Neural Stem Cells in the Adult Subventricular Zone Oxidize Fatty Acids to Produce Energy and Support Neurogenic Activity

Abstract

Neural activity is tightly coupled to energy consumption, particularly sugars such as glucose. However, we find that, unlike mature neurons and astrocytes, neural stem/progenitor cells (NSPCs) do not require glucose to sustain aerobic respiration. NSPCs within the adult subventricular zone (SVZ) express enzymes required for fatty acid oxidation and show sustained increases in oxygen consumption upon treatment with a polyunsaturated fatty acid. NSPCs also demonstrate sustained decreases in oxygen consumption upon treatment with etomoxir, an inhibitor of fatty acid oxidation. In addition, etomoxir decreases the proliferation of SVZ NSPCs without affecting cellular survival. Finally, higher levels of neurogenesis can be achieved in aged mice by ectopically expressing proliferator‐activated receptor gamma coactivator 1 alpha (PGC1α), a factor that increases cellular aerobic capacity by promoting mitochondrial biogenesis and metabolic gene transcription. Regulation of metabolic fuel availability could prove a powerful tool in promoting or limiting cellular proliferation in the central nervous system. Stem Cells 2015;33:2306–2319

Neural Stem Cells and Nutrients: Poised Between Quiescence and Exhaustion

“…This observation, which confirms previous findings on the key role of FA oxidation (FAO) in HSC self-renewal [36], is particularly relevant, since inborn defects in FAO are associated with developmental neuropsychiatric disorders including autism in humans [37]. Of note, FAO capacity is not restricted to embryonic NSCs, but also occurs in adult cells from SVZ [38].…”

“…These studies have indeed confirmed that NSC exit from quiescence is marked by downregulation of glycolysis [37], and FAO [38], and by an increase in ribosome biogenesis, protein synthesis, and mitochondrial oxidative phosphorylation.…”

“…In fact, cells committed to become fast-proliferating effector T lymphocytes inherit high mTOR and c-myc activity, which translates in a metabolic profile marked by lipogenesis and intense oxidative phosphorylation [77,78]. Conversely, cells inheriting low mTOR activity display lower glycolytic flux, reduced oxygen consumption, and prevalent fatty acid oxidation, which favor a quiescent, long-term memory phenotype [38].…”

Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer’s Disease

“…Under normal conditions, SVZ neural precursors depend on fatty acid oxidation for proliferation (Stoll et al, 2015), while baseline and exercise-induced hippocampal neurogenesis and cognitive enhancement require brain fatty acid synthesis (Chorna et al, 2013;Knobloch et al, 2013). However, alterations in lipid metabolism are associated with many cognitive disorders, including Huntington's, Parkinson's, and Niemann-Pick's diseases, as well as AD (Adibhatla and Hatcher, 2008;de la Monte and Tong, 2014;Guschina et al, 2011;Martinez-Vicente et al, 2010;Merlo et al, 2010;Sharon et al, 2003).…”

“…In the forebrain subventricular zone (SVZ) niche, lipid metabolism genes are among the major classes of transcriptional differences between quiescent and activated NSCs (Codega et al, 2014). Moreover, in both SVZ and hippocampal dentate gyrus (DG) niches, neural precursors require fatty acid oxidation for proliferation (Chorna et al, 2013;Knobloch et al, 2013;Matsumata et al, 2012;Stoll et al, 2015). NSCs are positioned particularly well in the SVZ to be regulated by environmental lipid signals.…”