Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption.
OBJECTIVE
It has been proposed that skeletal muscle insulin resistance arises from the accumulation of intramyocellular lipid metabolites that impede insulin signaling, including diacylglycerol and ceramide. We determined the role of de novo ceramide synthesis in mediating muscle insulin resistance.


METHODS
Mice were subjected to 12 weeks of diet-induced obesity (DIO), and then treated for 4 weeks with myriocin, an inhibitor of serine palmitoyl transferase-1 (SPT1), the rate-limiting enzyme of de novo ceramide synthesis.


RESULTS
After 12 weeks of DIO, C57BL/6 mice demonstrated a doubling in gastrocnemius ceramide content, which was completely reversed (141.5 ± 15.8 vs. 94.6 ± 10.2 nmol/g dry wt) via treatment with myriocin, whereas hepatic ceramide content was unaffected by DIO. Interestingly, myriocin treatment did not alter the DIO-associated increase in gastrocnemius diacyglycerol content, and the only correlation observed between lipid metabolite accumulation and glucose intolerance occurred with ceramide (R = 0.61). DIO mice treated with myriocin showed a complete reversal of glucose intolerance and insulin resistance which was associated with enhanced insulin-stimulated Akt and glycogen synthase kinase 3β phosphorylation. Furthermore, myriocin treatment also decreased intramyocellular ceramide content and prevented insulin resistance development in db/db mice. Finally, myriocin-treated DIO mice displayed enhanced oxygen consumption rates (3,041 ± 124 vs. 2,407 ± 124 ml/kg/h) versus their control counterparts.


CONCLUSIONS
Our results demonstrate that the intramyocellular accumulation of ceramide correlates strongly with the development of insulin resistance, and suggests that inhibition of SPT1 is a potentially promising target for the treatment of insulin resistance.
Department of Pediatrics, University of Alberta, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Edmonton, Canada. gary.lopaschuk@ualberta.ca
John R
JR
Ussher
Timothy R
TR
Koves
Virgilio J J
VJ
Cadete
Liyan
L
Zhang
Jagdip S
JS
Jaswal
Suzanne J
SJ
Swyrd
David G
DG
Lopaschuk
Spencer D
SD
Proctor
Wendy
W
Keung
Deborah M
DM
Muoio
Gary D
GD
Lopaschuk
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017079:Exercise Tolerance / Q000187:drug effects / Q000502:physiology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors; D013851:Thinness / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D002518:Ceramides; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D007328:Insulin; D014280:Triglycerides; D051102:Serine C-Palmitoyltransferase; C001996:thermozymocidin