Abstract | OBJECTIVE: RESEARCH DESIGN AND 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.
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Authors | John R Ussher, Timothy R Koves, Virgilio J J Cadete, Liyan Zhang, Jagdip S Jaswal, Suzanne J Swyrd, David G Lopaschuk, Spencer D Proctor, Wendy Keung, Deborah M Muoio, Gary D Lopaschuk |
Journal | Diabetes
(Diabetes)
Vol. 59
Issue 10
Pg. 2453-64
(Oct 2010)
ISSN: 1939-327X [Electronic] United States |
PMID | 20522596
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Blood Glucose
- Ceramides
- Dietary Fats
- Enzyme Inhibitors
- Fatty Acids, Monounsaturated
- Insulin
- Triglycerides
- Serine C-Palmitoyltransferase
- thermozymocidin
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Topics |
- Animals
- Blood Glucose
(drug effects, metabolism)
- Body Weight
(drug effects)
- Ceramides
(biosynthesis, metabolism)
- Dietary Fats
(pharmacology)
- Enzyme Inhibitors
(pharmacology)
- Exercise Tolerance
(drug effects, physiology)
- Fatty Acids, Monounsaturated
(pharmacology)
- Glucose Tolerance Test
- Insulin
(blood)
- Insulin Resistance
(physiology)
- Mice
- Mice, Inbred C57BL
- Obesity
(chemically induced, metabolism)
- Organ Size
(drug effects)
- Oxygen Consumption
(drug effects)
- Serine C-Palmitoyltransferase
(antagonists & inhibitors)
- Thinness
(metabolism)
- Triglycerides
(metabolism)
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