Biology subjects

Saavedra, P.

Publications and source records attributed to Saavedra, P..

3 recordsLinked to original sources

bioRxiv2023

Early life high fructose exposure disrupts microglia function and impedes neurodevelopment

Despite the success of fructose as a low-cost food additive, recent epidemiological evidence suggests that high fructose consumption by pregnant mothers or during adolescence is associated with disrupted neurodevelopment1-7. An essential step in appropriate mammalian neurodevelopment is the synaptic pruning and elimination of newly-formed neurons by microglia, the central nervous systems (CNS) resident professional phagocyte8-10. Whether early life high fructose consumption affects microglia function and if this directly impacts neurodevelopment remains unknown. Here, we show that both offspring born to dams fed a high fructose diet and neonates exposed to high fructose exhibit decreased microglial density, increased uncleared apoptotic cells, and decreased synaptic pruning in vivo. Importantly, deletion of the high affinity fructose transporter SLC2A5 (GLUT5) in neonates completely reversed microglia dysfunction, suggesting that high fructose directly affects neonatal development. Mechanistically, we found that high fructose treatment of both mouse and human microglia suppresses synaptic pruning and phagocytosis capacity which is fully reversed in GLUT5-deficient microglia. Using a combination of in vivo and in vitro nuclear magnetic resonance- and mass spectrometry-based fructose tracing, we found that high fructose drives significant GLUT5-dependent fructose uptake and catabolism, rewiring microglia metabolism towards a hypo-phagocytic state. Importantly, mice exposed to high fructose as neonates exhibited cognitive defects and developed anxiety-like behavior which were rescued in GLUT5-deficient animals. Our findings provide a mechanistic explanation for the epidemiological observation that early life high fructose exposure is associated with increased prevalence of adolescent anxiety disorders.

immunology↗

bioRxiv2022

Novel adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments

Apoptotic cell clearance (efferocytosis), a process essential for organismal homeostasis, is performed by phagocytes that inhabit a wide range of environments, including physiologic hypoxia. Here, we find macrophages, the predominant tissue-resident phagocyte, display enhanced efferocytosis under prolonged (chronic) physiological hypoxia, characterized by increased internalization and accelerated degradation of apoptotic cells. Analysis of mRNA and protein programs revealed that chronic physiological hypoxia induces two distinct but complimentary states in macrophages. The first, primed state consists of concomitant induction of transcriptional and translational programs broadly associated with metabolism in apoptotic cell-naive macrophages that persist during efferocytosis. The second, poised state consists of transcription, but not translation, of phagocyte function programs in apoptotic cell-naive macrophages that are subsequently translated during efferocytosis. Importantly, we discovered that both states are necessary for enhanced continual efferocytosis. Mechanistically, we find that one such primed state consists of the efficient flux of glucose into a noncanonical pentose phosphate pathway (PPP) loop, whereby PPP-derived intermediates cycle back through the PPP to enhance production of NADPH. Furthermore, we found that PPP-derived NADPH directly supports enhanced continual efferocytosis under chronic physiological hypoxia via its role in phagolysosomal maturation and maintenance of cellular redox homeostasis. Thus, macrophages residing under chronic physiological hypoxia adopt states that both support cell fitness and ensure ability to perform essential homeostatic functions rapidly and safely. Highlights- Macrophages residing in chronic physiological hypoxia have enhanced apoptotic cell uptake and degradation - Chronic physiological hypoxia induces both primed and poised states in macrophages - Both primed and poised state programs directly support enhanced continual efferocytosis - A noncanonical PPP loop, a unique primed state, directly supports enhanced efferocytosis and maintains redox homeostasis

immunology↗

bioRxiv2021

REPTOR/CREBRF encode key regulators of muscle energy metabolism

Metabolic flexibility of muscle tissue describes the capacity to use glucose or lipids as energy substrates and its disruption is associated with metabolic dysfunction. Cancer-induced cachexia is a metabolic syndrome linked with muscle wasting, changes in muscle energy metabolism and lower life expectancy in cancer patients. The molecular mechanisms driving metabolic changes in muscle, however, are poorly characterized. Here, using a Drosophila model of systemic metabolic dysfunction triggered by yorkie-induced gut tumors, we identify the transcription factor REPTOR as a key regulator of energy metabolism in muscle. We show that REPTOR is upregulated in muscles of adult flies with gut yorkie-tumors, where it is necessary to modulate glucose metabolism. REPTOR expression in muscles is induced by ImpL2, a tumor-derived insulin binding protein that reduces systemic insulin signaling, or by nutritional restriction. Further, in vitro and in vivo studies indicate that high activity of REPTOR is sufficient to increase glucose content, transcriptionally repress phosphofructokinase and increase mitochondrial respiration. Consistent with the fly studies, higher levels of CREBRF, the mammalian ortholog of REPTOR, reduce glycolysis in mouse myotubes while promoting an oxidative phenotype. Altogether, our results implicate REPTOR/CREBRF as key regulators of muscle metabolism and metabolic flexibility that share a conserved function as repressors of glycolysis and promoters of oxidative phosphorylation.

physiology↗