Inhibition of Sirt1 May be the Way to Control Obesity

Activation of the NAD⁺-dependent deacetylase, sirtuin-1 (Sirt1), has been linked to increased longevity in various species although further studies are needed to establish its role in human ageing. The beneficial effects of calorie restriction on lifespan and the proposed anti-ageing properties of resveratrol have both been linked to activation of sirtuins, although not without controversy. In a significant departure from previous studies which have focussed on activating Sirt1, research carried out at Brown University and Rhode Island Hospital has now suggested that inhibiting Sirt1 may be a way to control obesity.

In the first in-depth study of the metabolic role of Sirt1 in the brain, the researchers found that inhibiting Sirt1 appears to help control food intake. Calorie restriction increases expression of Sirt1 specifically in the hypothalamus, the primary brain centre that regulates food intake and body weight so the team hypothesised that hypothalamic Sirt1 is a metabolic factor controlling food intake. ICV administration of the selective Sirt1 inhibitor, EX527, in fasted rats resulted in decreased food intake and body weight gain. The weight gain was less than that of pair-fed counterparts suggesting that the decrease in weight gain was not exclusively due to the reduced food intake. The effects were shown to be Sirt1-specific since both were reversed by co-administration of a Sirt1 activator at a dose which alone did not change either food intake or weight gain. Knock-down of Sirt1 expression by infusion of Sirt1 specific siRNAs directly into the arcuate nucleus of the hypothalamus also led to lower food consumption and smaller weight gain. Co-administration of the melanocortin antagonist, SHU9119, with EX527 completely attenuated the lower food intake and reduced weight gain caused by EX527, indicating a role for melanocortin signalling in mediating the effects of Sirt1 on energy balance. Inhibition of hypothalamic Sirt1 activity was also shown to reverse fasting-induced decreases in S6 kinase signalling and to increase levels of serum thyroid hormones, which are strong stimulators of basic metabolic rate and thermogenesis.

The authors propose that central Sirt1 senses the nutritional status of the body and regulates hypothalamic melanocortin signalling together with the S6K pathway to govern food intake and body weight, and suggest that agents targeting this pathway may show promise for the treatment of obesity and associated metabolic disorders.

The study is published in PLoSone.