Nobiletin ameliorates high fat-induced disruptions in rhythmic glucagon-like peptide-1 secretion

Sci Rep. 2022 May 4;12(1):7271. doi: 10.1038/s41598-022-11223-7.


The incretin hormone glucagon-like peptide-1 (GLP-1) is secreted by the intestinal L cell in response to nutrient intake. However, GLP-1 secretion also follows a circadian rhythm which is disrupted by the saturated fatty acid palmitate in vitro and high-fat diet (HFD) feeding in vivo. The flavonoid nobiletin is a clock enhancer which improves metabolic homeostasis. Therefore, the aim of this study was to elucidate whether and how nobiletin mitigates the negative effects of palmitate and HFD-feeding on rhythmic GLP-1 release. Pre-treatment of murine GLUTag L cells with palmitate dampened the GLP-1 secretory response at the normal peak of secretion, while nobiletin co-treatment restored GLP-1 secretion and upregulated the 'metabolic pathway' transcriptome. Mice fed a HFD also lost their GLP-1 secretory rhythm in association with markedly increased GLP-1 levels and upregulation of L cell transcriptional pathways related to 'sensing' and 'transducing' cellular stimuli at the normal peak of GLP-1 release. Nobiletin co-administration reduced GLP-1 levels to more physiological levels and upregulated L cell 'oxidative metabolism' transcriptional pathways. Furthermore, nobiletin improved colonic microbial 16S rRNA gene diversity and reduced the levels of Proteobacteria in HFD-fed mice. Collectively, this study establishes that nobiletin improves the normal rhythm in GLP-1 secretion following fat-induced disruption.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Enteroendocrine Cells* / metabolism
  • Flavones
  • Glucagon-Like Peptide 1* / metabolism
  • Mice
  • Palmitates / pharmacology
  • RNA, Ribosomal, 16S / metabolism


  • Flavones
  • Palmitates
  • RNA, Ribosomal, 16S
  • Glucagon-Like Peptide 1
  • nobiletin

Grants and funding