Hypothalamic ceramide metabolism in obesity and dysregulation of glucose homeostasis

The central nervous system is a key regulator of energy and glucose homeostasis, integrating peripheral signals such as hormones and nutrients to maintain metabolic balance. Among its regions, the hypothalamus plays a central role in monitoring energy status and orchestrating physiological responses via neuronal and glial circuits. Recent research highlights the influence of de novo ceramide synthesis on central nervous system regulation of metabolism. Indeed, ceramides have emerged as critical signalling molecules linking fatty acid sensing to hypothalamic control of feeding, energy expenditure, and glucose regulation. This review details the mechanisms of de novo ceramide synthesis and explores how dysregulation of this pathway in the hypothalamus contributes to obesity and type 2 diabetes. Serine palmitoyl-transferase and specific ceramide synthase isoforms are shown to play roles in mediating neuronal responses to metabolic stress. The findings also emphasize that hypothalamic ceramide metabolism is modulated by both nutritional and hormonal cues and suggest that targeting this pathway may offer new strategies for treating metabolic disorders.