Obesity is associated with an increased risk of depression and anxiety disorders, but the nature of the relationship(s) between obesity and mental illness remains highly controversial. Some argue that depression and anxiety lead to increased consumption of "comfort foods," the intake of which reduces negative affect and promotes obesity. In contrast, others have theorized that negative affect results from chronic excessive consumption of highly palatable foods. The brain serotonin (5-HT) system has long been implicated in both the development and treatment of mental illness. Preclinical studies have shown that low brain 5-HT exacerbates depression-and anxiety-like behaviors induced by stress and blocks reductions in depression-like behavior induced by antidepressants, but the effects of brain 5-HT deficiency on responses to high-fat diet (HFD) have not been explored. The current work used genetically modified mice to evaluate the effects of low 5-HT on behavioral and molecular alterations induced by chronic exposure to HFD. Our results reveal that HFD decreases depression-like behavior and increases some anxiety-like behaviors in wild-type (WT) mice. However, genetic brain 5-HT deficiency blocks HFD-induced reductions in forced swim immobility and prevents HFD-induced increases in hippocampal GSK3β phosphorylation despite having no significant effects on HFD-induced changes in body weight or anxiety-like behavior. Together, our results suggest that brain 5-HT deficiency significantly impacts a subset of behavioral and molecular responses to HFD, a finding that could help explain the complex relationships between obesity and mental illness.

Obesity is associated with an increased risk of depression and anxiety disorders, but the nature of the relationship(s) between obesity and mental illness remain highly controversial. Some argue that depression and/or anxiety lead to increased consumption of ‘comfort foods’ to reduce negative affect and that chronic consumption of these foods promotes obesity. Alternatively, it has been suggested that chronic excessive consumption of highly palatable foods, such as those high in fats, could induce negative affective states in susceptible individuals. However, the genetic factors that influence food consumption and behavioral responses to high fat diets (HFDs) remain largely unknown. The brain serotonin (5‐HT) system has long been implicated in both the development and treatment of mental illness. Preclinical studies have shown that low brain 5‐HT exacerbates depression‐ and anxiety‐like behavior induced by stress and blocks reductions in depression‐like behavior induced by antidepressants, but the effects of brain 5‐HT deficiency on responses to HFD have not been explored. The current work used genetically modified mice to evaluate the effects of low brain 5‐HT on behavioral and molecular alterations induced by chronic exposure to HFD. Real‐time PCR was used to measure mRNA expression, and Western blotting was used to study protein phosphorylation. Our results reveal that HFD decreases depression‐like behavior and increases some anxiety‐like behaviors in wild‐type mice. However, genetic brain 5‐HT deficiency blocks HFD‐induced reductions in forced swim immobility and prevents HFD‐induced increases in hippocampal GSK3β phosphorylation. These effects occur despite the fact that low 5‐HT does not influence HFD‐induced changes in body weight or anxiety‐like behavior in the novel open field test or the elevated plus maze. Together, our results suggest that although brain 5‐HT deficiency does not alter HFD intake, low brain 5‐HT prevents therapeutic‐like responses to HFD and blocks the inhibition of GSK3 by HFD. Although GSK3 inhibition has been shown to lead to antidepressant‐like effects, whether GSK3 inhibition is required for the antidepressant‐like effects of HFD has not been established. Nonetheless, our results indicate that brain 5‐HT plays a major role in mediating some of the effects of HFD, which could help explain the complex relationships between obesity and mental illness.