The Eating-Disorder Associated HDAC4 A778T Mutation Alters Feeding Behaviors in Female Mice

Abstract

Background While eating disorders (EDs) are thought to result from a combination of environmental and psychological stressors superimposed on genetic vulnerability, the neurobiological basis of EDs remains incompletely understood. We recently reported that a rare missense mutation in the gene for the transcriptional repressor histone deacetylase 4 (HDAC4) is associated with the risk of developing an ED in humans. Methods To understand the biological consequences of this missense mutation, we created transgenic mice carrying this mutation by introducing the alanine to threonine mutation at position 778 of mouse Hdac4 (corresponding to position 786 of the human protein). Bioinformatic analysis to identify Hdac4-regulated genes was performed using available databases. Results Male mice heterozygous for HDAC4A778T did not show any metabolic or behavioral differences. In contrast, female mice heterozygous for HDAC4A778T display several ED-related feeding and behavioral deficits depending on housing condition. Individually housed HDAC4A778T female mice exhibit reduced effortful responding for high-fat diet and compulsive grooming, whereas group-housed female mice display increased weight gain on high-fat diet, reduced behavioral despair, and increased anxiety-like behaviors. Bioinformatic analysis identifies mitochondrial biogenesis including synthesis of glutamate/gamma-aminobutyric acid as a potential transcriptional target of HDAC4A778T activity relevant to the behavioral deficits identified in this new mouse model of disordered eating. Conclusions The HDAC4A778T mouse line is a novel model of ED-related behaviors and identifies mitochondrial biogenesis as a potential molecular pathway contributing to behavioral deficits.

The Science Behind the Academy for Eating Disorders' Nine Truths About Eating Disorders

“…No GWAS of BN or BED have been conducted to date. In addition to GWAS approaches, familial linkage analysis with whole‐genome and exome sequencing has identified two potential missense mutations (Cui et al, ), which evidences a connection with eating‐disordered behaviours in a recent mouse model (Lutter et al, ). Environmental factors play a role in eating disorder risk. …”

“…More sophisticated analytic techniques that examine the interplay between genetic risk and family environment indicate that the fit between an individual's genotype and his or her family environment may be relevant for eating disorder risk (Culbert et al, ). For example, following a report of a rare missense mutation being associated with the development of eating disorders, Lutter et al () found that group‐housed (vs. individually housed) transgenic female mice displayed irregular feeding and anxiety behaviours, preliminarily revealing both sex‐specific and gene‐by‐environment effects. In human studies, large samples using genome‐wide and phenome‐wide data are required for credible conclusions.…”

Behavioral Alterations in Mice Carrying Homozygous HDAC4A778T Missense Mutation Associated With Eating Disorder

“…Hdac4 A778T point mutant knock-in mouse was generated by introducing Hdac4 A778T mutation that correspond to human HDAC4 A786T mutation ( Figure 1A) by CRISPR technology as previously reported (Lutter et al, 2017). Heterozygous mice with mixed C57BL/6 and 129/Sv genetic background were further backcrossed to C57BL/6 female mice until reach over 98% of C57BL/6 background.…”

“…In the followup mouse studies, we found that Esrra knockout mice display behavioral deficits relevant to EDs, including reduced food intake, decreased motivation to work for high-fat diet (HFD), and social subordination (Cui et al, 2015). Furthermore, mice heterozygous for Hdac4 A778T [corresponding to the human HDAC4 A786T mutation which we previously reported to be a gain-of-function mutation in the catalytic domain of HDAC4 to increase gene suppression in cultured cells ] on a mixed C57BL/6 and 129/Sv genetic background display altered feeding behaviors depending on housing condition (Lutter et al, 2017). In order to definitively evaluate the biological consequence of Hdac4 A778T mutation, here we performed a comprehensive behavioral characterization in homozygous Hdac4 A778T mice that we further backcrossed onto C57BL/6 background till reach over 98% of purity.…”

Emerging Treatments in Eating Disorders

“…Our group has recently identified the first 2 rare, highly penetrant genetic variants that increase the risk of developing an EDs [55]. Importantly, mice that are genetically manipulated to replicate the disease-associated human variants display several behavioral phenotypes relevant to EDs, including decreased willingness to work for a high-fat diet after being fasted overnight [56,57]. These mouse lines with impaired behavioral responses to a negative energy state are the first monogenic models of AN and offer a unique opportunity for screening of novel pharmaceutical compounds.…”