Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis

Knobloch, Marlen; Braun, Simon M. G.; Zurkirchen, Luis; Schoultz, Carolin von; Zamboni, Nicola; Araúzo‐Bravo, Marcos J.; Kovacs, Werner J.; Karalay, Oezlem; Suter, Ueli; Machado, Raquel Arminda Carvalho; Roccio, Marta; Lütolf, Matthias P.; Semenkovich, Clay F.; Jessberger, Sebastian

doi:10.1038/nature11689

Cited by 420 publications

(413 citation statements)

References 21 publications

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“…In line with these results, [17] showed that de novo lipogenesis is important for NSCs proliferation. These cells have high enzymatic activity of fatty acid synthase (Fasn) and the inhibition of Fasn led to a significant reduction in proliferation.…”

Section: Fluxome Rearrangements During Astrocytic Differentiation Of supporting

confidence: 75%

Quantification of Metabolic Rearrangements During Neural Stem Cells Differentiation into Astrocytes by Metabolic Flux Analysis

et al. 2016

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Proliferation and differentiation of neural stem cells (NSCs) have a crucial role to ensure neurogenesis and gliogenesis in the mammalian brain throughout life. As there is growing evidence for the significance of metabolism in regulating cell fate, knowledge on the metabolic programs in NSCs and how they evolve during differentiation into somatic cells may provide novel therapeutic approaches to address brain diseases. In this work, we applied a quantitative analysis to assess how the central carbon metabolism evolves upon differentiation of NSCs into astrocytes. Murine embryonic stem cell (mESC)-derived NSCs and astrocytes were incubated with labelled [1-13 C]glucose and the label incorporation into intracellular metabolites was followed by GC-MS. The obtained 13 C labelling patterns, together with uptake/secretion rates determined from supernatant analysis, were integrated into an isotopic non-stationary metabolic flux analysis ( 13 C-MFA) model to estimate intracellular flux maps. Significant metabolic differences between NSCs and astrocytes were identified, with a general downregulation of central carbon metabolism during astrocytic differentiation. While glucose uptake was 1.7-fold higher in NSCs (on a per cell basis), a high lactate-secreting phenotype was common to both cell types. Furthermore, NSCs consumed glutamine from the medium; the highly active reductive carboxylation of alpha-ketoglutarate indicates that this was converted to citrate and used for biosynthetic purposes. In astrocytes, pyruvate entered the TCA cycle mostly through pyruvate carboxylase (81%). This pathway supported glutamine and citrate secretion, recapitulating well described metabolic features of these cells in vivo. Overall, this fluxomics study allowed us to quantify the metabolic rewiring accompanying astrocytic lineage specification from NSCs.

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Section: Fluxome Rearrangements During Astrocytic Differentiation Of supporting

confidence: 75%

Quantification of Metabolic Rearrangements During Neural Stem Cells Differentiation into Astrocytes by Metabolic Flux Analysis

et al. 2016

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“…Table 2), demonstrating similarities in metabolic programs between reactive astrocytes and NSCs different from the ones of normal parenchymal astrocytes. This is particularly intriguing, as metabolic pathways have been shown to be key in regulating fate decisions and changes (see, e.g., Maryanovich and Gross, 2013) and specific aspects of the lipid metabolism have been identified as a key pathway regulating adult NSC activity (Bracko et al, 2012; Codega et al, 2014; Knobloch et al, 2013). Thus, the metabolic signatures shared between SEZ NSCs and reactive astrocytes are likely involved in regulating the transition of astrocytes to a more plastic progenitor/NSC‐like phenotype after injury.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

Sirko

Irmler

Gascón

et al. 2015

Glia

108

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Astrocytes react to brain injury in a heterogeneous manner with only a subset resuming proliferation and acquiring stem cell properties in vitro. In order to identify novel regulators of this subset, we performed genomewide expression analysis of reactive astrocytes isolated 5 days after stab wound injury from the gray matter of adult mouse cerebral cortex. The expression pattern was compared with astrocytes from intact cortex and adult neural stem cells (NSCs) isolated from the subependymal zone (SEZ). These comparisons revealed a set of genes expressed at higher levels in both endogenous NSCs and reactive astrocytes, including two lectins—Galectins 1 and 3. These results and the pattern of Galectin expression in the lesioned brain led us to examine the functional significance of these lectins in brains of mice lacking Galectins 1 and 3. Following stab wound injury, astrocyte reactivity including glial fibrillary acidic protein expression, proliferation and neurosphere‐forming capacity were found significantly reduced in mutant animals. This phenotype could be recapitulated in vitro and was fully rescued by addition of Galectin 3, but not of Galectin 1. Thus, Galectins 1 and 3 play key roles in regulating the proliferative and NSC potential of a subset of reactive astrocytes. GLIA 2015;63:2340–2361

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“…However, FASN is an essential enzyme that has indispensable functions in energy homeostasis, membrane biology, and neurogenesis, which preclude long term FASN inhibition in vivo (10,33,34). We therefore searched for an alternative strategy to target the dysfunctional cardiac substrate metabolism.…”

Section: Grk2 Inhibition By Grkinh In Fasn Transgenicmentioning

confidence: 99%

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

Alla

Graemer

et al. 2016

Journal of Biological Chemistry

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Impairment of myocardial fatty acid substrate metabolism is characteristic of late-stage heart failure and has limited treatment options. Here, we investigated whether inhibition of G-protein-coupled receptor kinase 2 (GRK2) could counteract the disturbed substrate metabolism of late-stage heart failure. The heart failure-like substrate metabolism was reproduced in a novel transgenic model of myocardium-specific expression of fatty acid synthase (FASN), the major palmitate-synthesizing enzyme. The increased fatty acid utilization of FASN transgenic neonatal cardiomyocytes rapidly switched to a heart failure phenotype in an adult-like lipogenic milieu. Similarly, adult FASN transgenic mice developed signs of heart failure. The development of disturbed substrate utilization of FASN transgenic cardiomyocytes and signs of heart failure were retarded by the transgenic expression of GRKInh, a peptide inhibitor of GRK2. Cardioprotective GRK2 inhibition required an intact ERK axis, which blunted the induction of cardiotoxic transcripts, in part by enhanced serine 273 phosphorylation of Pparg (peroxisome proliferator-activated receptor ␥). Conversely, the dual-specific GRK2 and ERK cascade inhibitor, RKIP (Raf kinase inhibitor protein), triggered dysfunctional cardiomyocyte energetics and the expression of heart failure-promoting Pparg-regulated genes. Thus, GRK2 inhibition is a novel approach that targets the dysfunctional substrate metabolism of the failing heart.Heart failure is a debilitating syndrome that involves insufficient cardiac performance. Multiple pathomechanisms have been elucidated, but treatment options remain insufficient, and hence the mortality of heart failure is high (1). The causes of heart failure are complex with ischemic heart disease being the most frequently associated condition (2). Co-existing disorders such as diabetes, hypertension, and obesity further deteriorate symptoms (3). Despite having a different etiology, late-stage heart failure is commonly characterized by severe changes in myocardial substrate metabolism, with a switch from fatty acid oxidation toward predominant glycolysis (4 -6). Conflicting evidence exists as to whether this substrate switch is beneficial or detrimental (7), but several previous studies have indicated that an increased availability of lipid substrates that counteract the substrate switch could improve cardiac function (7,8). Moreover, treatment options, which improve substrate availability, are attractive because the failing heart is often considered to be "an engine running out of fuel" (9).Following this concept, we aimed to investigate the impact of improved cardiac substrate availability by generating transgenic mice with myocardium-specific expression of fatty acid synthase (FASN), the major palmitate-synthesizing enzyme. Such an approach is also supported by data obtained for myocardium-specific Fasn deficiency, which have revealed the cardioprotective potential of Fasn (10). Moreover, hearts from patients with heart failure showed an increased express...

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Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis

Cited by 420 publications

References 21 publications

Quantification of Metabolic Rearrangements During Neural Stem Cells Differentiation into Astrocytes by Metabolic Flux Analysis

Quantification of Metabolic Rearrangements During Neural Stem Cells Differentiation into Astrocytes by Metabolic Flux Analysis

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

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