The new protein called mesencephalic astrocyte-derived neurotrophic factor (MANF) also goes by the name arginine-rich mutation in early tumors (ARMET) or arginine-rich protein (ARP). MANF functions in cellular homeostasis and multiple other roles throughout the biological realm, so medical science has been interested. MANF is not the same type or function as traditional neurotrophic factors (NTFs). MANF has an N-terminal saposin-like lipid-binding domain and C-terminal SAF-A/B, acinar, and PIAS (SAP) domains connected by a short linker. These are two of MANF's operations that were briefly mentioned:
- It's a direct neuroprotective effect of the nervous system since it's a neurotrophic factor.
- Cytoprotective in animal models of non-neuronal disorders such as retinal damage, diabetes, liver damage, myocardial infarction, nephrotic syndrome, etc.
MANF is also needed for many physiological processes and it is cytoprotective for neuronal growth and survival. MANF also impacts synapse growth and expansion, neuronal differentiation, and cell migration. As well as the nervous system, MANF is also present in hyperactive secretory and metabolic tissues (pancreas, liver, hypothalamus, pituitary) that govern metabolism and suppress inflammation.
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MANF-associated Chronic Metabolic Diseases
MANF and chronic metabolic diseases illustrate the complexities of metabolism and homeostasis. MANF is found in varying quantities and plays a role in numerous pathologies. It could potentially be administered in the clinical management of various chronic metabolic diseases:
Diabetes
The relationship between diabetes and lowered insulin sensitivity in other tissues and pancreatic beta-cell loss is well established. MANF helps to sustain pancreatic beta-cells, and it's been shown that the loss of MANF can cause insulin resistance and beta-cell destruction. Endocrine stress can even contribute to insulin resistance with MANF.
Obesity
What leads to weight gain is the mismatch between calories burned and calories burned, and the MANF function as an energy control mechanism is finally getting some attention. There is an increased MANF in the serum of the obese and overweight, compared with the healthy population. MANF could be related to obesity because fat tissue is an arbiter of its levels. In obese patients, MANF has been demonstrated to stimulate adipocytes and lower inflammatory levels.
Metabolic Dysfunction-associated Fatty Liver
Metabolic dysfunction-associated fatty liver disease (MAFLD) has replaced the original term, non-alcoholic fatty liver disease. Current research, including both in vitro and in vivo studies, has revealed that MANF inhibits adipogenesis.
Cardiovascular Disease
CVD pathogenesis is multi-faceted and so is stress and inflammation at the endoplasmic reticulum. As has been shown in adult growth hormone-deficient patients, markedly reduced circulating levels of MANF predicted CVD risk in the future.
Kidney Disease
MANF also increases and releases from endoplasmic reticulum stress in podocytes and renal tubular cells, and urine MANF levels could be an endpoint to diagnosis of endoplasmic reticulum stress-associated kidney diseaseIt appears that MANF is a promising candidate for treating various types of kidney disease.
Metabolic Syndrome
MANF can also balance metabolism and reverse metabolic syndrome, for example by regulating glucose metabolism and lowering cholesterol.
Fig. 1 Metabolic functions of MANF (Wenzek F., et al. 2024).
Note that, while studies to date have demonstrated that MANF has biological relevance in these metabolic chronic diseases, additional studies are required to delineate its exact mechanism and therapeutic potential.
Therapeutic Potential of MANF
MANF looks promising as a therapy for neurodegenerative and metabolic disorders as well as cell stress pathologies. Unlocking the cytoprotective and homeostatic effects of MANF could also lead to new therapeutics in multimodality disease.
Mechanisms of Metabolism by MANF
MANF's functional domain is also broader than these conventional boundaries and encompasses intracellular and extracellular processes. Although its intracellular function in ER protein homeostasis is well-understood, more recent evidence has suggested that it is extracellular and could be involved in many more cellular interactions and cascades of signaling through the expression of secreted MANF.
The role of MANF in the regulation of metabolic processes goes beyond cell survival to the interconnected metabolic machinery that determines energy homeostasis, glucose metabolism, and insulin signaling. MANF orchestrates metabolic equilibrium by controlling metabolic pathways and cellular responses to metabolic stressors.
Conclusion
MANF defends all nerve cells, prolongs neuronal viability, prevents cell death, and counters neuroinflammation and oxidative stress. MANF is also deeply connected to several neurodegenerative diseases, including Parkinson's and Alzheimer's. Scientists are now focusing on MANF as a potential target for curing these diseases or, at the very least, halting their progression. MANF was associated with several metabolic processes; glucose regulation, insulin resistance, lipid metabolism, energy, and inflammation, among others. Still no clue on the exact mechanism, but so far discoveries have helped to understand how MANF works inside and outside the cell. Then there are studies of MANF in the management of metabolic diseases like diabetes, obesity, MAFLD, CVD, and kidney disease. As such, they will be hard to answer, and might also lead to new treatment approaches for metabolic disorders.
Reference
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Qin T.; et al. MANF: an emerging therapeutic target for metabolic diseases. Open access. 2022, 33(4): 236-246.
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