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The Eating-Disorder Associated HDAC4A778T 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.

      Keywords

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      Linked Article

      • Solving the Eating Disorders Puzzle Piece by Piece
        Biological PsychiatryVol. 81Issue 9
        • Preview
          Albeit slowly, we are beginning to piece together the complex biological puzzle of anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). The article by Lutter et al. (1) in this issue of Biological Psychiatry brings us one step closer to understanding these illnesses.
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