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

• Published in: Biological psychiatry (1969) Vol. 81; no. 9; pp. 770 - 777
• Main Authors: Lutter, Michael, Khan, Michael Z, Satio, Kenji, Davis, Kevin C, Kidder, Ian J, McDaniel, Latisha, Darbro, Benjamin W, Pieper, Andrew A, Cui, Huxing
• Format: Journal Article
• Language: English
• Published: United States 01.05.2017
• Subjects: Animals; Behavior, Animal; Computational Biology; Disease Models, Animal; Feeding and Eating Disorders - genetics; Feeding and Eating Disorders - metabolism; Feeding Behavior - physiology; Female; Histone Deacetylases - genetics; Male; Mice; Mice, Transgenic; Mitochondria - metabolism; Mutation, Missense; Histone deacetylase 4; Estrogen-related receptor alpha; Anorexia nervosa; Behavior; Eating disorders; Feeding
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2016.09.024

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. 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. Male mice heterozygous for HDAC4 did not show any metabolic or behavioral differences. In contrast, female mice heterozygous for HDAC4 display several ED-related feeding and behavioral deficits depending on housing condition. Individually housed HDAC4 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 HDAC4 activity relevant to the behavioral deficits identified in this new mouse model of disordered eating. The HDAC4 mouse line is a novel model of ED-related behaviors and identifies mitochondrial biogenesis as a potential molecular pathway contributing to behavioral deficits.