Ceramides are a group of bioactive sphingolipids that exert a wide range of cellular and metabolic effects. Excess accumulation of specific ceramide species is a key feature of obesity progression and is linked to the development of metabolic diseases including insulin resistance and hepatosteatosis. The liver has traditionally been viewed as the predominant synthesiser and exporter of ceramides to metabolic tissues throughout the body. Ceramide metabolism in the small intestine, by contrast, has been poorly characterised. As dietary lipids are, first, absorbed in the gut and distributed via lymphatic channels, we hypothesise that the intestinal-lymphatic route of ceramide synthesis and export is an important mechanism that contributes to whole-body metabolic dysfunction.
Since obesity is caused by an energy imbalance, therapeutic strategies have largely centred upon food intake and/or energy expenditure pathways. Notwithstanding a third, but often overlooked, component to energy balance is nutrient absorption and digestive efficiency. Decreased nutrient absorption is one reported mechanism for the weight loss effect of a diet rich in fiber, while the weight loss drug Orlistat, which inhibits lipase in the gut, works by inhibiting nutrient absorption by approximately 30%. Unfortunately, Orlistat is known to increase defecation and diarrhoea, limiting its therapeutic utility. Nonetheless, targeting pathways associated with lipid and/or carbohydrate absorption, metabolism and packaging to identify drug development targets to combat lipid-associated disorders is the research focus within our laboratory. Accordingly, we have characterised ceramide profiles throughout the intestinal-lymphatic system by adopting a targeted lipidomic workflow and generated a transgenic mouse that conditionally overexpresses the ceramide synthase 2 (CerS2) enzyme in intestinal epithelium. This results in an overexpression of long chain ceramides in the gut. We are currently exploring the hypothesis that manipulation of ceramide production in the intestine may be a new therapeutic target to reduce adiposity and improve glucose metabolism.