TY - JOUR
T1 - Pioglitazone inhibits periprostatic white adipose tissue inflammation in obese mice
AU - Miyazawa, Miki
AU - Subbaramaiah, Kotha
AU - Bhardwaj, Priya
AU - Zhou, Xi Kathy
AU - Wang, Hanhan
AU - Falcone, Domenick J.
AU - Giri, Dilip D.
AU - Dannenberg, Andrew J.
N1 - Funding Information:
This work was supported by the Prostate Cancer Foundation (Movember-Challenge Award, A.J. Dannenberg), Tokyo Association for Clinical Surgery (M. Miyazawa), Patricia and William Kleh (A.J. Dannenberg), and NIH/NCIP50 CA092629 (A.J. Dannenberg).
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/4
Y1 - 2018/4
N2 - Obesity is associated with an increased incidence of high-grade prostate cancer and poor prognosis for prostate cancer patients. Recently, we showed that obesityrelated periprostatic white adipose tissue (WAT) inflammation, characterized by crown-like structures (CLS) consisting of dead or dying adipocytes surrounded by macrophages, was associated with high-grade prostate cancer. It is possible, therefore, that agents that suppress periprostatic WAT inflammation will alter the development or progression of prostate cancer. Pioglitazone, a ligand of PPARγ, is used to treat diabetes and possesses antiinflammatory properties. Here, our main objectives were to determine whether pioglitazone inhibited obesityrelated periprostatic WAT inflammation in mice and then to elucidate the underlying mechanism. Treatment with pioglitazone reduced the density of CLS in periprostatic fat and suppressed levels of TNFα, TGFβ, and the chemokine monocyte chemoattractant protein-1 (MCP-1). Importantly, the ability of pioglitazone to suppress periprostatic WAT inflammation was abrogated in MCP-1 knockout mice. Pioglitazone caused dose-dependent induction of both adiponectin, an anti-inflammatory adipokine, and its receptor AdipoR2 in cultured 3T3-L1 cells and in periprostatic WAT of obesemice. Pioglitazone blocked TNFα-mediated induction of MCP-1 in 3T3-L1 cells, an effect that was attenuated when either adiponectin or AdipoR2 were silenced. Taken together, pioglitazone- mediated induction of adiponectin suppressed the elevation in MCP-1 levels, thereby attenuating obesity-related periprostatic WAT inflammation. These findings strengthen the rationale for future efforts to determine whether targeting the PPARγ-adiponectin- MCP-1 axis will decrease periprostatic adipose inflammation and thereby reduce the risk of high-grade prostate cancer or improve outcomes for men with prostate cancer.
AB - Obesity is associated with an increased incidence of high-grade prostate cancer and poor prognosis for prostate cancer patients. Recently, we showed that obesityrelated periprostatic white adipose tissue (WAT) inflammation, characterized by crown-like structures (CLS) consisting of dead or dying adipocytes surrounded by macrophages, was associated with high-grade prostate cancer. It is possible, therefore, that agents that suppress periprostatic WAT inflammation will alter the development or progression of prostate cancer. Pioglitazone, a ligand of PPARγ, is used to treat diabetes and possesses antiinflammatory properties. Here, our main objectives were to determine whether pioglitazone inhibited obesityrelated periprostatic WAT inflammation in mice and then to elucidate the underlying mechanism. Treatment with pioglitazone reduced the density of CLS in periprostatic fat and suppressed levels of TNFα, TGFβ, and the chemokine monocyte chemoattractant protein-1 (MCP-1). Importantly, the ability of pioglitazone to suppress periprostatic WAT inflammation was abrogated in MCP-1 knockout mice. Pioglitazone caused dose-dependent induction of both adiponectin, an anti-inflammatory adipokine, and its receptor AdipoR2 in cultured 3T3-L1 cells and in periprostatic WAT of obesemice. Pioglitazone blocked TNFα-mediated induction of MCP-1 in 3T3-L1 cells, an effect that was attenuated when either adiponectin or AdipoR2 were silenced. Taken together, pioglitazone- mediated induction of adiponectin suppressed the elevation in MCP-1 levels, thereby attenuating obesity-related periprostatic WAT inflammation. These findings strengthen the rationale for future efforts to determine whether targeting the PPARγ-adiponectin- MCP-1 axis will decrease periprostatic adipose inflammation and thereby reduce the risk of high-grade prostate cancer or improve outcomes for men with prostate cancer.
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U2 - 10.1158/1940-6207.CAPR-17-0296
DO - 10.1158/1940-6207.CAPR-17-0296
M3 - Article
C2 - 29222347
AN - SCOPUS:85047723856
SN - 1940-6207
VL - 11
SP - 215
EP - 226
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 4
ER -