Butyrate enhances the obesity reduction effect of Semaglutide

Obesity represents a global public health burden with continuously increasing prevalence over recent decades. Combination regimens pairing semaglutide (Sema) with additional therapeutic agents have emerged as a major focus for anti-obesity research.

In diet-induced obese (DIO) mice, we evaluated whether oxytocin (Oxt, 3 and 5 mg·kg-1), long-acting oxytocin (la‑Oxt), caffeine, or butyrate could potentiate the anti-obesity efficacy of Sema. We further compared hypothalamic neuronal activity and plasma metabolomic profiles following Sema treatment against dietary restriction (DR), an established intervention for weight loss and metabolic improvement.

Whereas Oxt, la‑Oxt, and caffeine did not augment Sema-mediated body weight reduction, butyrate produced significant potentiation of Sema's anti-obesity effects. Either Sema monotherapy or Sema-butyrate co-administration elevated the number of c-Fos-positive cells in the paraventricular nucleus (PVN) of the hypothalamus. By contrast, DR decreased PVN c-Fos-positive cell number. Butyrate amplified Sema-elicited activation of PVN neuronal activity. Plasma metabolomics revealed limited overlap between the pharmacological interventions and DR, demonstrating orthogonal metabolic responses.

These findings identify the Sema-butyrate combination as a promising anti-obesity strategy, and demonstrate that Sema and DR exert divergent effects on both hypothalamic neuronal activity and plasma metabolite levels.