RXR–PPAR-γ axis in adolescent depression: PPAR-γ coactivator 1α links cognition and appetite hormones

BACKGROUND: Major depressive disorder (MDD) is frequently accompanied by cognitive deficits and appetite hormone dysregulation. The retinoid X receptor-α (RXR-α)-peroxisome proliferator-activated receptor-γ (PPAR-γ) axis and its coactivator PPAR-γ coactivator 1α (PGC-1α) regulate metabolic, inflammatory, and neuroprotective processes, yet their role in first-episode adolescent MDD remains largely unexplored. METHODS: Adolescents between the ages of 12 and 17 with first-episode MDD and age-matched healthy controls were enrolled according to DSM-5 diagnostic criteria. Serum levels of RXR-α, PPAR-γ, PGC-1α, and appetite hormones (insulin, leptin, adiponectin) were measured. Executive function was assessed using the Wisconsin Card Sorting Test (WCST). Group differences and biomarker associations with cognitive and metabolic measures were analyzed using generalized linear models adjusted for age, sex, BMI, depression severity, and medication use. The association analyses were exploratory and not corrected for multiple comparisons. RESULTS: A total of 62 adolescents with first-episode MDD (mean age 15.92 years, 74.2% female and 25.8% male) and 64 healthy controls were recruited. Compared with controls, adolescents with MDD exhibited significantly lower PPAR-γ (p = 0.033) and PGC-1α levels (p = 0.024), although these differences did not remain significant after correction for multiple comparisons. Higher fasting insulin (p = 0.002) and leptin (p = 0.017) were also observed. After adjusting for covariates, PGC-1α-but not PPAR-γ or RXR-α-showed exploratory associations with WCST performance (fewer non-perseverative errors, p = 0.035) and was negatively correlated with insulin (p = 0.019) and leptin (p = 0.027) levels. CONCLUSION: In adolescents with first-episode MDD, lower PGC-1α levels were observed and were associated with both poorer WCST performance and disturbances in appetite hormone regulation. These preliminary findings suggest that PGC-1α may represent a candidate biomarker linking metabolic changes and cognitive deficits in early-stage MDD, warranting further investigation.