1. Academic Validation
  2. Theobromine suppresses adipogenesis through enhancement of CCAAT-enhancer-binding protein β degradation by adenosine receptor A1

Theobromine suppresses adipogenesis through enhancement of CCAAT-enhancer-binding protein β degradation by adenosine receptor A1

  • Biochim Biophys Acta Mol Cell Res. 2017 Dec;1864(12):2438-2448. doi: 10.1016/j.bbamcr.2017.09.017.
Takakazu Mitani 1 Shun Watanabe 2 Yasukiyo Yoshioka 3 Shigeru Katayama 2 Soichiro Nakamura 2 Hitoshi Ashida 4
Affiliations

Affiliations

  • 1 Department of Interdisciplinary Genome Sciences and Cell Metabolism, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, Japan.
  • 2 Department of Bioscience and Biotechnology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, Japan.
  • 3 Organization of Advanced Science and Technology, Kobe University, Nada-ku, Kobe, Japan.
  • 4 Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 6578501, Japan. Electronic address: ashida@kobe-u.ac.jp.
Abstract

Theobromine, a methylxanthine derived from cacao beans, reportedly has various health-promoting properties but molecular mechanism by which effects of theobromine on adipocyte differentiation and adipogenesis remains unclear. In this study, we aimed to clarify the molecular mechanisms of the anti-adipogenic effect of theobromine in vitro and in vivo. ICR mice (4week-old) were administered with theobromine (0.1g/kg) for 7days. Theobromine administration attenuated gains in body and epididymal adipose tissue weights in mice and suppressed expression of adipogenic-associated genes in mouse adipose tissue. In 3T3-L1 preadipocytes, theobromine caused degradation of C/EBPβ protein by the ubiquitin-proteasome pathway. Pull down assay showed that theobromine selectively interacts with Adenosine Receptor A1 (AR1), and AR1 knockdown inhibited theobromine-induced C/EBPβ degradation. Theobromine increased sumoylation of C/EBPβ at Lys133. Expression of the small ubiquitin-like modifier (SUMO)-specific protease 2 (SENP2) gene, coding for a desumoylation Enzyme, was suppressed by theobromine. In vivo knockdown studies showed that AR1 knockdown in mice attenuated the anti-adipogenic effects of theobromine in younger mice. Theobromine suppresses adipocyte differentiation and induced C/EBPβ degradation by increasing its sumoylation. Furthermore, the inhibition of AR1 signaling is important for theobromine-induced C/EBPβ degradation.

Keywords

Adenosine receptor; Adipogenesis; CCAAT/enhancer-binding protein; Sumoylation; Theobromine.

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