Dataset Information

The Eating-Disorder Associated HDAC4A778T Mutation Alters Feeding Behaviors in Female Mice.

ABSTRACT: 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 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.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.

SUBMITTER: Lutter M

PROVIDER: S-EPMC5386818 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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The Eating-Disorder Associated HDAC4<sup>A778T</sup> Mutation Alters Feeding Behaviors in Female Mice.

Lutter Michael M Khan Michael Z MZ Satio Kenji K Davis Kevin C KC Kidder Ian J IJ McDaniel Latisha L Darbro Benjamin W BW Pieper Andrew A AA Cui Huxing H

Biological psychiatry 20161013 9

<h4>Background</h4>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.<h4>Methods</h4>To understand the biological consequences of this missense m ...[more]

PMID: 27884425

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Project description:ObjectivesElevated glucose variability may be one mechanism that increases risk for significant psychological and physiological health conditions among individuals with binge-spectrum eating disorders (B-EDs), given the impact of eating disorder (ED) behaviors on blood glucose levels. This study aimed to characterize glucose variability among individuals with B-EDs compared with age-matched, sex-matched, and body mass index-matched controls, and investigate the association between frequency of ED behaviors and glucose variability.MethodsParticipants were 52 individuals with B-EDs and 22 controls who wore continuous glucose monitors to measure blood glucose levels and completed ecological momentary assessment surveys to measure ED behaviors for 1 week. Independent samples t-tests compared individuals with B-EDs and controls and multiple linear regression models examined the association between ED behaviors and glucose variability.ResultsIndividuals with B-EDs demonstrated numerically higher glucose variability than controls (t = 1.42, p = .08, d = 0.43), although this difference was not statistically significant. When controlling for covariates, frequency of ED behaviors was significantly, positively associated with glucose variability (t = 3.17, p = .003) with medium effect size (f2 = 0.25). Post hoc analyses indicated that binge eating frequency was significantly associated with glucose variability, while episodes of 5+ hours without eating were not.DiscussionGlucose variability among individuals with B-EDs appears to be positively associated with engagement in ED behaviors, particularly binge eating. Glucose variability may be an important mechanism by which adverse health outcomes occur at elevated rates in B-EDs and warrants future study.Public significanceThis study suggests that some individuals with binge ED and bulimia nervosa may experience elevated glucose variability, a physiological symptom that is linked to a number of adverse health consequences. The degree of elevation in glucose variability is positive associated with frequency of eating disorder behaviors, especially binge eating.

Dataset Information

The Eating-Disorder Associated HDAC4A778T Mutation Alters Feeding Behaviors in Female Mice.

Publications

The Eating-Disorder Associated HDAC4<sup>A778T</sup> Mutation Alters Feeding Behaviors in Female Mice.

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