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

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.

Dietary supplementation of barley and/or dates attenuate hypercholesterolemic‐induced endometrial dysfunction in Wistar albino rats via alleviation of apoptotic pathways and enhancing oxidative capacity

“…These findings implied that the increased hyperplasic endometrial lesions in hypercholesterolemic rats were owing to the elevated reactive oxygen species-mediated metabolic impairments. In agreement with these records, Heard et al, (2016) reported similar oxidative stress and methylation capacity in high fat diet-fed mice; manifested by decreased GSH and increased MDA and 3′-Nitrotyrosine. In addition, it was reported that increased oxidative redox is detrimental to female reproductive tract (Agarwal, Aponte-Mellado, Premkumar, Shaman, & Gupta, 2012).…”

“…Conclusively, we recorded elevated levels of assayed TNF-α in hypercholesterolemic rats. In line with these results, Heard et al (2016) illustrated that high fat diet promoted oxidative and inflammatory stress and dramatically Consistently, several studies have attributed the structural and functional impairments of endometrium to the increased endometrial proliferation rate and angiogenesis (Chae et al, 2008;Lin, Lai, Lei, & Wing, 2006). Indeed, high cholesterol diet-fed rats are thought to possess increased inflammatory reactions by activating macrophage-directed production of cytokines, growth factors (Lin et al, 2006), histamine, chemokines, proteases, and mast cell-specific chymase and tryptase (Zhang & Shi, 2012).…”

“…Conclusively, we recorded elevated levels of assayed TNF‐α in hypercholesterolemic rats. In line with these results, Heard et al () illustrated that high fat diet promoted oxidative and inflammatory stress and dramatically increased TNF‐α and F4/80 macrophage infiltration; resulting in endometriosis.…”

“…Our data were emphasized by a recent study of Cheng et al () who reported decreased expression of PCNA and increased nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) and peroxisome proliferator‐activated receptor gamma (PPARγ) signaling pathways in high fat diet‐fed C57BL/6 mice. In tandem with increased oxidative stress, it has been demonstrated that high fat diet is responsible for the increased endometrial cell apoptosis via increased expression of 8‐OHdG (Heard et al, ). Also, Onstad, Schmandt, and Lu () stated that DNA damage represents a key factor in developing endometrial hyperplasia and cancer progression.…”

Influence of diet on the risk of developing endometriosis

“…A high fat diet in which more than 45% of daily calorie requirements come from fat can also increase oxidative stress and inflammation in the body, thereby increasing the risk of developing endometriosis. This finding comes from a 2016 study by Heard et al conducted in mice in which the experimental group was on the diet of 45% of fat and the control group was on a diet of 17% of fat [34]. Another study performed on animals in 2013 by Herington et al seems to confirm the positive influence of fish oils on decreasing the risk of developing endometriosis, demonstrating that supplementation with fish oil reduced the development of postoperative adhesions connected with endometriosis [35].…”