Objectives

This study investigates the effect of seasonal photoperiod changes on the interaction between brain and brown adipose tissue (BAT) mu-opioid receptor (MOR) signaling in rats.

• It utilizes Partial Least Squares Regression (PLSR) to assess how well brain MOR availability predicts BAT MOR availability.
• The core finding is that shorter photoperiods (darker seasons) enhance the predictability (interaction) between brain and BAT MOR levels, while longer photoperiods reduce it.
• This suggests a dynamic, seasonal adaptation of brain-BAT communication related to the MOR system.

Methodology

The study reanalyzed existing [11C]carfentanil Positron Emission Tomography (PET) data from 9 rats (30 scans total) measuring MOR availability in the brain and BAT under varying photoperiods.

• Brain regional MOR availability was estimated using a simple reference model (non-displaceable binding potential).
• BAT MOR availability was quantified as the ratio of binding in BAT to foreleg muscle.
• Partial Least Squares Regression (PLSR) was employed to model the prediction of log-transformed BAT MOR availability (outcome Y) using log-transformed brain regional MOR availability (predictor X, component 1) and Age (predictor X, component 2).
• 10-fold cross-validation was used in PLSR.
• The resulting latent variables (LV1 for brain component, LV2 for Age component) were analyzed using mixed-effects models with photoperiod as a fixed effect and rat as a random effect.
• Unsupervised k-means clustering (with the Elbow Method for determining cluster number) was applied separately to LV1 and LV2 to identify subgroups and examine their relationship with photoperiod.

Results

• PLSR analysis demonstrated that brain MOR availability explained a significant portion of the variance in BAT MOR levels (22.82% for Component 1 across different brain regions), which was comparable to the variance explained by Age (approx. 23.00-23.37% for Component 2). (Table 1)
• Regression analysis showed a significant negative linear relationship between Latent Variable 1 (LV1, representing the brain-BAT MOR link) and photoperiod (beta = -4.32, 95% CI [-5.30, -3.35], p < 0.001), indicating stronger predictability during shorter days. B
• Latent Variable 2 (LV2, representing Age) showed no significant association with photoperiod (p > 0.7). (Table 2)
• K-means clustering identified 3 optimal clusters for LV1 and 4 for LV2. The distribution of data points within these clusters varied systematically with photoperiod, particularly for LV1 clusters, visually supporting the influence of photoperiod on the brain-BAT interaction strength. C

Discussions

• Limitation: The study acknowledges the relatively small sample size (N=9 rats, 30 scans total), which may limit the generalizability of the findings.
• Causality: The PLSR analysis reveals associations but cannot establish a causal direction between changes in brain MOR availability and BAT MOR availability; the interaction could be bidirectional or driven by a common factor influenced by photoperiod.
• Model Specificity: The analysis focused on linear relationships via PLSR. Investigating potential non-linear interactions between brain and BAT MOR signaling across seasons might provide further insights.
• Mechanistic Insight: While demonstrating enhanced interaction during shorter photoperiods, the study does not elucidate the specific biological mechanisms (e.g., altered neuronal firing rates, hormonal signaling changes) responsible for this modulation.
• Sex Differences: The study included both male and female rats but did not report separate analyses based on sex. Given potential sex differences in opioid signaling and metabolic responses, exploring this aspect could add value.

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Reference: Dark seasons enhance brain and brown adipose tissue interactions related to mu opioid receptor signaling