| First Author | Anagnostopoulos G | Year | 2022 |
| Journal | Cell Death Dis | Volume | 13 |
| Issue | 4 | Pages | 356 |
| PubMed ID | 35436993 | Mgi Jnum | J:327498 |
| Mgi Id | MGI:7265326 | Doi | 10.1038/s41419-022-04834-5 |
| Citation | Anagnostopoulos G, et al. (2022) An obesogenic feedforward loop involving PPARgamma, acyl-CoA binding protein and GABAA receptor. Cell Death Dis 13(4):356 |
| abstractText | Acyl-coenzyme-A-binding protein (ACBP), also known as a diazepam-binding inhibitor (DBI), is a potent stimulator of appetite and lipogenesis. Bioinformatic analyses combined with systematic screens revealed that peroxisome proliferator-activated receptor gamma (PPARgamma) is the transcription factor that best explains the ACBP/DBI upregulation in metabolically active organs including the liver and adipose tissue. The PPARgamma agonist rosiglitazone-induced ACBP/DBI upregulation, as well as weight gain, that could be prevented by knockout of Acbp/Dbi in mice. Moreover, liver-specific knockdown of Pparg prevented the high-fat diet (HFD)-induced upregulation of circulating ACBP/DBI levels and reduced body weight gain. Conversely, knockout of Acbp/Dbi prevented the HFD-induced upregulation of PPARgamma. Notably, a single amino acid substitution (F77I) in the gamma2 subunit of gamma-aminobutyric acid A receptor (GABAAR), which abolishes ACBP/DBI binding to this receptor, prevented the HFD-induced weight gain, as well as the HFD-induced upregulation of ACBP/DBI, GABAAR gamma2, and PPARgamma. Based on these results, we postulate the existence of an obesogenic feedforward loop relying on ACBP/DBI, GABAAR, and PPARgamma. Interruption of this vicious cycle, at any level, indistinguishably mitigates HFD-induced weight gain, hepatosteatosis, and hyperglycemia. |
