Abstract
All human behaviors, including the control of energy homeostasis, are ultimately mediated by neuronal activities in the brain. Neurotrophic factors represent a protein family that plays important roles in regulating neuronal development, function, and survival. It has been well established that canonical neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), play important roles in the central regulation of energy homeostasis. Recently, a class of non-canonical neurotrophic factors, represented by mesencephalic astrocyte-derived neurotrophic factor (MANF), has been discovered. MANF is structurally and functionally distinct from those canonical neurotrophic factors, hence raising the issue of MANF being non-canonical. Nonetheless, emerging evidence suggests that MANF is critically involved in many neuronal activities. Here, we review our current understanding about the functions of MANF in the brain, with a primary focus on the control of energy homeostasis.
Highlights
Specialty section: This article was submitted to Clinical and Translational Physiology, a section of the journal Frontiers in Physiology
The brain serves as a pivotal hub for information integration and processing, as different signals generated by the peripheral tissues, including leptin produced in the adipose tissues (Zhang et al, 1994), insulin produced by the pancreas (Woods et al, 1979; Baskin et al, 1999), ghrelin produced by the stomach (Nakazato et al, 2001), glucagon-like peptide 1 (GLP-1) and peptide YY 3-36 (PYY3−36) produced by the intestine (Turton et al, 1996; Batterham et al, 2002)
Two types of neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), have been linked to the central control of energy homeostasis, as mutations in the genes encoding BDNF and its receptor tropomyosin receptor kinase B (TrkB) are found in patients with severe obesity (Yeo et al, 2004; Gray et al, 2006; Han et al, 2008), and administration of CNTF protein leads to body weight loss in both human and mice (Miller et al, 1996; Gloaguen et al, 1997)
Summary
Neuronal activities are not merely controlled by secreted factors from peripheral tissues. Several lines of evidence support the extracellular functions of MANF: in cultured cells, addition of recombinant MANF protein into the culture medium is able to activate pro-survival signaling pathways, including PKC, AKT/GSK3β, AMPK/mTOR and STAT3 pathways (Yang S. et al, 2014; Zhang et al, 2017a,b; Tseng et al, 2018); in fruit fly and mouse, administration of recombinant MANF protein ameliorated retinal degeneration caused by various damaging stimuli, and the protective capacity could be derived from immune modulation (induction of alternative activation of microglia) (Neves et al, 2016); in rodent models of PD and stroke, administration of recombinant MANF protein reduced neuronal death (Airavaara et al, 2009; Voutilainen et al, 2009; Yang W. et al, 2014). ER stress, MANF could be either secreted to the extracellular space (Oh-Hashi et al, 2012; Hartley et al, 2013), or enter the nucleus to suppress the transcriptional activities of NF-κB pathway (Chen et al, 2015)
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