Sodium oxybate, a narcolepsy therapeutic, remodels the gut microbiota and alleviates metabolic dysfunction in developing and established obesity

Using diet-induced pre-obese and obese mouse models, we found that SXB reduced hepatic steatosis and inflammation in both conditions, together with increased expression of genes linked to mitochondrial respiratory function. In obese mice, SXB further improved insulin resistance and attenuated body weight gain by limiting fat mass expansion. These metabolic improvements were accompanied by enhanced adipose tissue function, reflected by reduced adipocyte hypertrophy and inflammation in white adipose tissue and by reduced lipid content and increased uncoupling protein 1 (UCP-1) abundance in brown adipose tissue. Mechanistically, SXB reshaped the gut microbiota in a manner that contributed toassociates with improved liver metabolic function. Consistent with a causal role for microbiota, fecal microbiota transplantation (FMT) from SXB-treated obese donors recapitulated these benefits in untreated obese recipients, rescuing diet-induced weight gain, hyperglycemia, and hepatic steatosis. These findings identify suggest the gut microbiota as a key potential mediator of the metabolic effects of SXB, support further investigation of gut microbiota alterations in narcolepsy, and underscore the broader translational relevance of drug-microbiota interactions in metabolic dysfunction.