BA10 - Adipokines and risk of obesity-related disease

Investigator Names and Contact Information

Gloria Ho (gho1@NSHS.edu)

Introduction/Intent

Obesity is a risk factor for several disease outcomes, including some types of cancer, type 2 diabetes, and cardiovascular disease (CVD). The biological mechanism underlying the association between obesity and these diseases may partially be mediated through adipokines (or adipocytokines), proteins produced by the adipocytes and other cells in adipose tissue. Adipokines have diverse bioactivities, such as regulating insulin sensitivity, the inflammatory response, blood coagulation, vascular endothelial function, sex steroid and lipid metabolisms, and cell proliferation, which contribute to disease pathogenesis.1-3
The purpose of this proposed study is to examine the associations between adipokines and risk of obesity-related diseases, particularly ischemic stroke and cancers of the breast, colorectum, and endometrium. The adipokines of interest include interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, adiponectin, leptin, resistin, hepatocyte growth factor (HGF), and plasminogen activator inhibitor (PAI)-1. In addition, C-reactive protein (CRP), a well established inflammatory marker and risk factor for cardiovascular disease (CVD), will also be measured.

To date, there are few epidemiologic data on the etiological roles of these adipokines in ischemic stroke and the 3 cancers under study. TNF-α, IL-6, adiponectin, and leptin have been studied more extensively in humans than the other adipokines, but their associations with stroke and cancer have only been evaluated in a few small nested case-control studies with fewer than 200 cases.4-10 This study will be the first large-scale prospective study to elucidate the effects of adipokine levels on risk of ischemic stroke and cancers of the breast, colorectum, and endometrium.

This Adipokine Study will be conducted within the Observational Study of the Women’s Health Initiative (WHI-OS). It will be an add-on to two funded WHI-OS ancillary studies conducted by our research team at the Albert Einstein College of Medicine: the INS/IGF Cancer Study, which is examining insulin, IGF-1, and estradiol at the serologic and genetic levels in 900 breast cancer, 500 colorectal cancer, 300 endometrial cancer, and 900 subcohort subjects, and the Stroke Study, which is a nested case-control study of the serum levels of inflammatory and thrombotic markers in 970 ischemic stroke cases and 970 matched controls. In the Adipokine Study proposed here, the complete panel of 7 adipokines and CRP will be measured in all of the subjects in the INS/IGF Cancer Study, whereas the 4 adipokines (adiponectin, leptin, resistin, and HGF) that are not already included in the Stroke Study will be assayed in the stroke cases and controls. By extending these studies, data that are available already (e.g., the HOMA index for insulin resistance) can be analyzed along with the adipokine data for their independent effects on the study outcomes.

Specific Aims:

1. To examine if plasma levels of IL-6, TNF-α, CRP, adiponectin, leptin, resistin, HGF, and PAI-1 at baseline are associated with risk of obesity-related diseases, particularly ischemic stroke and cancers of the breast, endometrium, and colorectum. It is hypothesized that low levels of adiponectin and high levels of the other adipokines are associated with elevated risk of the diseases under study.
   • a. Using available data in the INS/IGF Cancer Study, we will examine if the effects of adipokines on risk of the 3 cancers are independent of other obesity-related physiological factors, namely insulin resistance (as measured by homeostasis model assessment), estradiol, and free IGF-I.
   • b. In the Stroke Study, we will also assess the independent effects of adipokines and other obesity-related CVD risk factors, namely insulin resistance, dyslipidemia hypertension, and markers for vascular dysfunction [vascular cellular adhesion molecule (VAM)-1 and E-selectin].
2. To evaluate if adipokines and other obesity-related physiological factors, that are identified in Aim #1 to be significantly associated with study outcomes of interest (stroke and the 3 cancers), mediate the effect of obesity on the risk of these outcomes. We hypothesize that these factors are the intermediary parameters, and accounting for them will significantly attenuate the positive association between measures of obesity and risk of the diseases under study.
3. To assess cross-sectionally whether demographic and lifestyle risk factors identified in the INS/IGF Cancer Study and Stroke Study are associated with levels of adipokines.

Results/Findings Some of the publications related to this ancillary study are: 893, 894, 922, 1029, 1083, 1507.

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Papers section of this website.

References

1. Falk RT, Brinton LA, Madigan MP, et al., Interrelationships between serum leptin, IGF-1, IGFBP3, C-peptide and prolactin and breast cancer risk in young women. Breast Cancer Res Treat,2006.
2. Ritchie SA, Ewart MA, Perry CG, et al., The role of insulin and the adipocytokines in regulation of vascular endothelial function. Clin Sci (Lond) 107(6):519-32,2004.
3. Koerner A, Kratzsch J, and Kiess W, Adipocytokines: leptin--the classical, resistin--the controversical, adiponectin--the promising, and more to come. Best Pract Res Clin Endocrinol Metab 19(4):525-46,2005.
4. Krajcik RA, Massardo S, and Orentreich N, No association between serum levels of tumor necrosis factor- (TNF- ) or the soluble receptors sTNFR1 and sTNFR2 and breast cancer risk. Cancer Epidemiol Biomarkers Prev 12:945-6,2003.
5. Stattin P, Soderberg S, Biessy C, et al., Plasma leptin and breast cancer risk: a prospective study in northern Sweden. Breast Cancer Res Treat 86(3):191-6,2004.
6. Stattin P, Lukanova A, Biessy C, et al., Obesity and colon cancer: does leptin provide a link? Int J Cancer 109(1):149-52,2004.
7. Tamakoshi K, Toyoshima H, Wakai K, et al., Leptin is associated with an increased female colorectal cancer risk: a nested case-control study in Japan. Oncology 68(4-6):454-61,2005.
8. Soderberg S, Stegmayr B, Stenlund H, et al., Leptin, but not adiponectin, predicts stroke in males. J Intern Med 256(2):128-36,2004.
9. Wei EK, Giovannucci E, Fuchs CS, et al., Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study. J Natl Cancer Inst 97(22):1688-94,2005.
10. Lukanova A, Soderberg S, Kaaks R, et al., Serum adiponectin is not associated with risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 15(2):401-2,2006.