Inhibition of PPARγ by BZ26, a GW9662 derivate, attenuated obesity-related breast cancer progression by inhibiting the reprogramming of mature adipocytes into to cancer associate adipocyte-like cells

Liangge Li; Jiafeng Geng; Wen Yu; Feifei Zhou; Zhihuan Zheng; Kaiyue Fu; Junjie Kong; Xiujing Feng

doi:10.3389/fphar.2023.1205030

Inhibition of PPARγ by BZ26, a GW9662 derivate, attenuated obesity-related breast cancer progression by inhibiting the reprogramming of mature adipocytes into to cancer associate adipocyte-like cells

Front Pharmacol. 2023 Aug 15:14:1205030. doi: 10.3389/fphar.2023.1205030. eCollection 2023.

Authors

Liangge Li^{1

2}, Jiafeng Geng^{1

2}, Wen Yu³, Feifei Zhou³, Zhihuan Zheng^{1

2}, Kaiyue Fu^{1

2}, Junjie Kong^{1

2}, Xiujing Feng^{1

2}

Affiliations

¹ Department of Endocrinology, Key Laboratory of Endocrine Glucose and Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
² School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
³ State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.

Abstract

Obesity has been associated with the development of 13 different types of cancers, including breast cancer. Evidence has indicated that cancer-associated adipocytes promote the proliferation, invasion, and metastasis of cancer. However, the mechanisms that link CAAs to the progression of obesity-related cancer are still unknown. Here, we found the mature adipocytes in the visceral fat of HFD-fed mice have a CAAs phenotype but the stromal vascular fraction of the visceral fat has not. Importantly, we found the derivate of the potent PPARγ antagonist GW9662, BZ26 inhibited the reprogramming of mature adipocytes in the visceral fat of HFD-fed mice into CAA-like cells and inhibited the proliferation and invasion of obesity-related breast cancer. Further study found that it mediated the browning of visceral, subcutaneous and perirenal fat and attenuated inflammation of adipose tissue and metabolic disorders. For the mechanism, we found that BZ26 bound and inhibited PPARγ by acting as a new modulator. Therefore, BZ26 serves as a novel modulator of PPARγ activity, that is, capable of inhibiting obesity-related breast cancer progression by inhibiting of CAA-like cell formation, suggesting that inhibiting the reprogramming of mature adipocytes into CAAs or CAA-like cells may be a potential therapeutic strategy for obesity-related cancer treatment.

Keywords: PPARγ modulator; cancer-associated adipocytes; mature adipocytes; obesity-related cancer; reprogramming.

Grants and funding

This work was supported by the National Natural Science Foundation of China (82073911), the Taishan Scholars Program (Tsqn202211220) and the Shandong Traditional Chinese Medicine Science and Technology Project (M-2022261).