Using Synthetic Sphingolipids to Combat Obesity

Obesity has reached epidemic status, threatening millions of lives and straining national economies and health-care systems. Obesity is a chronic disease with diverse etiologies, arising from complex interactions between genetic, physiologic, psychologic and environmental factors that can undermine one’s ability to maintain a healthy weight. The current standard of care, behavioral and lifestyle interventions, has proven to be inadequate for a majority of obese patients thus use of pharmacotherapies has been proposed as an adjunct to lifestyle changes to overcome barriers to weight loss.However limited efficacy and poor safety prevent the widespread use of current pharmacotherapies, prompting the demand for new drug targets and novel therapeutics.893 was previously characterized as a synthetic sphingolipid analog that simultaneously blocks multiple pathways of cellular nutrient uptake. Because chronic nutrient overload underlies much of obesity pathologies, we hypothesized that such a molecule would be an effective anti-obesity agent by putting cells on a diet, rather than a whole patient. To test this, we used 893 in an established mouse model of diet-induced obesity (DIO) that recapitulates the gradual weight gain and metabolic decline that occurs in humans from passive overconsumption of energy dense foods. 893 safely restored normal body weight, reversed hepatic steatosis, and improved glucose homeostasis in obese mice maintained on a high-fat diet (HFD). 893 suppressed food intake and promoted whole body lipid metabolism in vivo. Prolonged HFD feeding induces ceramide-dependent mitochondrial fission that was directly blocked by 893 both in vitro and in vivo. This work demonstrates that 893 and related molecules represent a potential new strategy to tackle the growing obesity epidemic and highlights mitochondrial fission as a potential therapeutic target