Role of sphingolipid mediator ceramide in obesity and renal injury in mice fed a high-fat diet.
The present study tested a hypothesis that excess accumulation of sphingolipid, ceramide, its metabolites, or a combination contributes to the development of obesity and associated kidney damage. Liquid chromatography/mass spectrometry analysis demonstrated that C57BL/6J mice on the high-fat diet (HFD) had significantly increased plasma total ceramide levels compared with animals fed a low-fat diet (LFD). Treatment of mice with the acid sphingomyelinase (ASMase) inhibitor amitriptyline significantly attenuated the HFD-induced plasma ceramide levels. Corresponding to increase in plasma ceramide, the HFD significantly increased the body weight gain, plasma leptin concentration, urinary total protein and albumin excretion, glomerular damage index, and adipose tissue ASMase activity compared with the LFD-fed mice. These HFD-induced changes were also significantly attenuated by treatment of mice with amitriptyline. In addition, the decline of plasma glucose concentration after an intraperitoneal injection of insulin (0.15 U/kg b.wt.) was more sustained in mice on the HFD with amitriptyline than on the HFD alone. Intraperitoneal injection of glucose (3 g/kg b.wt.) resulted in a slow increase followed by a rapid decrease in the plasma glucose concentration in LFD and HFD plus amitriptyline-treated mice, but such blood glucose response was not observed in HFD-fed mice. Immunofluorescence analysis demonstrated a decrease in the podocin and an increase in the desmin in the glomeruli of HFD-fed mice compared with the LFD and HFD plus amitriptyline-treated mice. In conclusion, our results reveal a pivotal role for ceramide biosynthesis in obesity, metabolic syndrome, and associated kidney damage.
Boini
Krishna M
KM
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, 410 N, 12th St., Richmond, VA 23298, USA.
Zhang
Chun
C
Xia
Min
M
Poklis
Justin L
JL
Li
Pin-Lan
PL
D000273:Adipose Tissue / Q000473:pathology; D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism / Q000502:physiology*; D004032:Diet; D004041:Dietary Fats / Q000009:adverse effects*; D005455:Fluorescent Antibody Technique; D005951:Glucose Tolerance Test; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D020738:Leptin / Q000097:blood; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000503:physiopathology*; D009929:Organ Size / Q000187:drug effects; D011507:Proteinuria / Q000139:chemically induced; D020133:Reverse Transcriptase Polymerase Chain Reaction; D021241:Spectrometry, Mass, Electrospray Ionization; D013107:Sphingolipids / Q000502:physiology*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*
D000929:Antidepressive Agents, Tricyclic; D002518:Ceramides; D004041:Dietary Fats; D020738:Leptin; D013107:Sphingolipids; D000639:Amitriptyline; D013108:Sphingomyelin Phosphodiesterase