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

• Published in: Cell death & disease Vol. 13; no. 4; pp. 356 - 15
• Main Authors: Anagnostopoulos, Gerasimos, Motiño, Omar, Li, Sijing, Carbonnier, Vincent, Chen, Hui, Sica, Valentina, Durand, Sylvère, Bourgin, Mélanie, Aprahamian, Fanny, Nirmalathasan, Nitharsshini, Donne, Romain, Desdouets, Chantal, Sola, Marcelo Simon, Kotta, Konstantina, Montégut, Léa, Lambertucci, Flavia, Surdez, Didier, Sandrine, Grossetête, Delattre, Olivier, Maiuri, Maria Chiara, Bravo-San Pedro, José Manuel, Martins, Isabelle, Kroemer, Guido
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.04.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 101/58; 13/1; 13/106; 13/31; 13/51; 13/89; 14/63; 42/44; 42/70; 45/15; 45/41; 45/77; 45/91; 631/80; 64; 64/110; 64/60; 692/699; ACBP protein; Adipose tissue; Amino acid substitution; Antibodies; Appetite; Autophagy; Biochemistry; Biomedical and Life Sciences; Body fat; Body mass index; Body weight gain; Cell Biology; Cell Culture; Diazepam; Diazepam-binding inhibitor; Food; Gene expression; High fat diet; Hyperglycemia; Immunology; Life Sciences; Lipogenesis; Liver; Liver cancer; Obesity; Peroxisome proliferator-activated receptors; Plasma; Proteins; Rosiglitazone; Tumors; Weight control; γ-Aminobutyric acid; γ-Aminobutyric acid A receptors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04834-5

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 (GABA A R), which abolishes ACBP/DBI binding to this receptor, prevented the HFD-induced weight gain, as well as the HFD-induced upregulation of ACBP/DBI, GABA A R γ2, and PPARγ. Based on these results, we postulate the existence of an obesogenic feedforward loop relying on ACBP/DBI, GABA A R, and PPARγ. Interruption of this vicious cycle, at any level, indistinguishably mitigates HFD-induced weight gain, hepatosteatosis, and hyperglycemia.