Exploring the role of peroxisome proliferator-activated receptor γ (PPAR γ) in the beneficial effects of voluntary exercise in an endometriosis animal model

Endometriosis is a chronic gynecological disease defined by the presence of endometrial tissue outside the uterine cavity, causing symptoms such as dysmenorrhea, chronic pelvic pain, and infertility. Voluntary physical activity has been proven to reduce lesion development and inflammatory parameters in an animal model of endometriosis; however, the mechanisms remain unclear. Peroxisome proliferator-activated receptor γ (PPARγ), a transcription factor within the nuclear hormone receptor superfamily, can help regulate many physiological processes impacting inflammation and nociception. We previously found PPARγ to be overexpressed in vesicles of endometriosis animals receiving short-term exercise thus, we hypothesized that PPARγ mediates the beneficial effects of exercise in endometriosis. Methods: Female Sprague-Dawley rats were randomized to one of three groups: Endo Vehicle No-Exercise, Endo Vehicle Exercise, or Endo Drug Exercise (n=12/group). Endometriosis was induced by suturing four pieces of uterine horn on the intestinal mesentery (day 0). Animals receiving voluntary exercise had access to a running wheel through the remainder of the protocol. Pain behavior was assessed prior to surgery, prior to drug administration, and prior to sacrifice using Von Frey and hot plate. Endo Drug Exercise received a PPARγ antagonist (GW9662; 10 mg/kg) using a 1:1 mixture of peanut butter/cheese sauce from day 8 until sacrifice (day 61). Developed vesicles were identified and measured, and blood and peritoneal fluid collected. Colon, ileum, and mesenteric fat samples were stored for analysis. Results: Both exercise groups had significantly higher food consumption (p<0.001) when compared to non-exercise. No difference was observed between groups in weight change or absolute weight at time of sacrifice. The fat/body weight ratio was significantly decreased by exercise in both endometriosis groups (p<0.0001). All groups showed higher sensitivity to pain after surgery; the antagonist did not change this parameter. Exercise reduced the percentage of developed vesicles compared to non-exercise (64.6% vs. 85% respectively) and their size (area, length, weight), while this effect was reversed with the PPARγ antagonist, where 87.5% of vesicles developed. Exercise significantly decreased the colonic macroscopic damage (p<0.0001), and the antagonist reversed it (p<0.0001). The same trend was observed at the microscopic level. Microscopic analysis of the ileum revealed no significant impact of exercise or the antagonist. No significant differences were observed in cytokine levels in serum or peritoneal fluid aside from increased MIP3 alpha levels in serum of exercised animals (p<0.05), however there was a tendency for the antagonist to reverse trends observed with NrF2 and IFNγ. In conclusion:, our results reveal that PPARγ contributes to decreasing endometriosis lesion size via voluntary exercise since administering a PPARγ antagonist reverses its beneficial effects. Understanding how exercise improves endometriosis will help design more personalized non-pharmacological complementary patient interventions. R16GM149365, T34GM145504-01A1 & PRI MD summer program This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process. Information & Authors Information Published In Physiology Volume 40 • Issue S1 • May 2025 Copyright Copyright © 2025 Int. Union Physiol. Sci./Am. Physiol. Soc. History Published in print: May 2025 Published online: 12 May 2025

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