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. 2016 Jul;157(7):2870-82.
doi: 10.1210/en.2016-1092. Epub 2016 May 13.

High-Fat Diet Promotion of Endometriosis in an Immunocompetent Mouse Model is Associated With Altered Peripheral and Ectopic Lesion Redox and Inflammatory Status

Melissa E Heard  1 , Stepan B Melnyk  1 , Frank A Simmen  1 , Yanqing Yang  1 , John Mark P Pabona  1 , Rosalia C M Simmen  1
Affiliations

High-Fat Diet Promotion of Endometriosis in an Immunocompetent Mouse Model is Associated With Altered Peripheral and Ectopic Lesion Redox and Inflammatory Status

Melissa E Heard et al. Endocrinology. 2016 Jul.

Abstract

Endometriosis is a benign gynecological condition that causes considerable morbidity due to associated infertility, debilitating pelvic pain and inflammatory dysfunctions. Diet is a highly modifiable risk factor for many chronic diseases, but its contribution to endometriosis has not been extensively investigated, due partly to the paradoxical inverse association between obesity and disease incidence. Nevertheless, chronic exposure to dietary high-fat intake has been linked to greater systemic inflammation and oxidative stress, both features of women with endometriosis. Here, we evaluated the effects of a high-fat diet (HFD) (45% fat kcal) on endometriosis progression using an immunocompetent mouse model where ectopic lesion incidence was induced in wild-type recipients by ip administration of endometrial fragments from transcription factor Krüppel-like factor 9-null donor mice. We show that HFD significantly increased ectopic lesion numbers in recipient mice with no significant weight gain and modifications in systemic ovarian steroid hormone and insulin levels, relative to control diet-fed (17% fat kcal) mice. HFD promotion of lesion establishment was associated with reductions in stromal estrogen receptor 1 isoform and progesterone receptor expression, increased F4/80-positive macrophage infiltration, higher stromal but not glandular epithelial proliferation, and enhanced expression of proinflammatory and prooxidative stress pathway genes. Lesion-bearing HFD-fed mice also displayed higher peritoneal fluid TNFα and elevated local and systemic redox status than control diet-fed counterparts. Our results suggest that HFD intake exacerbates endometriosis outcome in the absence of ovarian dysfunction and insulin resistance in mice and warrants further consideration with respect to clinical management of endometriosis progression and recurrence in nonobese patients.

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Figures

Figure 1.
Figure 1.. Experimental design and characterization of endometrial-like lesions derived from mice fed CD or HFD.
A, Schematic representation of the generation of endometrial ectopic lesions in mice and their analyses. Klf9 WT mice were used as recipients of endometrial fragments from Klf9 null mice (donors), as previously described (28), with the indicated numbers of mice used for each diet group. B, Representative bright-field images of ectopic lesions isolated from WT recipients assigned to either CD or HFD groups, 4 weeks after ip administration of Klf9 null endometrium. Scale bar, 1 mm. C, H&E-stained sections of representative CD or HFD lesions at ×400 magnification. Scale bar, 20 μm. D, Representative sections of CD or HFD ectopic lesions showing Ki-67-positive stromal cells. E, Representative sections of CD or HFD ectopic lesions showing TUNEL-positive stromal cells. Red arrows indicate Ki-67-positive (D) and TUNEL staining (E) stromal cells. Four lesions per dietary group, each representing an individual mouse, were analyzed. Scale bar, 20 μm. For D and E, the percentages of staining cells (expressed as mean ± SEM) were quantified by counting the number of immunopositive nuclei over the total number of stromal cells per field and are presented as bar graphs; *, P < .05 by Student's t test.
Figure 2.
Figure 2.. Macrophage F4/80+ cells in CD and HFD ectopic lesions in mice.
A, Representative sections of ectopic lesions harvested from CD- and HFD-fed mice, showing positive immunostaining for F4/80 in HFD lesion-stromal cells. Scale bar, 100 μm. B, Graph represents percentages of F4/80+ areas in stromal cells of CD or HFD ectopic lesions, determined by counting the number of immunopositive areas over the total number of stromal areas evaluated ×100. Each point represents a lesion from an individual mouse.
Figure 3.
Figure 3.. ESR and PGR are differentially expressed in CD and HFD ectopic lesions in a mouse model.
A, Transcript levels of Pgr and Esr isoforms were determined in CD or HFD lesions by QPCR. Data (mean ± SEM) are expressed as FC from CD lesion group and were obtained from n = 7 lesions, with each lesion isolated from an individual mouse per diet group. B and C, Representative sections of CD and HFD ectopic lesions showing PGR-positive (B) and ESR1-positive (C) stromal cells (indicated by red arrowheads). Four lesions per dietary group, each representing an individual mouse, were analyzed. Scale bar, 20 μm. For B and C, the percentages of immunostaining cells (expressed as mean ± SEM) were quantified by counting the number of immunopositive stromal nuclei over the total number of stromal cells per field and are presented as bar graphs; *, P < .05 by Student's t test.
Figure 4.
Figure 4.. HFD intake altered inflammatory and oxidative stress signaling pathways in endometriotic lesions in a mouse model.
A, The top 50 up- or down-regulated genes by HFD in ectopic lesions were determined from microarray analysis. Confirmation of gene expression changes for genes associated with inflammation (B) or oxidative stress (C) from CD or HFD lesions was performed by QPCR. Data (mean ± SEM) are expressed as FC from CD lesions and were obtained from n = 7 (CD) and 8 (HFD) lesions; *, P < .05 by Student's t test. Bars with numerical P values show tendency for significance.
Figure 5.
Figure 5.. HFD induces systemic and local alterations in antioxidant/oxidant balance in recipient mice with lesions.
Levels of oxidants and antioxidants and their ratios in sera (A) and peritoneal fluids (B) of lesion-bearing mice fed CD or HFD are shown. Data are expressed as mean ± SEM and were obtained from n = 7 (CD) or 9 (HFD) mice. C, Levels of 8-OH-guanosine in DNA isolated from CD or HFD lesions. Data are expressed as mean ± SEM from n = 4 mice per diet group; *, P < .05 by Student's t test.
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