Walking 200 min per day keeps the bariatric surgeon away.

Exercise and increased physical activity are vital components of the standard treatment guidelines for many chronic diseases such as diabetes, obesity and cardiovascular disease. Although strenuous exercise cannot be recommended to people with numerous chronic conditions, walking is something most people can perform. In comparison to high-intensity training, the metabolic consequences of low-intensity walking have been less well studied. We present here a feasibility study of a subject who performed an exercise intervention of low-intensity, non-fatiguing walking on a deskmill/treadmill for 200 min daily, approximately the average time a German spends watching television per day. This low-impact physical activity has the advantages that it can be done while performing other tasks such as reading or watching TV, and it can be recommended to obese patients or patients with heart disease. We find that this intervention led to substantial weight loss, comparable to that of bariatric surgery. To study the metabolic changes caused by this intervention, we performed an in-depth metabolomic profiling of the blood both directly after walking to assess the acute changes, as well as 1.5 days after physical activity to identify the long-term effects that persist. We find changes in acylcarnitine levels suggesting that walking activates fatty acid beta oxidation, and that this mitochondrial reprogramming is still visible 1.5 days post-walking. We also find that walking mildly increases gut permeability, leading to increased exposure of the blood to metabolites from the gut microbiome. Overall, these data provide a starting point for designing future intervention studies with larger cohorts.

Dietary stearic acid regulates mitochondria in vivo in humans.

Since modern foods are unnaturally enriched in single metabolites, it is important to understand which metabolites are sensed by the human body and which are not. We previously showed that the fatty acid stearic acid (C18:0) signals via a dedicated pathway to regulate mitofusin activity and thereby mitochondrial morphology and function in cell culture. Whether this pathway is poised to sense changes in dietary intake of C18:0 in humans is not known. We show here that C18:0 ingestion rapidly and robustly causes mitochondrial fusion in people within 3 h after ingestion. C18:0 intake also causes a drop in circulating long-chain acylcarnitines, suggesting increased fatty acid beta-oxidation in vivo. This work thereby identifies C18:0 as a dietary metabolite that is sensed by our bodies to control our mitochondria. This could explain part of the epidemiological differences between C16:0 and C18:0, whereby C16:0 increases cardiovascular and cancer risk whereas C18:0 decreases both.

Evidence Against a Role for the Parkinsonism-associated Protein DJ-1 in Methylglyoxal Detoxification.

Methylglyoxal (MG) is a reactive metabolite that forms adducts on cysteine, lysine and arginine residues of proteins, thereby affecting their function. Methylglyoxal is detoxified by the Glyoxalase system, consisting of two enzymes, Glo1 and Glo2, that act sequentially to convert MG into d-lactate. Recently, the Parkinsonism-associated protein DJ-1 was described in vitro to have glyoxalase activity, thereby detoxifying the MG metabolite, or deglycase activity, thereby removing the adduct formed by MG on proteins. Since Drosophila is an established model system to study signaling, neurodegeneration, and metabolic regulation in vivo, we asked whether DJ-1 contributes to MG detoxification in vivo Using both DJ-1 knockdown in Drosophila cells in culture, and DJ-1ß knock-out flies, we could detect no contribution of DJ-1 to survival to MG challenge or to accumulation of MG protein adducts. Furthermore, we provide data suggesting that the previously reported deglycation activity of DJ-1 can be ascribed to a TRIS buffer artifact.