SHORT COMMUNICATION Baseline Leptin Levels Predict Change in Leptin Levels During Weight Loss in Obese Breast Cancer Survivors Ananda Sen, PhD,* Kai-Lin Catherine Jen, PhD,† and Zora Djuric, PhD* *Department of Family Medicine, University of Michigan, Ann Arbor, Michigan; and †Department of Nutrition and Food Science, Wayne State University, Detroit, Michigan n Abstract: Leptin is an adipocyte-derived hormone involved in regulation of satiety, and it also appears to have a role in breast cancer risk. Leptin therefore might be a useful indicator of the potential preventive effects of weight loss in breast cancer survivors. In this study we examined whether the change in leptin levels could be predicted by weight loss in obese breast can- cer survivors. The subjects in this study were participating in a randomized trial of an individualized approach towards weight loss in Detroit, MI. Breast cancer survivors (body mass index of 30–44 kg ⁄ m2) were enrolled and fasting blood samples were obtained for leptin analysis over 1 year of study. Leptin levels were available from at least two time points for 36 women, and weight change ranged from a gain of 11% to a loss of 25% of baseline weight. Using a repeated-measures regression model, both baseline leptin level and concurrent percent body fat were found to synergistically predict leptin levels. Thus, for women with the same body fat, those with higher baseline leptin levels are predicted to exhibit smaller decreases in leptin with weight loss. Similar results were obtained for body weight and body weight change, but the associations with body fat were stronger. Breast cancer survivors with initially higher leptin levels may differ with regard to regulation of change in leptin during weight loss resulting in relatively smaller changes in leptin with equivalent amounts of weight loss. n Key Words: breast cancer, leptin, obesity, weight loss eight gain leading to overweight and obesity is (8–11). In a Canadian study, weight gain after a diagno- W becoming a world-wide epidemic that has sis of breast cancer was greater in women treated with increased dramatically in prevalence during recent years chemotherapy (2.5 kg in the year after diagnosis) than (1). This is a matter of great importance for the treat- with surgery and ⁄ or hormonal therapy alone (0.6 kg) ment of breast cancer as recurrence rates and survival in (12). One small study showed that weight gain in breast early-stage disease are both negatively impacted by cancer patients was not greater than that in control increased body weight in the vast majority of studies women; however, the breast cancer patients were that have been conducted (2–4). Unlike the effects of unique in that there was a significant increase in body obesity on de novo breast cancer risk, which is different fat 6 months after chemotherapy (13). Other studies in pre- and postmenopausal women, the adverse effect also have shown that chemotherapy for breast cancer of increased body weight on recurrence risk and survi- results in sarcopenic weight gain, perhaps as a result of val has been evident in both pre- and postmenopausal decreased physical activity levels (10,14,15). women (3,5). For example, in a large study of young Several metabolic alterations associated with the women, higher body mass was associated with tumors adverse health effects of increased body weight, and in of higher cellular proliferation and decreased survival particular an increase in body fat, may affect breast from breast cancer (6). Obesity also has been shown to cancer recurrence risk. These include the effects of obes- increase the risk of contralateral breast cancer (7). ity on insulin levels and oxidative stress (16–18). Eleva- Weight gain after treatment for breast cancer can ted leptin levels also have been associated with exacerbate pre-existing overweight. Women diagnosed increased breast cancer risk and poor prognosis in with breast cancer have been observed to gain weight, breast cancer (19,20), although not all studies agree which can negatively affect health status in survivorship (21–24). Leptin is, however, associated with insulin resistance, breast cancer cell proliferation, and possibly Address correspondence and reprint requests to: Zora Djuric, Depart- ment of Family Medicine, 2150 Cancer and Geriatrics Center, 1500 E. Med- anti-estrogen resistance (25–28). Leptin is an obesity- ical Center Drive, Ann Arbor, MI 48109-0930, USA, or e-mail: related hormone secreted by adipose tissue, and it is [email protected] decreased following weight loss. The physiological role ª 2007 Blackwell Publishing, Inc., 1075-122X/07 The Breast Journal, Volume 13 Number 2, 2007 180–186 of leptin may include signaling an increase in fat stores Leptin and Weight Loss • 181 to suppress hunger (29). In obese persons, however, lep- past 4 years and were free of any recurrence as con- tin resistance develops. Leptin resistance has been sug- firmed by a physician. Chemotherapy or radiation gested to occur at levels higher than 25 ng ⁄ mL as therapy was to have been completed at least 3 months transport of leptin to the brain is saturated at those lev- previously with the exception of tamoxifen. Recruit- els (29). Thus, very high levels of leptin might not be ment sources included direct mail to Race for the Cure incrementally effective for curbing energy intake. This participants, press releases and brochures at breast brings into concern the observations made in most stud- clinics. The study was reviewed and approved by the ies that breast cancer patients have significantly higher Institutional Review Board of Wayne State University. blood leptin levels than women without cancer, but this Subjects gave informed, written consent to participate. might not be the case in premenopausal women which Details of the study have been published previously is consistent with observations that obesity protects (44), and in the present analysis 36 women who com- against premenopausal breast cancer risk (20,30–35). pleted 12 months of study were included. We reported previously that the obese breast cancer sur- Forty-eight subjects were randomly assigned to one vivors in our study had higher leptin levels than those of four groups: control, Weight Watchers (WW), indi- reported for breast cancer patients of mixed body vidualized counseling, or a combination of WW and weight status (36). In breast cancer patients, regulation individualized counseling. Nine of the forty-eight of leptin pathways has not been investigated in as much women did not complete 12 months of participation. detail as it has in other obese persons. Subjects in the control arm received the National Can- A number of mechanisms by which leptin can cer Institute’s ‘‘Action Guide to Healthy Eating’’ and increase breast cancer risk are currently being exam- the ‘‘Food Guide Pyramid’’ pamphlets, but they ined. In vitro, leptin exerts proliferative effects in breast received no other dietary or exercise instructions or cancer cells (37–39). Leptin also appears to be angio- help. For the WW arm, women were given free cou- genic (19). In human breast tissues, leptin was detected pons and encouraged to attend WW meetings but in the cancerous tissue, the surrounding normal tissue, received no other dietary or exercise instruction. For and in areas of atypical hyperplasia, but it was not the Individualized arm, women received telephone localized in the normal breast (37). Leptin has therefore counseling with a registered dietitian. Finally, for the been hypothesized to be a reasonable target for inter- Combination arm, subjects received both individual- ventions that aim to decrease breast cancer risk (40). ized counseling and were asked to attend weekly WW Leptin decreased more in obese breast cancer survivors meetings using free coupons. This resulted in a popu- who lost 10% of their initial body weight versus those lation of women with varying amounts of weight loss losing less weight over 12 months (36). A decrease in at 12 months. leptin levels, if disclosed to study subjects, might be a motivating factor to lose weight because of its relation- Assessments ship to breast cancer risk. Previous studies in obese Women were asked to come to the appointments women, however, have indicated that high leptin levels after an overnight fast and to drink two glasses of are associated with low resting energy expenditure water in the morning. Plasma was prepared immedi- thereby affecting the extent of weight loss achieved ately after drawing blood at baseline, 3, 6 and (41–43). It was therefore important to determine whe- 12 months and stored frozen at )70°C until analysis. ther or not change in leptin levels can simply be predic- Leptin levels were determined with commercial ted by extent of weight or body fat loss in obese breast enzyme immunoassays kits using a high-affinity poly- cancer survivors or whether baseline leptin and body clonal capture antibody (Linco Research, St. Charles, fat do affect the subsequent rate of change in leptin lev- MO). Levels of insulin were also measured by radio- els over time. immunoassay (ICN Biomedicals Inc., Costa Mesa, CA), and glucose levels were measured using a spec- trophotometric assay with glucose oxidase (Sigma METHODS Chemical Co., St. Louis, MO). Questionnaires were administered at baseline and intervals thereafter to Subjects capture demographic and health factors. At baseline, Eligible subjects were aged 18–70. Study subjects 3, 6, 9 and 12 months, the women were weighed in had stage I or II breast cancer diagnosed within the clothing but without shoes using a Health-o-Meter 182 • sen et al. Professional Beam Scale, model 402KLS (Bridgeview, 47–34) and after 12 months it was 37.5% (SD 3.8, IL). Percent body fat was measured using tetrapolar n ¼ 36, range 44–25). bioelectrical impedance (model BIA101S; RJL Sys- At baseline, leptin levels were available for 35 tems, Clinton Township, MI).