Abstract
Dietary restriction induces beneficial metabolic changes and prevents age-related deterioration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) shows protective effects on cells in various models of degenerative diseases. Here we studied whether circulating concentrations of MANF are associated with fasting-induced positive effects. We quantified the levels of circulating MANF from 40 human subjects before and after therapeutic fasting. As measured by an enzyme-linked immunosorbent assay (ELISA), the mean concentration of plasma MANF increased after an average fasting of 15 days. Plasma MANF levels correlated inversely with adiponectin, a hormone that regulates metabolism, thus suggesting that MANF levels are related to metabolic homeostasis. To study the effects of dietary intervention on MANF concentrations in mice, we developed an ELISA for mouse MANF and verified its specificity using MANF knock-out (KO) tissue. A switch from high-fat to normal diet increased MANF levels and downregulated the expression of unfolded protein response (UPR) genes in the liver, indicating decreased endoplasmic reticulum (ER) stress. Liver MANF and serum adiponectin concentrations correlated inversely in mice. Our findings demonstrate that MANF expression and secretion increases with dietary intervention. The MANF correlation to adiponectin and its possible involvement in metabolic regulation and overall health warrants further studies.
Highlights
Fasting is the voluntary restriction of food intake for a defined period and can be therapeutically used for different indications[1]
Another recent study suggested that Mesencephalic astrocyte-derived neurotrophic factor (MANF) can regulate energy homeostasis, as transgenic overexpression of MANF in the brain hypothalamus led to overfeeding and obesity in mice[35]
In light of these new findings, and together with previous studies that have shown protective effects of MANF in animal models of neurodegenerative diseases[9,12,13,14], we first aimed to determine if MANF is induced upon health-promoting dietary restriction in humans
Summary
Fasting is the voluntary restriction of food intake for a defined period and can be therapeutically used for different indications[1]. Fasting regimes induce adaptive programs to reduce metabolism in response to food deprivation, promote health, and extend lifespan in multiple model organisms[6,7]. Proliferation and survival of pancreatic beta cells in Manf−/− mice were compromised due to chronic ER stress, suggesting that MANF is important for the maintenance of ER homeostasis in the cells[15]. In a recently published study, systemic MANF was shown to have anti-aging properties related to the regulation of metabolism and immune response[30]. Using heterochronic parabiosis, which connects the blood circulation from young and old mice, the authors demonstrated that the presence of MANF in the young blood was required for the rejuvenating effect of parabiosis on age-related liver degeneration in old mice. Systemic delivery of recombinant MANF protein was able to alleviate age-related liver damage in mice[30]
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