Abstract
Overnutrition-induced hypothalamic inflammation greatly disturbs feeding behavior and energy homeostasis as well as the pathogenesis of obesity. Butyrate, a short-chain fatty acid, reportedly participates in the regulation of the immune response and energy metabolism in the body. However, the role of butyrate in overnutrition-induced microglial activation and hypothalamic inflammation remains unclear. In the present study, we established a high-fat diet (HFD)-induced hypothalamic inflammation model in mice. Oral supplementation with sodium butyrate (NaB) significantly reduced HFD-induced microgliosis, inflammatory cytokine expression, endoplasmic reticulum (ER) stress, neuronal apoptosis, and neuropeptide Y (NPY) expression in the mouse hypothalamus. Utilizing a high-glucose (HG)-stimulated microglial activation model in vitro, we found that NaB inhibited the HG-induced expression of the inflammatory factor IL-1β. Moreover, NaB exerted an antioxidant effect by balancing HO-1 and NOX4 expression, thus preventing reactive oxygen species (ROS) production in HG-treated microglia. Interestingly, NaB treatment promoted microglial process formation and extension via the Akt/Cdc42 pathway under both normal and HG-stimulated conditions, indicating a resting morphology of microglia. Taken together, our study revealed for the first time the anti-inflammatory and antioxidant effects of NaB in overnutrition-induced microglial activation and hypothalamic inflammation, which might become a potential therapeutic option for obesity prevention and treatment.