DSOK ‐0011 Potentially Regulates Circadian Misalignment and Affects Gut Microbiota Composition in Activity‐Based Anorexia Model

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Abstract
Objective: Anorexia nervosa (AN) is a metabolic‐psychiatric disorder characterized by severe weight loss, hypercortisolemia, and hypothalamic–pituitary–adrenal (HPA) axis activation. In this study, we investigated the effect of inhibiting cortisol regeneration via the enzyme 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) on the pathophysiology of AN. Method: Female C57BL/6J mice underwent a 7‐day activity‐based anorexia (ABA) paradigm, involving 3 h daily feeding and free access to wheels, until 25% body weight loss or experiment completion. Mice were orally treated once daily with a potent 11β‐HSD1 inhibitor, DSOK‐0011, or vehicle. Body weight, food intake, and activity transitions were recorded; plasma corticosterone and cholesterol levels were measured using a fluorometric assay; gut microbiota were analyzed using 16S rRNA sequencing; and hippocampal glial cells were analyzed using immunohistochemistry. Results: DSOK‐0011‐treated mice exhibited a modest but significant increase in postprandial wheel‐running activity compared to baseline (4–5 p.m., p = 0.018; 5–6 p.m., p = 0.043), whereas vehicle‐treated mice showed higher preprandial activity (9–10 a.m., p = 0.0229). Gut microbiota analysis revealed increased alpha diversity in ABA mice, with a specific enrichment of the Lachnospiraceae family in the DSOK‐0011 group. However, DSOK‐0011 did not significantly affect body weight, food intake, corticosterone, and lipid levels, or hippocampal glial cell populations. Conclusion: Inhibition of 11β‐HSD1 by DSOK‐0011 was associated with microbiota alterations and subtle shifts in activity timing under energy‐deficient conditions. These findings suggest that peripheral glucocorticoid metabolism may influence microbial and behavioral responses in the ABA model, although its metabolic impact appears limited in the acute phase.
Funding Information
  • Japan Society for the Promotion of Science (22K07616)
  • Japan Society for the Promotion of Science (23H04235)
  • Japan Society for the Promotion of Science (24K10679)
  • Japan Society for the Promotion of Science (24K10733)
  • Japan Society for the Promotion of Science (24KK0155)
  • Japan Society for the Promotion of Science (25K19080)

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