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Animal Models

HFD-induced energy states-dependent bidirectional control of anxiety levels in mice



The association between the development of obesity and its metabolic comorbidities, and chronic consumption of high-fat diet (HFD) has been well-demonstrated. Interestingly, emerging evidence indicates that obesity is also associated with an increased risk for psychiatric disorders including anxiety and depression. Although HFD feeding is associated with anxiety-related behaviors, previous studies have reported inconsistent findings on the direction of this relationship. Therefore, in this study we sought to investigate the link between HFD feeding, body weight, energy states and anxiety levels in mice and specifically to determine if the duration of HFD exposure has distinct effects on anxiety-related behaviors.


To disentangle the temporal dynamic effects of HFD feeding on anxiety-related behaviors, mice were fed a HFD or regular chow (RC) diet and were assayed periodically for anxiety-related behaviors by using behavioral tests (open field test; OFT) and the elevated plus maze. To determine if obesity phenotypes correlate with anxiety-related behaviors, changes in anxiety-related behaviors in OFTs were correlated with changes in both body weight and glucose sensitivity following various levels of HFD and RC exposure.


Our results demonstrate a time-dependent biphasic effect of HFD feeding on anxiety-related behaviors. At 5 weeks, mice fed HFD show a reduction in anxiety-related behaviors when compared to pair-fed RC mice. At 8 weeks of HFD or RC feeding, anxiety levels were the same in both groups. Following 15 weeks of HFD and RC feeding, however, mice displaying metabolic symptoms of obesity showed increased anxiety-related behaviors relative to mice resilient to obesity phenotypes, independent of feeding conditions.


Taken together our findings suggest that HFD bi-directionally effects anxiety-related behaviors such that short-term exposure to a HFD reduces anxiety levels, while longer exposure to a HFD promotes anxiety levels selectively in mice that display metabolic symptoms of obesity. Regardless of diet (HFD or RC), heavier animals display increased anxiety-like behaviors. These findings indicate diverse overlapping roles for HFD and body weight in modulating anxiety-related behaviors, and may partly resolve previous inconsistencies in studies examining the relationship between HFD feeding and anxiety.

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We thank all the members of Yang laboratory for discussion and critical comments on this project. We also thank R. Quinn for mouse husbandry. This research was supported by the State University of New York and NIH (R01 MH109441A to YY). YY conceived the idea. PS, KO and YY designed this study. PS, KO, and ZX performed the experiments and analyzed the data. PS, KO and YY wrote the paper with the inputs from other authors.

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Correspondence to Y Yang.

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Supplementary Information accompanies this paper on International Journal of Obesity website

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Sweeney, P., O'Hara, K., Xu, Z. et al. HFD-induced energy states-dependent bidirectional control of anxiety levels in mice. Int J Obes 41, 1237–1245 (2017).

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