1. Hepatic ceramide may mediate brain insulin resistance and neurodegeneration in type 2 diabetes and non-alcoholic steatohepatitis.
- Author
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Lyn-Cook LE Jr, Lawton M, Tong M, Silbermann E, Longato L, Jiao P, Mark P, Wands JR, Xu H, and de la Monte SM
- Subjects
- Analysis of Variance, Animals, Body Weight drug effects, Brain drug effects, Diabetes Mellitus, Type 2 chemically induced, Dietary Fats adverse effects, Disease Models, Animal, Gene Expression Regulation drug effects, Gene Expression Regulation physiology, Male, Mice, Mice, Inbred C57BL, Nerve Degeneration metabolism, Serine C-Palmitoyltransferase genetics, Serine C-Palmitoyltransferase metabolism, Sphingomyelin Phosphodiesterase genetics, Sphingomyelin Phosphodiesterase metabolism, Time Factors, Brain metabolism, Ceramides metabolism, Diabetes Mellitus, Type 2 pathology, Fatty Liver metabolism, Insulin Resistance physiology, Nerve Degeneration etiology
- Abstract
Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) can be complicated by cognitive impairment and neurodegeneration. Experimentally, high fat diet (HFD)-induced obesity with T2DM causes mild neurodegeneration with brain insulin resistance. Since ceramides are neurotoxic, cause insulin resistance, and are increased in T2DM, we investigated the potential role of ceramides as mediators of neurodegeneration in the HFD obesity/T2DM model. We pair-fed C57BL/6 mice with a HFD or control diet for 4-20 weeks and examined pro-ceramide gene expression in liver and brain and neurodegeneration in the temporal lobe. HFD feeding gradually increased body weight, but after 16 weeks, liver weight surged (P<0.001) due to lipid (triglyceride) accumulation (P<0.001), and brain weight declined (P<0.0001-Trend analysis). HFD feeding increased ceramide synthase, serine palmitoyl transferase, and sphingomyelinase expression in liver (P<0.05-P<0.001), but not brain. In HFD fed mice, temporal lobe levels of ubiquitin (P<0.001) and 4-hydroxynonenal (P<0.05 or P<0.01) increased, and tau, beta-actin, and choline acetyltransferase levels decreased (P<0.05-P<0.001) with development of NASH. In obesity, T2DM, or NASH, neurodegeneration with brain insulin resistance may be mediated by excess hepatic production of neurotoxic ceramides that readily cross the blood-brain barrier.
- Published
- 2009
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