Disclosure: No potential conflicts of interest relevant to this article were reported. A subset of this data was presented at the Keystone Symposia on Type 2 Diabetes, Insulin Resistance and Metabolic Dysfunction (J1), Keystone Resort, Keystone, Colorado, 2011 (Poster # 134).
Reduced skeletal muscle oxidative capacity and elevated ceramide but not diacylglycerol content in severe obesity
Article first published online: 31 MAY 2013
Copyright © 2013 The Obesity Society
Volume 21, Issue 11, pages 2362–2371, November 2013
How to Cite
Coen, P.M., Hames, K.C., Leachman, E.M., DeLany, J.P., Ritov, V.B., Menshikova, E.V., Dubé, J.J., Stefanovic-Racic, M., Toledo, F.G.S. and Goodpaster, B.H. (2013), Reduced skeletal muscle oxidative capacity and elevated ceramide but not diacylglycerol content in severe obesity. Obesity, 21: 2362–2371. doi: 10.1002/oby.20381
Funding agencies: This study was supported by the University of Pittsburgh CTRC (M01RR00056), the Obesity and Nutrition Research Center (1P30DK46204), and a grant from the Commonwealth of Pennsylvania Department of Health.
- Issue published online: 1 NOV 2013
- Article first published online: 31 MAY 2013
- Accepted manuscript online: 20 MAR 2013 02:48AM EST
- Manuscript Accepted: 28 DEC 2012
- Manuscript Received: 9 SEP 2012
The link between a reduced capacity for skeletal muscle mitochondrial fatty acid oxidation (FAO) and lipotoxicity in human insulin resistance has been the subject of intense debate. The objective of this study was to investigate whether reduced FAO is associated with elevated acyl CoA, ceramide, and diacylglycerol (DAG) in severely obese insulin resistant subjects.
Muscle biopsies were conducted in lean (L, 22.6 ± 0.5 kg/m2, n = 8), Class I (CI, 32.1 ± 0.4 kg/m2, n = 7) and Class II&III obese (CII&III, 45.6 ± 1.1 kg/m2, n = 15) women for acyl CoA, sphingolipid and DAG profiling. Intramyocellular triglyceride (IMTG) content was determined by histology. FAO was assessed by incubating muscle homogenates with [1-C]palmitate and measuring CO2 production. Cardiolipin content was quantified as an index of mitochondrial content. Lipid metabolism proteins, DGAT1, PLIN5, and PNPLA2 were quantified in biopsy samples by western blot.
CII&III were more insulin resistant (HOMA-IR: 4.5 ± 0.5 vs. 1.1 ± 0.1, P < 0.001), and had lower FAO (∼58%, P = 0.007) and cardiolipin content (∼31%, P = 0.013) compared to L. IMTG was elevated in CI (P = 0.04) and CII&III (P = 0.04) compared to L. Sphingolipid content was higher in CII&III compared to L (13.6 ± 1.1 vs. 10.3 ± 0.5 pmol/mg, P = 0.031) whereas DAG content was not different among groups. DGAT1 was elevated in CII&III, and PLIN5 was elevated in CI compared to L.
Severe obesity is associated with reduced muscle oxidative capacity and occurs concomitantly with elevated IMTG, ceramide and insulin resistance.