The ATF3 inducer protects against diet-induced obesity via suppressing adipocyte adipogenesis and promoting lipolysis and browning

Hui-Chen Ku; Tsai-Yun Chan; Jia-Fang Chung; Yung-Hsi Kao; Ching-Feng Cheng

doi:10.1016/j.biopha.2021.112440

The ATF3 inducer protects against diet-induced obesity via suppressing adipocyte adipogenesis and promoting lipolysis and browning

Biomed Pharmacother. 2022 Jan:145:112440. doi: 10.1016/j.biopha.2021.112440. Epub 2021 Nov 25.

Authors

Hui-Chen Ku¹, Tsai-Yun Chan¹, Jia-Fang Chung¹, Yung-Hsi Kao², Ching-Feng Cheng³

Affiliations

¹ Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan.
² Department of Life Sciences, National Central University, Taoyuan 320, Taiwan.
³ Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Department of Pediatrics, Tzu Chi University, Hualien 97004, Taiwan. Electronic address: chengcf@mail.tcu.edu.tw.

PMID: 34839254
DOI: 10.1016/j.biopha.2021.112440

Abstract

In this study, we investigated whether the activating transcription factor 3 (ATF3) inducer ST32db, a synthetic compound with a chemical structure similar to that of native Danshen compounds, exerts an anti-obesity effect in 3T3-L1 white preadipocytes, D16 beige cells, and mice with obesity induced by a high-fat diet (HFD). The results showed that ST32db inhibited 3T3-L1 preadipocyte differentiation by inhibiting adipogenesis/lipogenesis-related gene (and protein levels) and enhancing lipolysis-related gene (and protein levels) via the activation of β3-adrenoceptor (β3-AR)/PKA/p38, AMPK, and ERK pathways. Furthermore, ST32db inhibited triacylglycerol accumulation in D16 adipocytes by suppressing adipogenesis/lipogenesis-related gene (and protein levels) and upregulating browning gene expression by suppressing the β3-AR/PKA/p38, and AMPK pathways. Intraperitoneally injected ST32db (1 mg kg^-1 twice weekly) inhibited body weight gain and reduced the weight of inguinal white adipose tissue (iWAT), epididymal WAT (eWAT), and mesenteric WAT, with no effects on food intake by the obese mice. The adipocyte diameter and area of iWAT and eWAT were decreased in obese mice injected with ST32db compared with those administered only HFD. In addition, ST32db significantly suppressed adipogenesis and activated lipolysis, browning, mitochondrial oxidative phosphorylation, and β-oxidation-related pathways by suppressing the p38 pathway in the iWAT of the obese mice. These results indicated that the ATF3 inducer ST32db has therapeutic potential for reducing obesity.

Keywords: activating transcription factor 3 inducer; adipocyte; adipogenesis; anti-obesity; browning; lipolysis.

MeSH terms

3T3-L1 Cells
Activating Transcription Factor 3* / drug effects
Activating Transcription Factor 3* / metabolism
Adipocytes / drug effects
Adipocytes / metabolism
Adipogenesis / drug effects
Adipose Tissue, White / drug effects
Animals
Anti-Obesity Agents* / pharmacology
Cell Differentiation / drug effects
Diet, High-Fat / adverse effects
Lipolysis / drug effects
Male
Mice
Mice, Inbred C57BL
Obesity* / drug therapy
Weight Gain / drug effects

Substances

Activating Transcription Factor 3
Anti-Obesity Agents
Atf3 protein, mouse
ST32db