Dietary Weight Loss and Exercise Effects on Serum Biomarkers of Angiogenesis in Overweight Postmenopausal Women: A Randomized Controlled Trial

Abstract

Obese and sedentary persons have an increased risk for cancer, but underlying mechanisms are poorly understood. Angiogenesis is common to adipose tissue formation and remodeling, and to tumor vascularization. 439 overweight/obese, healthy, postmenopausal women (body mass index (BMI)>25 kg/m2) aged 50-75 years, recruited between 2005-2008 were randomized to a 4-arm 12-month randomized controlled trial, comparing a caloric restriction diet arm (goal: 10% weight-loss, N=118), aerobic exercise arm (225 min/week of moderate-to-vigorous activity, N=117), a combined diet+exercise arm (N=117), or control (N=87) on circulating levels of angiogenic biomarkers. Vascular endothelial growth factor (VEGF), plasminogen activator inhibitor-1 (PAI-1); and pigment epithelium-derived factor (PEDF) were measured by immunoassay at baseline and 12-months. Changes were compared using generalized estimating equations, adjusting for baseline BMI age, and race/ethnicity. Participants randomized to the diet+exercise arms had statistically significantly greater reductions in PAI-1 at 12-months compared to controls (-19.3% vs. +3.48% respectively, P<0.0001). Participants randomized to the diet and diet+exercise arms had statistically significantly greater reductions in PEDF (-9.20%, -9.90% respectively, both P<0.0001) and VEGF (-8.25%, P=0.0005; -9.98%, P<0.0001, respectively) compared to controls. There were no differences in any of the analytes in participants randomized to the exercise arm compared to controls. Increasing weight-loss was statistically significantly associated with linear trends of greater reductions in PAI-1, PEDF and VEGF. Weight-loss is significantly associated with reduced circulating VEGF, PEDF and PAI-1, and could provide incentive for reducing weight as a cancer prevention method in overweight and obese individuals.

Long-Term Effects of Weight Loss and Exercise on Biomarkers Associated with Angiogenesis

“…There was a statistically significant linear trend of reductions in PEDF and VEGF with increasing weight loss among participants randomized to both the diet and diet+exercise arm (all P trend <0.0001). Participants randomized to the exercise arm also had statistically significant linear trend of reductions in PEDF with increasing levels of weight loss (12)…”

“…In our prior studies of the impact of weight loss on reducing levels of circulating biomarkers of angiogenesis (10,12), we discussed the potential utility of weight loss as a chemopreventive approach targeting both angiogenesis and inflammation in healthy individuals. (35) Again, while it is currently impossible to ascertain whether reductions in circulating levels of angiogenic factors might inhibit tumor cell growth and progression by blocking the vascularization of indolent tumors, the long-term maintenance of reduced levels of VEGF and PEDF can only reflect a more beneficial angiogenic profile.…”

“…To correct for assay drift over time and to incorporate these data into the baseline and 12-month data, we included a series of baseline and 12-month samples that matched samples that had been previously assayed in each batch of 30-month samples. (12) We compared the results from these samples with previously measured results, and used mean of the difference to normalize the newly assayed 30-month data.…”

“…Increasing weight loss was statistically significantly associated with linear trends of greater reductions in PAI-1, PEDF and VEGF. (12) However, it is currently unknown whether beneficial changes in these and other cancer-related biomarkers persist long-term. Some studies on diabetes prevention indicate that, despite weight regain, risk of developing diabetes is reduced on average for several years.…”

Effect of Weight Loss Surgery on Biomarkers of Angiogenesis in Obese Patients

“…Weight loss surgery has become the most popular method to treat morbidly obese patients because it has substantial beneficial associations with weight loss and several clinical outcomes [18]. The recent studies showed that obesity-associated weight loss via diet contributed to the reduction in some circulating levels of positive regulators of angiogenesis [19,20], depending on the extent of weight loss [19]. Other authors demonstrated that PDGF-B-PDGFRβ signaling regulates adipose tissue expansion and glucose metabolism via vascular remodeling in an animal model of diet-induced obesity [5].…”