Selective transcriptomic dysregulation of metabolic pathways in liver and retina by short and long-term dietary hyperglycemia

Authors: MONDAL, ANUPAM - National Institutes Of Health (NIH); BROCK, DANIEL - National Institutes Of Health (NIH); ROWAN, SHELDON - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; YANG, ZHI-HONG - National Institutes Of Health (NIH); ROJULPOTE, KRISHNA - National Institutes Of Health (NIH); SMITH, KELSEY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; FRANCISCO, SARAH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; BEJARANO-FERNANDEZ, ELOY - University Of Cardenal Herrera-Ceu; ENGLISH, MILTON - National Institutes Of Health (NIH); DEIK, AMY - Broad Institute Of Mit/harvard; JEANFAVRE, SARAH - Broad Institute Of Mit/harvard; CLISH, CLARY - Broad Institute Of Mit/harvard; REMALEY, ALAN - National Institutes Of Health (NIH); TAYLOR, ALLEN - Tufts University; SWAROOP, ANAND - National Institutes Of Health (NIH)

Submitted to: iScience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/16/2024
Publication Date: 2/16/2024
Citation: Mondal, A.K., Brock, D.C., Rowan, S., Yang, Z., Rojulpote, K.V., Smith, K.M., Francisco, S.G., Bejarano-Fernandez, E., English, M., Deik, A., Jeanfavre, S., Clish, C.B., Remaley, A.T., Taylor, A., Swaroop, A. 2024. Selective transcriptomic dysregulation of metabolic pathways in liver and retina by short and long-term dietary hyperglycemia. iScience. https://doi.org/10.1016/j.isci.2024.108979.
DOI: https://doi.org/10.1016/j.isci.2024.108979

Interpretive Summary: Dietary glycemic exposure impacts blood-glucose levels, which when unchecked leads to insulin resistance and irregular metabolic control across multiple organ systems, resulting in increased risk for type 2 diabetes, cardiovascular disease, and obesity. We hypothesized that tissues adapt differently to dietary glycemic exposure and that the response is dependent upon age and duration of diet consumption. In this animal study, we evaluated tissue-specific responses to a high glycemic index diet after short-term feeding or after long-term feeding using measures of gene expression and lipids. We found that short-term glycemic exposure increased genes involved in inflammation and lipid production and with subsequent aging we found signatures of liver and retina disease.

Technical Abstract: A High Glycemic Index (HGI) diet induces hyperglycemia, an etiologic risk factor in major diseases affecting multiple organ systems. In this study, we evaluated tissue-specific adaptation to HGI diet after one- or 12-months in the liver and retina of C57BL/6J wild-type mice. In the liver, genes associated with inflammation and fatty acid metabolism were altered within one-month of HGI diet, whereas 12-month HGI diet-fed group showed dysregulated expression of cytochrome P450 genes and overexpression of key lipogenic factors including Srebf1 and Elovl5. In contrast, retinal transcriptomes exhibited fewer HGI-related changes after one-month, and notable alterations in energy metabolism genes were apparent after 12-months. Fatty acid profiles of liver samples revealed elevated levels of monounsaturated fatty acids and reduced saturated and polyunsaturated fatty acids in the HGI group. Additionally, HGI resulted in an increase in blood low-density lipoprotein, and diet-aging interactions were found to affect liver expression of mitochondrial oxidative phosphorylation genes, and disease-associated genes in the retina. Our findings provide new insights into retinal and hepatic adaptive mechanisms to dietary hyperglycemia.