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 utilisation 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.

"These results show that new synthetic SIRT1 activators can reproduce the positive metabolic effects that were previously demonstrated using resveratrol," said Dr Johan Auwerx of the Swiss Federal Polytechnic Academy of Lausanne (EPFL). "But unlike resveratrol, these new chemical entities target only the SIRT1 pathway, making them more selective and potent for achieving these metabolic benefits."

Professor Auwerx explained that the major advantage SRT1720 has over resveratrol is that it is likely to come with fewer side effects; however, further study is needed to confirm this. "The observation that SRT1720 transiently affects core body temperature and spontaneous locomotor activity could constitute potential side effects for the treatment of metabolic disorders," the study reports, "but could also be explored for other therapeutic interventions."

The authors conclude, "We believe that SRT1720 could act as a calorie restriction mimetic, which would induce a global metabolic adaptation similar to what occurs under low energetic levels." The main limitation of SRT1720, they found, is that the observed effects, in particular the anti-diabetic actions of the drug, were only achieved using fairly high doses.

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Cell Metabolism

Ecole Polytechnique Fédérale de Lausanne

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