Abstract
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.
Highlights
Major depressive disorder is currently ranked by the Global Burden of Disease Report as the second leading cause of worldwide disability (Ferrari et al, 2014), and anxiety disorders are debilitating conditions that affect approximately 20% of the US population (Kessler et al, 2012)
For the open field test (OFT), there was a main effect of diet, with high-fat diet (HFD) decreasing the distance traveled in the center of the field (main effect of diet; F(1,35) = 5.58, p = 0.024, Figure 2A) and decreasing the number of entries made to the center of the field (main effect of diet; F(1,35) = 6.29, p = 0.019, Figure 2B)
The current study shows that HFD led to a significant reduction in immobile episodes in WT mice in the forced swim test (FST), a finding that is consistent with prior studies showing that HFD can lead to therapeutic-like effects (Maniam and Morris, 2010a,b; Finger et al, 2011; Dornellas et al, 2018)
Summary
Major depressive disorder is currently ranked by the Global Burden of Disease Report as the second leading cause of worldwide disability (Ferrari et al, 2014), and anxiety disorders are debilitating conditions that affect approximately 20% of the US population (Kessler et al, 2012). To evaluate the impact of genetically induced brain 5-HT deficiency on changes in body weight and depressionand anxiety-like behaviors following chronic HFD, the current work examined the tryptophan hydroxylase 2 (Tph2) R439H knock-in (KI) mouse line, which harbors a partial loss-offunction mutation in the brain 5-HT synthesis enzyme, Tph (Beaulieu et al, 2008). Homozygous KI animals from this line have 60–80% less brain 5-HT than their homozygous wildtype (WT) littermates (Beaulieu et al, 2008; Jacobsen et al, 2012) These animals have been shown to exhibit increased susceptibility to anxiety- and depression-like behavior induced by stress (Sachs et al, 2015), but whether low levels of brain 5-HT alter behavioral responses to other potential environmental risk factors for mental illness (such as HFD) has not been established
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