The saturated fatty acid, palmitic acid, induces anxiety-like behavior in mice

Metabolism. 2014 Sep;63(9):1131-40. doi: 10.1016/j.metabol.2014.06.002. Epub 2014 Jun 9.


Objectives: Excess fat in the diet can impact neuropsychiatric functions by negatively affecting cognition, mood and anxiety. We sought to show that the free fatty acid (FFA), palmitic acid, can cause adverse biobehaviors in mice that last beyond an acute elevation in plasma FFAs.

Methods: Mice were administered palmitic acid or vehicle as a single intraperitoneal (IP) injection. Biobehaviors were profiled 2 and 24 h after palmitic acid treatment. Quantification of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and their major metabolites was performed in cortex, hippocampus and amygdala. FFA concentration was determined in plasma. Relative fold change in mRNA expression of unfolded protein response (UPR)-associated genes was determined in brain regions.

Results: In a dose-dependent fashion, palmitic acid rapidly reduced mouse locomotor activity by a mechanism that did not rely on TLR4, MyD88, IL-1, IL-6 or TNFα but was dependent on fatty acid chain length. Twenty-four hours after palmitic acid administration mice exhibited anxiety-like behavior without impairment in locomotion, food intake, depressive-like behavior or spatial memory. Additionally, the serotonin metabolite 5-HIAA was increased by 33% in the amygdala 24h after palmitic acid treatment.

Conclusions: Palmitic acid induces anxiety-like behavior in mice while increasing amygdala-based serotonin metabolism. These effects occur at a time point when plasma FFA levels are no longer elevated.

Keywords: Anxiety; Free fatty acid; Palmitic acid.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / antagonists & inhibitors
  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Amygdala / metabolism*
  • Animals
  • Anxiety / blood
  • Anxiety / etiology*
  • Behavior, Animal
  • Cerebral Cortex / metabolism
  • Diet, High-Fat / adverse effects
  • Fatty Acids, Nonesterified / administration & dosage
  • Fatty Acids, Nonesterified / adverse effects*
  • Fatty Acids, Nonesterified / blood
  • Gene Expression Regulation
  • Hippocampus / metabolism
  • Hydroxyindoleacetic Acid / metabolism
  • Hyperphagia / metabolism
  • Hyperphagia / physiopathology
  • Injections, Intraperitoneal
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism*
  • Palmitic Acid / administration & dosage
  • Palmitic Acid / adverse effects*
  • Palmitic Acid / blood


  • Atf4 protein, mouse
  • Fatty Acids, Nonesterified
  • Nerve Tissue Proteins
  • Activating Transcription Factor 4
  • Palmitic Acid
  • Hydroxyindoleacetic Acid