A recent EU-funded study by a Swiss-led international team of researchers has found that a new synthetic drug, developed by researchers in the US, protects against diet-induced obesity.
At the same time, it improves glucose tolerance and insulin sensitivity and increases exercise endurance by enhancing fat utilization in certain tissues. The study has been published online in the journal Cell Metabolism
Although reducing caloric intake by around 20% can provide significant metabolic benefits, diet and exercise alone are rarely successful in curbing obesity and related metabolic disorders. Studies into possible pharmacological interventions have demonstrated that large doses of resveratrol, a substance naturally occurring in red wine, can provide metabolic benefits such as protecting against diabetes and diet-induced obesity.
Taking resveratrol and cutting calories both activate SIRT1, an enzyme that is an important regulator of several metabolic processes that occur when energy supply is low. The current study hypothesised that because SIRT1 is activated by caloric restriction, inducing its activity "opens the possibility to pharmacologically mimic low energetic levels and, thereby, stimulate fat utilisation to prevent diet-induced obesity and its associated disorders."
The researchers used a new chemical entity, SRT1720, in mouse models to activate the SIRT1 pathway, and assessed its role in obesity, diabetes, ageing and endurance. They found that mice fed a high-fat diet and treated with high doses of SRT1720 over a 15-week period did not become obese. Importantly, the triglyceride, cholesterol, fasting blood glucose and insulin levels of the mice were all reduced. They also performed significantly better than control animals in an endurance exercise test.
"SIRT1720 made the animals run twice as long," Professor Auwerx said, referring to the exercise testing. In fact, the voluntary activity of the mice actually declined over the course of the study as they endeavoured to save energy; the drug works by shifting the body's metabolism to a 'fat-burning' mode, which normally takes over when energy levels are low.
The research demonstrated that activating the SIRT1 pathway does in fact protect against diet-induced obesity by enhancing fat utilisation in skeletal muscle, liver, and brown adipose tissue. It also showed that SRT1720 induces metabolic adaptations that involve activation of another enzyme, AMPK, which regulates skeletal muscle glucose and fatty-acid metabolism.