The adipokine secretion profile created from adipose tissue may represent the molecular mechanism behind the obesity‐breast cancer association. Two adipokines, adiponectin (ADIPO), and leptin (LEP), are altered with obesity and exert antagonistic effects on breast cancer proliferation. We set out to determine whether the adipose‐dependent tumor promoting growth environment created by a high‐fat diet (HFD) in female Sprague‐Dawley rats is altered compared to established responses in male rats and whether voluntary physical activity (PA) ameliorates any HFD‐dependent effects. We found that conditioned media (CM) created from the adipose tissue of female HFD‐fed rats increased the proliferation of MCF7 cells compared to those cells grown in CM prepared from lean adipose tissue. HFD‐CM inhibited AMPK and activated Akt signaling, decreased p27 phosphorylation at T198, reduced total p27 and AdiporR1 protein levels and promoted cell‐cycle entry. PA reversed the proliferative effects of HFD‐CM on MCF7 cells by preventing the effects of HFD on AMPK, Akt, p27 and AdipoR1, ultimately resulting in cell‐cycle withdrawal. Overexpressing AdipoR1 abolished the proliferative effects of the HFD‐CM on MCF7 cells and enhanced the anti‐proliferative effects PA on the HFD‐CM. Thus, PA represents a means to prevent deleterious obesity‐related alterations in tumor growth environment which are brought about by changes in adipokine secretion profile from adipose tissue in the presence of estrogen. Furthermore, although adipose produces hundreds of adipokines, the ADIPO:LEP ratio may serve to indicate the contribution of adipose in creating a tumor growth microenvironment.