Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.07.20.212597

Production of the Short Chain Fatty Acid, Acetic Acid/Acetate from Ethanol Metabolism Activates NMDAR

Chapp, A.·Huber, M.·Driscoll, K.·Behnke, J.·Larson, R.·Schum, S.·Shan, Z.·Zhang, L.·Chen, Q.
View original source ↗Export metadata ↓

Abstract

Binge alcohol consumption elicits robust sympathoexcitation and excitatory neuronal output. However, the central mechanism that mediates these effects remains elusive. We investigated the effects of ethanol metabolism within the central nucleus of the amygdala (CeA) on sympathoexcitation, and elucidated the role of acetate in these excitatory responses. In vivo arterial blood pressure, heart rate and sympathetic nerve activity responses to CeA microinjected ethanol or acetate with appropriate inhibitors/antagonists were tracked. In vitro whole-cell electrophysiology recording responses to acetate in CeA neurons with axon projecting to the rostral ventrolateral medulla (CeA-RVLM) were investigated, and cytosolic calcium responses in primary neuronal cultures were quantified. We demonstrate that in Sprague Dawley rats, local brain metabolism of ethanol in the CeA to acetic acid/acetate elicits sympathoexcitatory responses in vivo through activation of NMDA receptor (NMDAR). Alcohol dehydrogenase or aldehyde dehydrogenase inhibition using fomepizole or cyanamide and NMDAR antagonism using AP5 or memantine blunted these effects. Whole-cell patch-clamp recordings in brain slices containing autonomic CeA-RVLM neurons revealed a dose-dependent increase in neuronal excitability in response to acetate. NMDAR antagonists suppressed the acetate-induced increase in CeA-RVLM neuronal excitability, and memantine suppressed the direct activation of NMDAR-mediated inward currents by acetate in brain slices. We observed that acetate increased cytosolic Ca2+ in a time-dependent manner in primary neuronal cell cultures. The acetate enhancement of calcium signaling was abolished by memantine. These findings suggest that within the CeA, ethanol is sympathoexcitatory through local brain metabolism, which generates acetic acid/acetate leading to activation of NMDAR. NEW AND NOTEWORTHYBrain ethanol metabolism to acetic acid (vinegar)/acetate causes activation of N-methyl-D-aspartate receptors (NMDARs) in the central nucleus of the amygdala and elicits sympathoexcitatory responses. This excitatory mechanism is opposite to the inhibitory effects of ethanol at NMDAR. Understanding the active compounds that arise from ethanol metabolism, and the molecular mechanisms by which they influence alcohol reward and cardiovascular function, may be beneficial in developing targeted intervention strategies for both alcohol use disorder and its cardiovascular sequelae. Graphical Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/212597v4_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@18d8ec9org.highwire.dtl.DTLVardef@996b70org.highwire.dtl.DTLVardef@5cbecaorg.highwire.dtl.DTLVardef@f1cd4b_HPS_FORMAT_FIGEXP M_FIG Proposed mechanisms for ethanol and acetate induced increases in sympathoexcitation within the central nucleus of the amygdala (CeA). Abbreviations: Acetic acid (HOAc), acetate (-OAc), ADH (alcohol dehydrogenase), ALDH (aldehyde dehydrogenase), BBB (blood brain barrier), FOM (fomepizole), CYAN (cyanamide), CYP450 (cytochrome P450), IML (intermediolateral nucleus), RVLM (rostral ventrolateral medulla), SNA (sympathetic nerve activity). C_FIG

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Chapp, A., Huber, M., Driscoll, K., Behnke, J., Larson, R., Schum, S., Shan, Z., Zhang, L., Chen, Q.. 2020-07-22. Production of the Short Chain Fatty Acid, Acetic Acid/Acetate from Ethanol Metabolism Activates NMDAR. https://doi.org/10.1101/2020.07.20.212597

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The canine hair metabolome encodes age and coat exposure in over 700 dogs

Hair can be collected noninvasively and stored for years, making it a practical sample for studying physiology and environmental exposure. Yet the chemical information it carries in dogs remains largely unexplored. We profiled 782 banked hair samples from 700 Golden Retrievers by untargeted liquid chromatography-mass spectrometry, detecting 4,533 compound groups and revealing an unexpectedly rich chemical profile. Prominent signals reflected skin-surface and hair chemistry, including amino acids, peptides and urocanic acid, alongside surfactants, plasticizers and pesticides detectable despite washing. A signal annotated as imidacloprid distinguished dogs receiving topical products containing this insecticide from dogs receiving no flea or tick preventive (AUC 0.865). Hair chemistry also varied with age, most strongly between puppyhood and early adulthood. Oxidized lipids generally declined, whereas amino acids and peptides remained largely stable. A multivariate model estimated age with moderate accuracy (cross-validated r = 0.66) and assigned a higher age to the later sample in 64 of 75 repeatedly sampled dogs. Because age and collection date were strongly correlated, their effects could not be fully separated, although date-restricted analyses supported an age-related contribution. Together, these findings establish banked dog hair as a promising resource for studying chemical exposure and life-stage-associated changes in chemistry.

physiology↗
bioRxiv2026

Dietary Human HSP90 Promotes Longevity and Healthspan in Caenorhabditis elegans via a Multi-Branched Stress Signaling Pathway

The loss of proteostasis is one of the primary drivers of aging. Despite the important role of the molecular chaperone HSP90 in maintaining proteostasis, its systemic role in aging appears contradictory because its inhibitors can effectively extend lifespan across diverse species. This study showed that dietary HSP90 supplementation via Escherichia coli significantly extended lifespan and healthspan of Caenorhabditis elegans without fertility trade-offs. Exogenous HSP90 likely acts as an extracellular signaling ligand that engages downstream kinase networks to drive the activation of three major longevity-associated transcription factors: DAF-16, SKN-1, and HSF-1. In addition, we demonstrated the additive effect of combining dietary HSP90 supplementation with the senolytic HSP90 inhibitor tanespimycin, indicating that extracellular proteostatic signaling and the intracellular inhibition of HSP90 can work together to enhance longevity. Finally, we engineered an antibiotic-free E. coli Nissle 1917 probiotic that constitutively expresses HSP90, which successfully extended the lifespan of C. elegans.

physiology↗
bioRxiv2026

Sex differences in myocardial ketone oxidation capacity in cardiometabolic disease with coincident ischemic heart disease

Background: Myocardial infarction (MI) in patients with heart failure with preserved ejection fraction (HFpEF) is associated with worse outcomes than MI in individuals without HFpEF. However, the molecular mechanisms underlying this increased vulnerability remain poorly understood. We investigated sex differences in cardiac ketone body (KB) metabolism in patients with diabetes-associated ischemic heart disease, and in a mouse model of HFpEF complicated by MI (HFpEF-MI). Methods: Cardiac BDH1 and OXCT1 expression was assessed in male and female patients with diabetes, with or without ischemic heart disease. Male and female mice received a high-fat diet and L-NAME for 10 weeks to induce HFpEF, followed by coronary artery ligation to induce MI. Glucose tolerance, cardiac function, survival, cardiac KB oxidative capacity, and circulating KB levels were evaluated. Results: Cardiac BDH1 and OXCT1 abundance was significantly reduced in male patients with diabetes-associated ischemic heart disease but preserved in female patients. In mice, 10 weeks of high-fat diet and L-NAME administration increased fasting blood glucose and impaired glucose tolerance. MI reduced systolic function in control and HFpEF mice of both sexes. Male HFpEF-MI mice exhibited higher mortality than female HFpEF-MI mice. Consistent with our human results, male HFpEF-MI mice showed reduced cardiac ketolytic enzyme expression alongside elevated circulating KB levels, whereas female mice maintained cardiac KB oxidative capacity. Conclusion: Reduced cardiac ketolytic enzyme expression and impaired KB oxidative capacity are associated with greater mortality in male HFpEF-MI mice, whereas female mice exhibit preserved KB oxidative capacity and improved survival. Similar sex differences in ketolytic enzyme expression were observed in patients with diabetes-associated ischemic heart disease. These findings identify cardiac ketone metabolism as a potential therapeutic target warranting further investigation in HFpEF complicated by MI.

physiology↗