Disruption of the retinoid X receptor-PPAR-γ axis is associated with appetite hormone dysregulation and cognitive dysfunction: A cross-sectional study of adolescents with first-episode bipolar disorder.

Background: The role of the retinoid X receptor (RXR) and peroxisome proliferator-activated receptor-γ (PPAR-γ) axis in the pathophysiology of bipolar disorder (BD) remains poorly understood. The relationship of RXR-PPAR-γ axis disruption with cognitive impairment and appetite hormone dysregulation has yet to be clearly established in individuals with BD.

Methods: A total of 46 adolescents with first-episode BD and 46 age- and sex-matched neurotypical controls were enrolled in this study. All participants underwent assessments of RXR-α, PPAR-γ, and PPAR-γ coactivator (coA) 1α, as well as appetite-related hormones, including insulin, leptin, and adiponectin. Cognitive performance was evaluated using a visual divided attention task.

Results: A generalized linear model with adjustments for demographic characteristics, clinical symptoms, and medication use revealed that BD status was associated with significantly lower levels of PPAR-γ coA 1α (p = 0.029). Lower PPAR-γ coA 1α levels were significantly associated with longer mean reaction times (p = 0.038) and greater variability in reaction time (p = 0.004) during the visual divided attention task and higher insulin levels (p = 0.014).

Discussion: Early-stage BD is characterized by the disruption of the RXR-PPAR-γ axis, as indicated by decreased PPAR-γ coA 1α levels. This disruption is further associated with cognitive impairment and appetite hormone dysregulation, particularly involving insulin. This study provides the first known direct evidence associating decreased PPAR-γ coA 1α levels with both impaired cognitive performance and disrupted insulin regulation in adolescents with first-episode BD.