DSOK-0011 Potentially Regulates Circadian Misalignment and Affects Gut Microbiota Composition in Activity-Based...

Area of Science:

• Metabolic Psychiatry
• Neuroendocrinology
• Microbiome Research

Background:

• Anorexia nervosa (AN) is a complex metabolic-psychiatric disorder associated with hypercortisolemia and hypothalamic-pituitary-adrenal (HPA) axis activation.
• 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a crucial role in regulating intracellular glucocorticoid levels and is implicated in metabolic and psychiatric conditions.

Purpose of the Study:

• To investigate the therapeutic potential of inhibiting 11β-HSD1 in the context of anorexia nervosa.
• To examine the effects of the 11β-HSD1 inhibitor DSOK-0011 on the pathophysiology of an activity-based anorexia (ABA) mouse model.

Main Methods:

• Female C57BL/6J mice were subjected to a 7-day ABA paradigm involving restricted feeding and wheel running.
• Mice received daily oral administration of the 11β-HSD1 inhibitor DSOK-0011 or vehicle.
• Measurements included body weight, food intake, activity patterns, plasma corticosterone and cholesterol, gut microbiota composition, and hippocampal glial cell populations.

Main Results:

• DSOK-0011 treatment led to subtle but significant shifts in wheel-running activity timing, with increased postprandial activity.
• Gut microbiota analysis revealed increased alpha diversity and enrichment of the Lachnospiraceae family in the DSOK-0011 group.
• No significant effects were observed on body weight, food intake, corticosterone levels, lipid profiles, or hippocampal glial cells.

Conclusions:

• Inhibition of 11β-HSD1 by DSOK-0011 influences gut microbiota and activity patterns in an energy-deficient state.
• These findings suggest a potential role for peripheral glucocorticoid metabolism in modulating microbial and behavioral responses in AN models.
• The metabolic impact of 11β-HSD1 inhibition appears limited during the acute phase of the ABA model.