Intermittent methionine restriction and selenium supplementation protect against inflammation and the development of dermatitis

Dietary methionine restriction (MR) produces multiple metabolic health benefits and extends the healthspan of several model organisms, including rodents. MR is feasible for humans, and studies have reported that methionine-restricted human subjects receive similar benefits to rodents. However, long-term adherence to continuous MR is likely to be challenging (if not impossible) for many individuals. Another obstacle to the successful translation of this intervention is the fact that multiple deleterious effects of continuous MR have been reported for mice and humans, including loss of musculoskeletal mass, increased bone marrow adipogenesis, and an increased incidence of fractures. To address these issues, we developed two novel interventions that produce similar health benefits to continuous MR, but without the same deleterious side effects. The first is an intermittent form of MR (IMR) that requires only 3 days of reduced methionine intake per week; the second involves supplementation of an otherwise normal diet with sodium selenite. For the current study, we considered the possibility that these interventions might also prevent and/or ameliorate diet-induced chronic inflammation, as well as pathologies that result from this condition. Accordingly, we tested whether IMR or selenium supplementation were able to protect high-fat diet-fed mice against both inflammation and the development of inflammation-induced ulcerative dermatitis. Here, we show that high-fat diet-fed mice undergoing both interventions not only have relatively low levels of inflammation, but are also protected against the development of dermatitis. We also propose a model for the mechanistic basis of such benefits, which involves reduced activation of leptin-responsive pro-inflammatory pathways.