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.

High plasma concentrations of acyl‐coenzyme A binding protein (ACBP) predispose to cardiovascular disease: Evidence for a phylogenetically conserved proaging function of ACBP

“…and in adipose tissues (in mice and humans) (Bravo-San Pedro, Sica, Martins, , suggesting that transcriptional upregulation accounts for the surge in circulating ACBP/DBI protein (Anagnostopoulos et al, 2022). Indeed, ACBP/DBI mRNA has been found upregulated in the liver of aged mice (Wang et al, 2021), as well as in the brain of aged Macaca fascicularis (https://ngdc.cncb.…”

“…However, we are not aware of any report describing the senescence‐associated secretion of ACBP/DBI. In obesity, another condition in which autophagy is suppressed (Kitada & Koya, 2021 ; López‐Otín et al, 2016 ), circulating ACBP/DBI levels are elevated, correlating with increased mRNA and protein levels of ACBP/DBI in the liver (in mice) and in adipose tissues (in mice and humans) (Bravo‐San Pedro, Sica, Martins, Anagnostopoulos, et al, 2019 ), suggesting that transcriptional upregulation accounts for the surge in circulating ACBP/DBI protein (Anagnostopoulos et al, 2022 ). Indeed, ACBP/DBI mRNA has been found upregulated in the liver of aged mice (Wang et al, 2021 ), as well as in the brain of aged Macaca fascicularis ( https://ngdc.cncb.ac.cn ), suggesting that an age‐associated transcriptional upregulation might contribute to the elevation of plasma ACBP/DBI.…”

Acyl coenzyme A binding protein (ACBP): An aging‐ and disease‐relevant “autophagy checkpoint”

“…For ACBP binding, the GABA A receptor must contain the γ2 isoform (GABRG2). A point mutation (F77I) in GABRG2 abrogates ACBP binding (Anagnostopoulos et al, 2022), as well as the effects of ACBP on neurogenesis (Dumitru et al, 2017). This mutation also abolishes the binding and hypnotic effects of zolpidem (Cope et al, 2005), in line with the fact that ACBP/DBI and benzodiazepines act on the same receptor, which has been dubbed as "central benzodiazepine receptor."…”

“…Moreover, Dbi KO protects adult mice from weight gain induced by long-term rosiglitazone administration (which, in wild type mice, causes the upregulation of Dbi mRNA through an effect on the transcription factor PPARγ) (Anagnostopoulos et al, 2022) and enhanced weight loss upon switching from high-fat to normal diet (Bravo-San Pedro, Sica, Martins, Pol, et al, 2019). The resistance against high-fat diet-induced obesity observed after the inducible whole-body Dbi KO could be recapitulated by a cell type-specific constitutive knockout of Dbi in white adipose tissue (Joseph et al, 2021), supporting a role for ACBP/DBI in local adipogenesis, perhaps by favoring adipocyte differentiation, which is stimulated by ACBP/DBI in a cellautonomous fashion (Mandrup et al, 1998).…”

Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer

“…Acyl-coenzyme-A-binding protein (ACBP) is a direct downstream effector of PPARγ that induces lipogenesis [ 423 ]. The long non-coding RNA MALAT1 acts upstream of PPARγ and might directly activate the PPARγ promoter to induce adipogenesis.…”