1. OBESITY AND THE REGULATION OF BODY WEIGHT

2. OBESITY: A Huge Public Health Problem Definition of obesity: BMI>30 BMI = weight (kg)/ height 2 (m) 30% of the US population are obese Another 35% are overweight The incidence of obesity and overweight is increasing Obesity is becoming more common in children Obesity is also increasing in other parts of the world

3. What’s my BMI?

4. About 30.5 (based on height of 1.87 m and weight of 107 kg)

5. Obesity Trends* Among U.S. Adults BRFSS, 1985 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% www.cdc.gov

6. Obesity Trends* Among U.S. Adults BRFSS, 1986 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14%

7. Obesity Trends* Among U.S. Adults BRFSS, 1987 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14%

8. Obesity Trends* Among U.S. Adults BRFSS, 1988 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14%

9. Obesity Trends* Among U.S. Adults BRFSS, 1989 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14%

10. Obesity Trends* Among U.S. Adults BRFSS, 1990 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14%

11. Obesity Trends* Among U.S. Adults BRFSS, 1991 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

12. Obesity Trends* Among U.S. Adults BRFSS, 1992 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

13. Obesity Trends* Among U.S. Adults BRFSS, 1993 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

14. Obesity Trends* Among U.S. Adults BRFSS, 1994 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

15. Obesity Trends* Among U.S. Adults BRFSS, 1995 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

16. Obesity Trends* Among U.S. Adults BRFSS, 1996 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

17. Obesity Trends* Among U.S. Adults BRFSS, 1997 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% ≥20%

18. Obesity Trends* Among U.S. Adults BRFSS, 1998 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% ≥20%

19. Obesity Trends* Among U.S. Adults BRFSS, 1999 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% ≥20%

20. Obesity Trends* Among U.S. Adults BRFSS, 2000 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% ≥20%

21. Obesity Trends* Among U.S. Adults BRFSS, 2001 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

22. (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) Obesity Trends* Among U.S. Adults BRFSS, 2002 No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

23. Obesity Trends* Among U.S. Adults BRFSS, 2003 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

24. Obesity Trends* Among U.S. Adults BRFSS, 2004 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

25. Obesity Trends* Among U.S. Adults BRFSS, 2005 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

26. Obesity Trends* Among U.S. Adults BRFSS, 2006 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

27. Obesity Trends* Among U.S. Adults BRFSS, 2007 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

28. www.cdc.gov/nccdphp/dnpa/obesity/trend/index.htm

29. From: Handbook of Obesity: Etiology and Pathophysiology, 2 nd edition, G.A. Bray and C. Bouchard, editors, Marcel Dekker, NY,2004 %

30. Obesity is a risk factor for: 1)Type II diabetes 2)Hypertension 3)Atheroschlerosis 4)Some types of cancer 5)Asthma 6)Gall bladder problems 7)Gastroesophageal reflux 8)Sleep apnea 9)Fertility problems 10) Osteoarthritis

31. Prevalence of type II diabetes by BMI From: Handbook of obesity, Marcel Dekker Inc, 2004

32. Source: Mokdad et al., Diabetes Care 2000;23:1278-83; J Am Med Assoc 2001;286:10. Diabetes Trends* Among Adults in the U.S., (Includes Gestational Diabetes) BRFSS, 1990,1995 and 2001 19901995 2001

33. From: Handbook of Obesity: Etiology and Pathophysiology, 2 nd edition, G.A. Bray and C. Bouchard, editors, Marcel Dekker, NY,2004

36. Risk of premature death BMI 20 25 30 3515

37. From: Ludwig, D.S. New England Journal Of Medicine 357:2325-27, 2007.

38. Risk factors for the development of obesity Genetics twin concordance rates are very high (80%) obesity is higher in certain ethnic groups (Pacific Islanders, native American’s, African Americans) animals can be bred for fatness there are inbred strains of mice and rats that are spontaneously obese whole genome wide studies have replicated in a large number of studies, an association of a SNP in the FTO gene with obesity Environment Animals on a high fat diet gain weight Human who live in other cultures gain weight when they move to the US or other places with a Western diet Sleep duration affects BMI

39. Ob/Ob Wildtype (C57BL/6J)

40. Risk factors for the development of obesity Genetics twin concordance rates are very high (80%) obesity is higher in certain ethnic groups (Pacific Islanders, native American’s, African Americans) animals can be bred for fatness there are inbred strains of mice and rats that are spontaneously obese whole genome wide studies have replicated in a large number of studies, an association of a SNP in the FTO gene with obesity Environment Animals on a high fat diet gain weight Human who live in other cultures gain weight when they move to the US or other places with a Western diet Sleep duration affects BMI

41. From: Frayling, TM et al Science 316:889, 2007 Association of a SNP in the FTO gene with obesity

43. Short sleep duration increases BMI From: Taheri et al, PLoS Med 3:e62, 2004

44. -Elevations of BMI are observed in subjects who sleep fewer than 6 h per night -Experimental acute sleep curtailment increases hunger and appetite especially for energy rich foods -Mice in which circadian rhythms are disrupted become obese -More than 33% of adolescents get less sleep than recommended Sleep and Obesity

45. WHY IS OBESITY INCREASING ? 1) Genetics? Unlikely. It takes thousands of years to change the gene pool that drastically. 2) Changes in environment? Diet: more carbohydrates and less fat, also different types of fat Exercise: more sedentary lifestyles 3) Gene environment interactions? Susceptibility genes that are only expressed in conjunction with certain diets

46. Not all fats are created equal: Amount of trans fat in diet is significantly related to waist circumference gain Total amount of fat in diet is not Koh-Banerjee et al, Am J Clin Nutr, 2003

47. Also called “partially hydrogenated” oil Performed to increase shelf life and increase flavor stability Present in most processed foods Makes fat solid at room temperature

48. Okie, S. New York to Trans Fats: You're Out! NEJM: 356:2017-2021, 2007

49. Consumption of trans fats increases the risk of heart disease Mozaffarian et al NEJM 354:1601-1613, 2007

51. HOW IS BODY WEIGHT REGULATED? Body weight represents a balance between calorie input and calorie expenditure. InputsExpenditures food eatenbasal metabolic rate cost of food digestion (liver) exercise

52. (ex: PYY)

53. GHRELIN (meal initiation) Peptide hormone produced by the stomach Levels rise just before a meal and fall afterwards Levels are low in obesity and rise after weight loss Acts in the hypothalamus to stimulate appetite Inhibits leptin-induced appetite suppression Also stimulates glucose production in liver and inhibits glucose uptake in muscle and fat

55. Ghrelin is produced in the stomach Normal Gastric Resection

56. PYY (involved in meal termination) Peptide hormone produced by the small intestines and colon Secreted postprandially in proportion to calories ingested Causes satiety and meal termination -effects on gut motility -effects on sensory neurons signaling satiety Fasting levels are reduced in obesity and levels don’t increase to the same extent as in lean subjects even after a large meal

57. Endogenous PYY after a meal in lean and obese subjects Batterham et al.New Engl.J. Med. 349:941-948, 2003

58. Batterham et al. N Engl J Med. 2003 349:941-8. Calorie intake after PYY infusion

59. What is actually regulated? Data suggest that input is matched to expenditures over long periods of time (weeks to months) but not over shorter periods (days). Suggests something that doesn’t change much acutely, for example, body energy stores are what is regulated. Body fat!

60. Daily food intakeWeekly food intake Daily energy expenditure Weekly energy expenditure What is actually regulated? Data suggest that input is matched to expenditures over long periods of time (weeks to months) but not over shorter periods (days). Suggests that something that doesn’t change much acutely, for example, body energy stores, is what is regulated. Body fat!

61. An extra 10 calories a day results in an approximate 12 pound weight gain over 10 years.

62. How is body fat regulated? Leptin: Hormone produced in adipocytes in proportion to fat mass Acts in hypothalamus to signal satiety (prevent eating) Also acts in hypothalamus to increase metabolism Acts in muscle to prevent lipid storage and to promote utilization of fatty acids to produce ATP

63. Ob/Ob Wildtype (C57BL/6J)

68. Genetic defects in leptin are not very common in humans Genetic variations in the leptin receptor also very uncommon Obese humans have increased serum leptin (because they have more fat and fat makes leptin) How come the leptin doesn’t prevent them from eating? - leptin resistance just like insulin resistance in type II diabetes? - leptin doesn’t get across the blood brain barrier Leptin and human obesity

69. From: Taheri et al, PLoS Med 3:e62, 2004 Short sleep duration is associated with increased grelin and decreased leptin leptin ghrelin

70. ADIPOSE TISSUE CYTOKINES TNF  IL-6 IL-1 PBEF TGF  IL-10 CHEMOKINES IL-8 Eotaxin MCP-1 MIP-1  ENERGY REGULATING HORMONES Leptin Adiponectin Resistin ACUTE PHASE REACTANTS Serum amyloid A C-reactive protein PAI-1  1-acid glycoprotein OTHER FACTORS Angiotensinogen Complement B, C3, D Acylation-stimulating protein VEGF IL-1RA Retinol-binding protein-4

71. Macrophage specific antigen F4/80 in adipose tisse Lean female Lean male Agouti female DIO male Ob/ob Ob/ob male Weisberg et al, JCI 112:1796-1808,2003

72. Macrophage specific antigen F4/80 in skeletal muscle Ob/ob Lean muscle liver

73. Wang et al, Am. J. Clin. Nutr. 81:555-63, 2005 Abdominal fat is more important than subcutaneous fat for type 2 diabetes

74. ADIPONECTIN Produced by adipocytes Most abundant gene product in adipocytes Decreases in obesity and increases during weight loss No effect on body weight Effects on are energy metabolism - causes glucose uptake - promotes fatty acid oxidation - inhibits gluconeogenesis Improves glucose tolerance and increases insulin sensitivity Reduces hyperglycemia in animal models of type II diabetes Animals with no adiponectin are susceptible to atherosclerosis

75. Bobbert et al, Diabetes 54:7212-9, 2005 HMW Adiponectin

76. Mice overexpressing Adiponectin using a Liver specific promoter Yamauchi et al, J. Biol. Chem. 278:2461, 2003

77. Yamauchi et al, J. Biol. Chem. 278:2461, 2003

78. From: Kubota et al, J. Biol. Chem. 277:25863, 2002. Adiponectin knockout mice are susceptible to atheroschlerosis

79. Pajvani et al, J Biol Chem 279:12152-62, 2004 Rosiglitazone induced changes in insulin sensitivity correlate with changes in adiponectin

80. TREATMENT OF OBESITY 1)Liposuction 2)Gastric reduction surgery (side effects) 3)Wiring of the jaw 4)Drugs (side effects) 5)Diet and exercise 6)Behavior modification