and Young AdulthoodSteven 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

  39. From The Sunday Times February 10, 2008 Face it, fatty, your genes are innocent India Knight Shouting abuse at fat people is not just fun. It’s socially useful ROD LIDDLE Spectator 08 JULY 2009

  40. Anti-gluttony (sorry, bariatric) surgery is nonsense By Dr Bob Bury – Hospital Doctor 12th September 2010 8:57pm 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.

  41. Thanks to… Colleagues and Collaborators Referring physicians Funders MRC Wellcome Trust NIHR EU Framework programme Patients and Families Fido and owners Presentation of clinical images is with explicit, informed consent of patients, parents and/or guardians

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