Role of Ceramide Accumulation in the Ventromedial Hypothalamus in Driving Systemic Metabolic Impairments During Obesity

Obesity remains a tremendous national and global health epidemic and causes increased risk for any number of serious diseases. In the field of obesity, the idea of lipotoxicity (accumulation of toxic lipids in cells unable to handle them) has become an accepted concept, with increases in tissue lipids being recognized to cause tissue dysfunction during obesity. One of these lipotoxic lipids is ceramide, a sphingolipid. Ceramides have been demonstrated to blunt insulin sensitivity and contribute to numerous obesity-related impairments of tissue function, as seen in vascular endothelium, pancreatic islets, heart failure, and muscle, liver, and adipose insulin signaling. Recently, it has been shown that during obesity ceramides accumulate in the hypothalamus, the region of the brain known to regulate many aspects of metabolism. As hypothalamic lipid metabolism is rapidly being established as a key player in whole-body metabolic homeostasis, we became interested in whether this ceramide accumulation in the brain is another avenue via ceramide accumulation during obesity causes its numerous deleterious effects. To study this, we have overexpressed acid ceramidase in neurons in the ventromedial hypothalamus (VMH); this will decrease ceramide content specifically in this brain region vital to the control of glucose homeostasis and body weight. We found that ceramide accumulation in the VMH during obesity drives glucose intolerance without changing body weight or insulin sensitivity, and that this effect is due to an increase in glucagon sensitivity. Furthermore, we have included a general investigation on ceramide synthesis in response to high fat diet, as well as a blueprint for future studies of sphingolipid metabolism in the brain.