1. The Relationship of Leptin and Stress Among Worksite Employees Rachel M. Ceballos April 20, 2007

2. I. Background: Leptin ■ Hormone – Released: adipocytes, ovaries, mammary glands ■ Receptors – Distributed: throughout the body (central/peripheral) ■ Function: – Leptin can contribute to the regulation of… -Metabolism -Puberty -Hematopoiesis -Immune Function -Stress Systems

3. ■What is the relevance to cancer prevention and control? I. Background: Leptin & Stress Stress Immune Function Cancer Leptin - - + - (e.g. TH1)

4. Animal Model ■Lower leptin levels –Wistar Male and Sprague-Dawley Male and Female rats –Immobilization Stress: 3 hrs/day for 3-10 days or 20 min/day for 21 days (Harris et al., 2002; Makino et al., 1999: Gomez, Houshyar, & Dallman, 2002;Ceballos et al, 2006) ■Higher leptin levels – Long Evans Male and Female rats – Immobilization Stress: 20 min/day for 21 days (Ceballos, Faraday & Klein, 2006) I. Background: Leptin and Stress

5. Human Model Lower leptin levels Lower leptin levels –Female medical students –Post-menopausal women exposed to acute laboratory stressor stressor –Healthy adults following physical activity (Al-Ayadhi, et al, 2005; Ceballos,et al, in preparation;Legakis et al, 2004) (Al-Ayadhi, et al, 2005; Ceballos,et al, in preparation; Legakis et al, 2004) No difference No difference – Healthy men and pre-menopausal women exposed to acute laboratory stressor acute laboratory stressor (Ceballos, et al, in preparation) (Ceballos, et al, in preparation) ■ High Leptin Levels – Male Japanese government employees (Otsuka, et al, 2006) I. Background: Leptin and Stress

6. I. Background: Purpose Pilot Study to examine the relationship between leptin and stress in a community based sample

7. II. Methods Randomized Trial: Promoting Activity and Changes In Eating, PACE (Beresford, S.A.A., P.I.) ■ 30 Worksites in the Seattle area – Worksites with 40 and 350 employees – Pair-matched on several characteristics (e.g., size, % women, baseline response rate) – Worksites randomly assigned to intervention or comparison (delayed intervention) arm – Subgroup of individuals asked to provide blood sample and complete additional questionnaires

8. II. Methods ■ Participants –10 worksites –N=80 33 Men, 47 Women Mean Age: 41.62 (11.13) Education: % Some high School 1.10 High School Graduate/GED 9.89 Technical/Business School17.58 Some college23.08 College graduate36.26 Post graduate/professional 12.09 –Randomly selected half of the individuals from the PACE intensive subgroup

9. II. Methods Assessment Baseline assessment 10-Item Perceived Stress Scale – Cohen, Kamarck, & Mermelstein,1983 – “in the last week” Serum leptin (ng/mL) – UW Northwest Lipid Research Laboratory – Radioimmunoassay (RIA)

10. Analysis ■ Mixed Analysis –Continuous –Categorical –Independent Variable: 4 categories of stress –Dependent Variable: Serum Leptin ■ Leptin data log transformed ■ Covariates: –Worksite (random) –Gender and Body Mass Index (fixed) II. Methods

11. Mean (SD)RangeMinMax Body Mass Index29.99 (7.52)34.7818.1552.93 Leptin (ng/mL)16.98 (14.59)56.71.057.7 Perceived Stress11.76 (6.73)28.01.029.0 III. Results Descriptives:

12. ■ Stress entered as continuous predictor variable F-value (df)p-value Perceived Stress 0.14 (1,71) 0.71 Gender 50.09 (1,71) 0.001 Body Mass Index118.10 (1,71) 0.001 III. Results

13. ■ Stress entered as categorical variable Quartile Scores: Low (1-6)Moderate (11-15) Low Moderate (7-10) High (16-29) F-value (df)p-value Perceived Stress 0.37 (3,69) 0.78 Gender 48.93 (1,69) 0.001 BMI 117.95 (1,69) 0.001

14. III. Results t-value (df)p-value Quartile 1- Quartile 2 0.35 (69) 0.73 Quartile 1- Quartile 3 0.76 (69) 0.45 Quartile 1- Quartile 4 0.95 (69) 0.34 Quartile 2- Quartile 3 0.48 (69) 0.64 Quartile 2- Quartile 4 0.68 (69) 0.50 Quartile 3- Quartile 4 0.17 (69) 0.86 Stress entered as categorical variable (cont.)

15. Mean (SD) t-valuep-value MenWomen Body Mass Index30.40 (5.46)29.69 (8.73)0.42 (78)0.68 Leptin (ng/mL)10.04 (8.16)22.26 (16.31)-4.15 (78)0.00 Perceived Stress9.63 (6.01)13.59 (6.67)-2.63 (78)0.01 III. Results Effect of Gender

16. III. Results ■ Stress entered as continuous predictor variable F-value (df)p-value F-value (df)p-value Perceived Stress 0.00 (1,70) 0.949 Perceived Stress 0.00 (1,70) 0.949 Gender 22.55 (1,70) 0.001 Gender 22.55 (1,70) 0.001 Perceived Stress*Gender 1.85 (1,70) 0.178 Perceived Stress*Gender 1.85 (1,70) 0.178 Body Mass Index 122.07 (1,70) 0.001 Body Mass Index 122.07 (1,70) 0.001

17. ■ No significant relationship between leptin and stress ■ Preliminary analyses conducted to determine appropriate sample size ■ Range of stress scores comparable to other studies ■ Menstrual cycle, use of medication, diet, etc. were not controlled IV. Conclusion

18. ■ Changes in leptin may only be evident following acute stress ■ Higher levels of stress may be required to see a change in leptin levels ■ Action of chronic stress on immune function may not be mediated by leptin – leptin may not contribute to changes in the microenvironment of tumor cells IV. Conclusion

19. ■ May want to consider – Stress type and duration – Dietary intake ■ CARB Study, Glycemic Load and Obesity Effects on Cancer Biomarkers (Neuhouser, M., Lampe, J.W., PI) ■ Health SMART, Stress Management and Relaxation Training (McGregor, B.A., PI) ■ Conduct additional analyses on PACE data IV. Future Directions

20. Acknowledgements ■ Shirley Beresford, Ph.D. ■ Dale McLerran ■ Sonia Bishop ■ Bonnie McGregor, Ph.D.