MANF: an emerging therapeutic target for metabolic diseases.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum-resident protein and a secretory factor and has beneficial effects in multiple diseases. Recent evidence shows that its circulating levels in humans are dynamically regulated under various metabolic diseases, including diabetes, obesity, fatty liver, and cardiovascular diseases, suggesting that MANF may play a role in these pathological states. Also, its downregulation in mice impairs glucose homeostasis, promotes lipid accumulation in the liver, reduces energy expenditure, and induces inflammation. Conversely, MANF overexpression prevents or mitigates some of these metabolic disturbances. In particular, systemic MANF administration alleviates dietary obesity and related metabolic disorders in obese mice. We therefore propose that MANF might be a promising target for treating chronic metabolic diseases.