An obesogenic feedforward loop involving PPARγ, acyl-CoA binding protein and GABAA receptor.

Abstract

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 (PPARγ) is the transcription factor that best explains the ACBP/DBI upregulation in metabolically active organs including the liver and adipose tissue. The PPARγ 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 PPARγ. Notably, a single amino acid substitution (F77I) in the γ2 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 γ2, and PPARγ. Based on these results, we postulate the existence of an obesogenic feedforward loop relying on ACBP/DBI, GABAAR, and PPARγ. Interruption of this vicious cycle, at any level, indistinguishably mitigates HFD-induced weight gain, hepatosteatosis, and hyperglycemia.

• Authors: Gerasimos Anagnostopoulos, Omar Motiño, Sijing Li, Vincent Carbonnier, Hui Chen, Valentina Sica, Sylvère Durand, Mélanie Bourgin, Fanny Aprahamian, Nitharsshini Nirmalathasan, Romain Donne, Chantal Desdouets, Marcelo Simon Sola, Konstantina Kotta, Léa Montégut, Flavia Lambertucci, Didier Surdez, Grossetête Sandrine, Olivier Delattre, Maria Chiara Maiuri, José Manuel Bravo-San Pedro, Isabelle Martins, Guido Kroemer
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 4 Pg. 356 (04 18 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 35436993 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Carrier Proteins
• Diazepam Binding Inhibitor
• PPAR gamma
• Receptors, GABA
• Receptors, GABA-A
• gamma-Aminobutyric Acid
• Coenzyme A

Topics

• Animals
• Carrier Proteins
• Coenzyme A (metabolism)
• Diazepam Binding Inhibitor (genetics, metabolism)
• Mice
• PPAR gamma (genetics, metabolism)
• Receptors, GABA (metabolism)
• Receptors, GABA-A (genetics, metabolism)
• Weight Gain
• gamma-Aminobutyric Acid