Fetal alcohol spectrum disorder predisposes to metabolic abnormalities in adulthood
Olivia Weeks, … , Pouneh K. Fazeli, Wolfram Goessling
Olivia Weeks, … , Pouneh K. Fazeli, Wolfram Goessling
Published March 23, 2020
Citation Information: J Clin Invest. 2020;130(5):2252-2269. https://doi.org/10.1172/JCI132139.
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Research Article Development Metabolism

Fetal alcohol spectrum disorder predisposes to metabolic abnormalities in adulthood

Abstract

Prenatal alcohol exposure (PAE) affects at least 10% of newborns globally and leads to the development of fetal alcohol spectrum disorders (FASDs). Despite its high incidence, there is no consensus on the implications of PAE on metabolic disease risk in adults. Here, we describe a cohort of adults with FASDs that had an increased incidence of metabolic abnormalities, including type 2 diabetes, low HDL, high triglycerides, and female-specific overweight and obesity. Using a zebrafish model for PAE, we performed population studies to elucidate the metabolic disease seen in the clinical cohort. Embryonic alcohol exposure (EAE) in male zebrafish increased the propensity for diet-induced obesity and fasting hyperglycemia in adulthood. We identified several consequences of EAE that may contribute to these phenotypes, including a reduction in adult locomotor activity, alterations in visceral adipose tissue and hepatic development, and persistent diet-responsive transcriptional changes. Taken together, our findings define metabolic vulnerabilities due to EAE and provide evidence that behavioral changes and primary organ dysfunction contribute to resultant metabolic abnormalities.

Authors

Olivia Weeks, Gabriel D. Bossé, Isaac M. Oderberg, Sebastian Akle, Yariv Houvras, Paul J. Wrighton, Kyle LaBella, Isabelle Iversen, Sahar Tavakoli, Isaac Adatto, Arkadi Schwartz, Daan Kloosterman, Allison Tsomides, Michael E. Charness, Randall T. Peterson, Matthew L. Steinhauser, Pouneh K. Fazeli, Wolfram Goessling

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Figure 7

Ethanol impairs embryonic liver growth and alters liver response to HFHC diet.

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Ethanol impairs embryonic liver growth and alters liver response to HFHC...
(A) EtOH (12 hpf–78 hpf) reduces the size of the fabp10a:mKate+ liver and the size and complexity of the tp1glob:eGFP+ biliary tree at 78 hpf. Liver and biliary volumes were achieved through 3D reconstruction based on confocal imaging of the Tg(fabp10a:mKate+) and Tg(tp1glob:eGFP) reporters. Confocal imaging and Imaris 3D spot detection of nuclei in Tg(fabp10a:NLS-mcherry) embryos demonstrate that EtOH exposure reduces hepatocyte nuclei number. Scale bars: 60 μm. (B) EAE reduces liver volume relative to body size. ****P < 0.0001, unpaired 2-tailed Student’s t test. (C and D) EAE reduces biliary tree volume, but proportionally to liver volume reduction. ****P < 0.0001, unpaired 2-tailed Student’s t test. (E) Hepatocyte number is reduced in 1% EtOH larvae relative to matched controls. ****P < 0.0001, unpaired 2-tailed Student’s t test. (F) Schematic of RNA-Seq of adult livers after 8 weeks of normal and HFHC diet challenge. (G and H) Heatmap of dysregulated (P < 0.05) genes following sequencing of 0% and 1% EtOH (12 hpf–5 dpf) adults receiving ND and HFHC diet. (I) GSEA of genes significantly dysregulated (P < 0.05) in 1% EtOH (12 hpf–5 dpf) adults receiving the HFHC diet. (J) Alterations in hepatic transcripts following HFHC diet challenge (P < 0.05). Heatmap P values were determined using a negative binomial test with Wald’s test from RNA-Seq analysis. Sample numbers (n) noted under figure panels.