Poster Presentation 4th Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity Meeting 2024

A single dose of psilocybin increases susceptibility to diet-induced weight loss in obese mice (#170)

Ryan J Keenan 1 , Rifa T Haque 1 , Tomris Mustafa 1 , Xiangjun Jin 1 , Kayla Elysee 1 , Angel Zi Shan Wee 1 , Stephanie Simonds 1 , Claire J Foldi 1 , Michael A Cowley 1
  1. Department of Physiology, Monash University, Clayton, VIC, Australia

Prolonged obesity induces persistent changes within neural circuitry that helps maintain a higher body weight “set point”1. A potential novel therapeutic strategy to facilitate weight loss is therefore to promote synaptic structural plasticity. Psilocybin (PSI) promotes neural plasticity2-4 which can remodel neural circuits via many potential mechanisms, including a pathway involving brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB)2,5. TrkB receptors are expressed in nuclei within the hypothalamus that play a key role in regulating feeding behaviour6-8. We aimed to explore the influence of PSI on body weight, feeding and energy expenditure in diet-induced obese (DIO) mice after “dieting” (access to standard Chow only).    

Male C57BL/6 DIO mice were allocated to either being maintained on high-fat diet (HFD) or switched to Chow and received either 0.9% saline (HFD-SAL; Chow-SAL) or 1 mg/kg PSI (HFD-PSI; Chow-PSI). Body weight and food intake were measured daily for 28 days. Energy expenditure was assessed using a TSE PhenoMaster system.

DIO mice were categorised as either being resistant or susceptible to diet-induced weight loss (based on the mean weight change of 13% reduction from baseline). PSI increased the probability of mice becoming susceptible to diet-induced weight loss 2.5-fold compared with SAL controls, but did not alter body weight trajectories when mice were maintained on HFD. Susceptible mice had significantly reduced food and energy intake, and a reduced feeding efficiency, however, PSI treatment did not alter measures of energy expenditure.

These data suggest PSI increases weight loss induced by dieting in obese mice predominantly through reduced food intake, as opposed to enhanced energy expenditure or altered substrate utilisation. Whether or not mechanisms including the action of PSI on TrkB receptors in the hypothalamus are responsible for this phenotype will be revealed by ongoing studies.     

 

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