1. Alternate day fasting For weight loss and heart disease risk reduction Krista Varady, Ph.D. Associate Professor of Nutrition University of Illinois, Chicago

2. 65% of Americans are overweight or obese

3. Obesity greatly increases the risk of coronary heart disease (CHD)

4. Losing weight helps to lower the risk of CHD

5. Most commonly used weight loss intervention: Calorie restriction (CR)

6. What is Calorie restriction (CR)?

7. Reducing energy intake by 15-40% of daily needs What is Calorie restriction (CR)?

8. Calorie restriction is effective for weight loss Chaston TB & Dixon JB, Int J Obesity. 2008.

9. Weight loss 10-15% in 3 months Calorie restriction is effective for weight loss

10. Problem with calorie restriction: Dietary adherence begins to decline after 8 weeks

11. How can we increase adherence to calorie restriction to ensure consistent weight loss?

12. Perhaps by only requiring calorie restriction every other day? Day of ad libitum feedingDay of 75% restriction

13. Feed day Fast day Day of ad libitum feedingDay of 75% restriction Alternate day fasting (ADF)

14. In this way, the person always gets to look forward to the day of eating anything they want Fast day Feed day

15. How did the idea of ADF come about?

16. Fasting in the absence of weight loss How did the idea of ADF come about?

17. Fasting in the absence of weight loss Effect on cell proliferation rates of various tissues (Cancer risk) How did the idea of ADF come about?

18. But the mice always lost weight!

19. Would we see the same weight loss in humans with ADF? ?

20. STUDY 1 – Pilot study Study objectives Is ADF an effective strategy for weight loss? What is the effect of this diet on CHD risk parameters? What dietary adaptations occur in individuals undergoing ADF?

21. Figure 1.1 Study design: Pilot study Week 1-2 Week 3-6 Week 7-10 Body weight Body composition Blood draw Body weight Body composition Blood draw Body weight Body composition Blood draw Body weight Body composition Blood draw

22. Table 1.1 Nutrient composition of the fast day meals provided Varady KA et al, AJCN. 2009.

23. Meals were prepared for individual subjects in a metabolic kitchen

24. Table 1.2 Subject characteristics at baseline who completed the study Varady KA et al, AJCN. 2009.

25. Figure 1.2 Body weight changes Varady KA et al, AJCN. 2009. -5.6 kg

26. Table 1.3 Body composition changes Bhutani et al, Obesity. 2010. All values reported as mean  SEM. * Significantly different from baseline (week 3), P < 0.05 (One-factor ANOVA with Bonferroni analysis)

27. Is ADF effective for weight loss? Bhutani et al, Obesity. 2010. All values reported as mean  SEM. * Significantly different from baseline (week 3), P < 0.05 (One-factor ANOVA with Bonferroni analysis) Table 1.3 Body composition changes

28. Bhutani et al, Obesity. 2010. All values reported as mean  SEM. * Significantly different from baseline (week 3), P < 0.05 (One-factor ANOVA with Bonferroni analysis) Table 1.3 Body composition changes

29. Is ADF cardio-protective? What is the effect of ADF on CHD risk parameters?

30. Is ADF cardio-protective? Figure 1.3 LDL cholesterol concentrations Week 7 Week 10 Feed day Fast day Bhutani et al, Obesity. 2010.

31. Figure 1.4 HDL cholesterol concentrations Bhutani et al, Obesity. 2010. Week 7 Week 10 Feed day Fast day

32. Bhutani et al, Obesity. 2010. Figure 1.5 Triglyceride concentrations Week 7 Week 10 Feed day Fast day

33. Figure 1.6 Systolic blood pressure changes Varady KA et al, AJCN. 2009. -6 mmHg

34. Figure 1.7 Heart rate changes Varady KA et al, AJCN. 2009. - 4 beats/min

35. Dietary adherence? Amount of food consumed on feed day? Overall energy restriction? What dietary adaptations occur in individuals undergoing ADF?

36. Adherence to fast day diet assessed using an “Extra food log”

37. What dietary adaptations occur with ADF? Figure 1.8 Adherence to fast day diet Varady KA et al, AJCN. 2009.

38. Figure 1.9 Hyperphagic response on feed day to lack of food on fast day Klempel MC et al, Nutr J. 2010. Feed day intake: 110% of needs

39. Figure 1.10 Percent energy restriction at each week of the trial Klempel MC et al, Nutr J. 2010. 37% restriction

40. How are hunger and satiety affected?

41. Hunger was measured by a validated visual analog scale (VAS)

42. Figure 1.11 Hunger during each week of the trial Klempel MC et al, Nutr J. 2010.

43. Figure 1.12 Satiety during each week of the trial Klempel MC et al, Nutr J. 2010.

44. Is ADF potentially effective for weight loss? YES

45. All previous studies of ADF used a low-fat background diet (25% fat)

46. But most Americans consume a diet high in fat (35-45% fat)

47. All previous studies of ADF used a low-fat background diet (25% fat) But most Americans consume a diet high in fat (35-45% fat) Is ADF still effective with a high-fat background diet?

48. STUDY 2 – High fat/low fat study Study objectives Do similar changes in weight occur on an ADF high-fat diet? What is the effect of an ADF high-fat diet on CHD risk?

49. Figure 2.1 Study design: High fat study ADF-LF group ADF-HF group

50. Table 2.1 Nutrient composition of the feed and fast day meals provided Klempel MC et al, 2012. Metabolism.

51. Table 2.2 Subject characteristics at baseline Klempel MC et al, 2012. Metabolism.

52. Figure 2.2 Body weight changes -5.3 kg LF -6.5 kg HF Klempel MC et al, 2012. Metabolism.

53. Figure 2.3 Body composition changes Klempel MC et al, 2012. Metabolism.

54. Figure 2.4 Waist circumference changes -10.1 cm LF -10.0 cm HF Klempel MC et al, 2012. Metabolism.

55. Figure 2.5 Plasma lipid changes Klempel MC et al, 2012. Metabolism.

56. Are the beneficial effects of ADF still observed with a high fat background diet? YES

57. STUDY 3 – Exercise study Study objectives Is it possible to exercise on the fast day? What are the effects this combination therapy on body weight? What are the effects on CHD risk?

58. Figure 3.1 Study design: ADF plus exercise

59. Table 3.1 Subject characteristics at baseline CombinationADFExerciseControl n18252416 Age (y) 45  542  2 49  2 Body weight (kg) 91  694  393  293  5 BMI (kg/m2) 35  1 Waist circum (cm) 92  1100  298  299  3 Total-C (mg/dl) 190  10171  8181  6185  7 LDL-C (mg/dl) 125  9113  8113  5119  6 HDL-C (mg/dl) 50  349  251  252  3 TG (mg/dl) 77  781  774  697  13 No significant differences between groups (One-way ANOVA)

60. Figure 3.2 Percent exercise sessions scheduled by subjects on feed/fast day Bhutani S et al, 2013. Int J Sports Nutr.

61. Figure 3.3 Percent cheating on the fast day in relation to timing of the exercise session Bhutani S et al, 2013. Int J Sports Nutr.

62. Figure 3.4 Changes in body weight and body composition after 12 weeks Means with different letters significantly different (P < 0.05; One-way ANOVA). Bhutani S et al, 2013. Obesity.

63. Table 3.2 Change in plasma lipids and LDL particle size after 12 weeks CombinationADFExerciseControl Total-C (% change) -2  57  40  31  4 LDL-C (% change) -12  5-1  60  53  5 HDL-C (% change) 18  9 a 0  4 b 2  3 b 8  5 b TG (% change) 13  116  67  65  7 LDL size (Å) 4  1 a 5  1 a 1  1 b 0  1 b Large LDL (% change) 7  515  31  51  4 Small LDL (% change) -7  2 a -12  3 a -1  4 b 1  3 b Means with different letters significantly different for each parameter (P < 0.05; One-way ANOVA). Bhutani S et al, 2013. Obesity.

64. Table 3.2 Change in plasma lipids and LDL particle size after 12 weeks CombinationADFExerciseControl Total-C (% change) -2  57  40  31  4 LDL-C (% change) -12  5-1  60  53  5 HDL-C (% change) 18  9 a 0  4 b 2  3 b 8  5 b TG (% change) 13  116  67  65  7 LDL size (Å) 4  1 a 5  1 a 1  1 b 0  1 b Large LDL (% change) 7  515  31  51  4 Small LDL (% change) -7  2 a -12  3 a -1  4 b 1  3 b Means with different letters significantly different for each parameter (P < 0.05; One-way ANOVA). Bhutani S et al, 2013. Obesity.

65. Weight loss ADF produces a 3-7 kg weight loss after 8-12 weeks ADF-HF diets are just as effective as ADF-LF diets for weight loss Adding endurance exercise may enhance weight loss Body composition Fat mass decreased, with potential retention of lean mass Waist circumference decreases by 4-10 cm Summary of findings

66. Coronary heart disease risk LDL cholesterol reduced by 0-25% Triglycerides lowered by 0-30% Systolic blood pressure also decreased ADF-HF is just as effective as ADF-LF for CHD risk reduction Adding endurance exercise may increase HDL cholesterol levels Summary of findings

67. Dietary adaptations Approximately 110% of energy needs consumed on the feed day to compensate for the lack of food on the fast day 80-90% of subjects can adhere to ADF short-term Hunger decreases after 2 weeks of diet Summary of findings

68. Goal is to examine whether ADF is effective for weight maintenance, and to compare ADF to daily calorie restriction Hypothesized findings (from grant application) Year-long ADF study currently underway…

69. All of these findings are summarized in the book: US versionUK version

70. Many thanks to my students…Faculty Surabhi Bhutani (PhD Student)  Dr. Shane Phillips Monica Klempel (PhD Student)  Dr. Daniel Corcos John Trepanowski (PhD Student)  Dr. Carol Braunschweig Cynthia Kroeger (PhD Student)  Dr. Eric Ravussin Kristin Hoddy (PhD Student)  Dr. Sally Freels Adrienne Barnosky (Postdoc)  Dr. Marian Fitzgibbon Funding NIH National Heart Lung and Blood Institute R01HL106228-01 American Heart Association 09SDG2170077 and 12PRE8350000 International Life Sciences Institute UIC Chancellor’s Discovery Fund (Co-PI Shane Phillips) Acknowledgements