Hepatic ceramide may mediate brain insulin resistance and neurodegeneration in type 2 diabetes and non-alcoholic steatohepatitis.
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.
Lyn-Cook
Lascelles E
LE
Department of Medicine, Division of Gastroenterology, and the Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Lawton
Margot
M
Tong
Ming
M
Silbermann
Elizabeth
E
Longato
Lisa
L
Jiao
Ping
P
Mark
Princess
P
Wands
Jack R
JR
Xu
Haiyan
H
de la Monte
Suzanne M
SM
D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000473:pathology*; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism; D051102:Serine C-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D002518:Ceramides; D004041:Dietary Fats; D051102:Serine C-Palmitoyltransferase; D013108:Sphingomyelin Phosphodiesterase