MANF: an emerging therapeutic target for metabolic diseases

Abstract

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. HighlightsMesencephalic astrocyte-derived neurotrophic factor (MANF) is highly expressed in metabolically active tissues such as pancreas, liver, and hypothalamus. MANF circulating level is dynamically regulated under various metabolic diseases such as type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and obesity.MANF downregulation in mice induces various metabolic disturbances. Conversely, increasing MANF expression prevents or mitigates these disorders.Systemic MANF protein administration retards body weight gain and improves glucose homeostasis in obese mice.MANF can function intracellularly (via endoplasmic reticulum stress-dependent and -independent mechanisms) and extracellularly (via receptors or endocytosis).

Mesencephalic astrocyte‐derived neurotrophic factor alleviates non‐alcoholic steatohepatitis induced by Western diet in mice

“…Consistent with MANF overexpression, these results demonstrated that exogenous supplementation MANF protected against lipid deposition and inflammation response, and inhibited SREBP1 and NF‐κB signaling with PA treatment, which indicated that exogenous supplementation MANF play a role in lipid metabolism and inflammation response at least in part. Previous studies proposed that extracellular MANF likely functions by three major pathways, including endocytosis, binding to its receptor NPTN and KDELR 20 . However, whether and how MANF acts in autocrine/paracrine manner will need more investigations.…”

“…Previous studies proposed that extracellular MANF likely functions by three major pathways, including endocytosis, binding to its receptor NPTN and KDELR. 20 However, whether and how MANF acts in autocrine/paracrine manner will need more investigations.…”

“…19 Emerging studies have demonstrated that MANF is a regulator of metabolic homeostasis and inflammation. 20 MANF downregulated lipid level and inhibited genes related to fatty acid synthesis and lipid uptake in HepG2 cell. 21 MANF was shown to protect against liver damage induced by senility, ischaemiareperfusion, rifampicin, and alcohol.…”

Nuclear Receptor RORα/γ: Exciting Modulators in Metabolic Syndrome and Related Disorders

“…As a complex condition, MetS conditions often occurs together and elevates the risk of type 2 diabetes, prevalence of stroke and myocardial infarction, and mortality rate of cardiovascular diseases, as well as compromise life quality and cause great economic burden (3). Given the primary pathological components in MetS, including impaired glucose and lipid metabolism, the current treatments of healthy lifestyles changes, including improved dietary plans, regular physical activity, reducing stress, and stopping smoking are helping, but not enough (4)(5)(6). For the purposes of drug discovery, nuclear receptors (NRs) like peroxisome proliferator-activated receptor (PPARs), liver X receptor (LXRs), REV-ERBs, and retinoic acid receptor-related orphan receptors (RORs) have favorable attributes, with most containing protected internal cavities predisposed for occupation with hydrophobic molecules of volumes typical of drugs.…”

Glucose Stimulates Glial Cell Line-Derived Neurotrophic Factor Gene Expression in Microglia through a GLUT5-Independent Mechanism

“…Moreover, hypothalamus-specific enhancement of GDNF expression resulted in reduced food intake and body weight as well as increased energy expenditure in rats [8,9]. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a non-canonical neurotrophic factor that does not share any homology of its protein sequence with other canonical neurotrophic factors [10]. It was initially isolated from a rat mesencephalic type-1 astrocyte cell line and was shown to have neurotrophic effects 2 of 13 on dopaminergic neurons [11].…”