The metabolic regulator USF1 is involved in the control of affective behaviour in mice

Abstract Epidemiological studies indicate a bidirectional association between metabolic disturbances, including obesity and related pathological states, and mood disorders, most prominently major depression. However, the biological mechanisms mediating the comorbid relationship between the deranged metabolic and mood states remain incompletely understood.Here we tested the hypothesis that the enhanced activation of brown fat tissue (BAT), known to beneficially regulate obesity and accompanying dysfunctional metabolic states, is also paralleled by an alteration of affective behaviour. We used upstream stimulatory factor 1 (USF1) knock-out mice as a genetic model of constitutively activated BAT and positive cardiometabolic traits, and we found a reduction of depression-like and anxiety-like behaviours associated with USF1 deficiency. Surgical removal of interscapular BAT did not impact the behavioural phenotype of USF1 KO mice. Further, the absence of USF1 did not lead to alterations of adult hippocampal neural progenitor cell proliferation, differentiation, or survival. RNAseq analysis characterized the molecular signature of USF1 deficiency in the hippocampus and revealed a significant increase in the expression of several members of the X-linked lymphocyte-regulated (xlr) genes, including xlr3b and xlr4b. Xlr genes are the mouse orthologues of the human FAM9 gene family and are implicated in the regulation of dendritic branching, dendritic spine number and morphology. These molecular changes were associated with morphological alterations in hippocampal neurons, manifested in reduced dendritic length and complexity.Collectively these data suggest that the metabolic regulator USF1 is involved in the control of affective behaviour in mice and that this modulation of mood states is unrelated to USF1-dependent BAT activation, but instead reflected in structural changes in the brain.