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
M.-H. Chen1,2, H.-J. Wu1,2, J.-W. Hsu1,2, Y.-M. Bai1,2, W.-C. Lin1,2
1Taipei Veterans General Hospital, Psychiatry, Taipei, Taiwan, 2National Yang Ming Chiao Tung University, Psychiatry, Taipei, Taiwan
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.
Aims & Objectives: This study aims to clarify the role of the RXR–PPAR-γ axis in BD, as well as its connection to cognitive impairment and appetite hormone dysregulation.
Method: 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 = .029). Lower PPAR-γ coA 1α levels were significantly associated with longer mean reaction times (p = .038) and greater variability in reaction time (p = .004) during the visual divided attention task and higher insulin levels (p = .014).
Discussion & Conclusions: 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.
| Visual divided attention task | |||
| errors | Mean time (ms) | SD of mean time (ms) | |
| Levels of PPAR-γ coactivator 1α | |||
| B | 0.056 | -0.001 | -0.001 |
| p-value | 0.268 | 0.038 | 0.038 |
| Appetite hormone levels | |||
| Insulin | Leptin | Adiponectin | |
| Levels of PPAR-γ coactivator 1α | |||
| B | -0.002 | -0.000 | 0.000 |
| p-value | 0.014 | 0.059 | 0.144 |
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