Selective activation of PPARα maintains thermogenic capacity of beige adipocytes

Gentaro Egusa; Haruya Ohno; Gaku Nagano; Junji Sagawa; Hiroko Shinjo; Yutaro Yamamoto; Natsumi Himeno; Yoshimi Morita; Akinori Kanai; Ryuta Baba; Kazuhiro Kobuke; Kenji Oki; Masayasu Yoneda; Noboru Hattori

doi:10.1016/j.isci.2023.107143

Selective activation of PPARα maintains thermogenic capacity of beige adipocytes

iScience. 2023 Jun 19;26(7):107143. doi: 10.1016/j.isci.2023.107143. eCollection 2023 Jul 21.

Authors

Affiliations

¹ Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
² Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
³ Department of Preventive Medicine for Diabetes and Lifestyle-related Diseases, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Abstract

Beige adipocytes are inducible thermogenic adipocytes used for anti-obesity treatment. Beige adipocytes rapidly lose their thermogenic capacity once external cues are removed. However, long-term administration of stimulants, such as PPARγ and β-adrenergic receptor agonists, is unsuitable due to various side effects. Here, we reported that PPARα pharmacological activation was the preferred target for maintaining induced beige adipocytes. Pemafibrate used in clinical practice for dyslipidemia was developed as a selective PPARα modulator (SPPARMα). Pemafibrate administration regulated the thermogenic capacity of induced beige adipocytes, repressed body weight gain, and ameliorated impaired glucose tolerance in diet-induced obese mouse models. The transcriptome analysis revealed that the E-twenty-six transcription factor ELK1 acted as a cofactor of PPARα. ELK1 was mobilized to the Ucp1 transcription regulatory region with PPARα and modulated its expression by pemafibrate. These results suggest that selective activation of PPARα by pemafibrate is advantageous to maintain the function of beige adipocytes.

Keywords: Animal Physiology; Cell biology; Molecular biology.