Integrated lipidomic and transcriptomic analyses identify altered nerve triglycerides in mouse models of prediabetes and type 2 diabetes
Year: 2019
Type: article
Abstract: Peripheral neuropathy (PN) is a complication of prediabetes and type 2 diabetes (T2D). Increasing evidence suggests that factors besides hyperglycaemia contribute to PN development, including dyslipidaemia. The objective of this study was to determine differential lipid classes and altered gene expression profiles in prediabetes and T2D mouse models in order to identify the dysregulated pathways in PN. Here, we used high-fat diet (HFD)-induced prediabetes and HFD/streptozotocin (STZ)-induced T2D mouse models that develop PN. These models were compared to HFD and HFD-STZ mice that were subjected to dietary reversal. Both untargeted and targeted lipidomic profiling, and gene expression profiling were performed on sciatic nerves. Lipidomic and transcriptomic profiles were then integrated using complex correlation analyses, and biological meaning was inferred from known lipid-gene interactions in the literature. We found an increase in triglycerides (TGs) containing saturated fatty acids. In parallel, transcriptomic analysis confirmed the dysregulation of lipid pathways. Integration of lipidomic and transcriptomic analyses identified an increase in diacylglycerol acyltransferase 2 (DGAT2), the enzyme required for the last and committed step in TG synthesis. Increased DGAT2 expression was present not only in the murine models but also in sural nerve biopsies from hyperlipidaemic diabetic patients with PN. Collectively, these findings support the hypothesis that abnormal nerve-lipid signalling is an important factor in peripheral nerve dysfunction in both prediabetes and T2D.This article has an associated First Person interview with the joint first authors of the paper.
Source: Disease Models & Mechanisms
DOI: 10.1242/dmm.042101
Authors: Phillipe D. O'Brien, Kai Guo, Stephanie A. Eid, Amy E. Rumora, Lucy M. Hinder, John M. Hayes, Faye E. Mendelson, Junguk Hur, Eva L. Feldman
Institutions: University of Michigan, University of North Dakota
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,750
Funders: American Diabetes Association, University of North Dakota, A. Alfred Taubman Medical Research Institute, Sinai Medical Staff Foundation, Novo Nordisk Foundation Center for Basic Metabolic Research, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: G117257630, G2019238319, G2308883343, G2644544784, G3032218960, Vanderbilt Mouse Metabolic Phenotyping Center, G346212879, G3759388441, G3795453992, University of Michigan O'Brien Kidney Translational Core Center, G3920820023, Vanderbilt Mouse Metabolic Phenotyping Center, G4193660722, Tissue-Specific Metabolic Reprogramming in Diabetic Complications, G5436572433, G59109511, Identifying Alterations in Mitochondrial Dynamics Associated with Diabetic Neuropathy, G8565868909, G9000030862, G9000104968, G9000336748
OpenAlex ID: W2995466115