1. Academic Validation
  2. Characterization of a new selective glucocorticoid receptor modulator with anorexigenic activity

Characterization of a new selective glucocorticoid receptor modulator with anorexigenic activity

  • Sci Rep. 2024 Apr 3;14(1):7844. doi: 10.1038/s41598-024-58546-1.
Junekyoung Lee # 1 Yeonghun Song # 1 Young A Kim 1 Intae Kim 1 Jooseon Cha 1 Su Won Lee 1 Yoonae Ko 1 Chong-Su Kim 2 Sanghee Kim 3 Seunghee Lee 4
Affiliations

Affiliations

  • 1 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea.
  • 2 Department of Food and Nutrition, College of Natural Information Sciences, Dongduk Women's University, Seoul, 02748, Korea.
  • 3 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea. pennkim@snu.ac.kr.
  • 4 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea. leeseung@snu.ac.kr.
  • # Contributed equally.
Abstract

Obesity, a worldwide epidemic, leads to various metabolic disorders threatening human health. In response to stress or fasting, glucocorticoid (GC) levels are elevated to promote food intake. This involves GC-induced expression of the orexigenic neuropeptides in agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus (ARC) via the GC receptor (GR). Here, we report a selective GR modulator (SGRM) that suppresses GR-induced transcription of genes with non-classical glucocorticoid response elements (GREs) such as Agrp-GRE, but not with classical GREs, and via this way may serve as a novel anti-obesity agent. We have identified a novel SGRM, 2-O-trans-p-coumaroylalphitolic acid (Zj7), a triterpenoid extracted from the Ziziphus jujube plant, that selectively suppresses GR transcriptional activity in Agrp-GRE without affecting classical GREs. Zj7 reduces the expression of orexigenic genes in the ARC and exerts a significant anorexigenic effect with weight loss in both high fat diet-induced obese and genetically obese db/db mouse models. Transcriptome analysis showed that Zj7 represses the expression of a group of orexigenic genes including Agrp and Npy induced by the synthetic GR ligand dexamethasone (Dex) in the hypothalamus. Taken together, Zj7, as a selective GR modulator, showed beneficial metabolic activities, in part by suppressing GR activity in non-classical GREs in orexigenic genes. This study demonstrates that a potential anorexigenic molecule may allow GRE-specific inhibition of GR transcriptional activity, which is a promising approach for the treatment of metabolic disorders.

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