AIMS: the molecular processes leading to cardiac insulin resistance induced via a high-fat diet (HFD) remain unclear. We examined the changes in cardiac insulin sensitivity and the potential mechanism(s) involved following HFD in mice. METHODS AND RESULTS: C57BL/6 mice were fed either a low-fat diet (LFD, 4% kcal fat) or a HFD (60% kcal fat) for 3 or 10 weeks. Insulin-stimulated glucose oxidation in isolated working hearts was decreased at 10 weeks of HFD compared with mice on LFD (249 ± 19 to 399 ± 46 vs. 551 ± 97 to 1464 ± 243 nmol/g dry wt/min; P < 0.05). The accumulation of myocardial diacylglycerol (DAG; 479 ± 174 vs. 266 ± 29 micromol/g wet wt; P < 0.05), but not long-chain acyl CoA, ceramide, or triacylglycerol, correlated with the development of insulin resistance. The accumulation of DAG occurred concomitantly with an increase in glycerol phosphate acyltransferase activity, a decrease in DAG acyltransferase activity, as well as an increase in the translocation of protein kinase C-α (PKCα) and phosphorylation of p70s6k. Neither HFD-induced accumulation of cardiac DAG nor up-regulation of phosphorylated p70s6k occurred in mice lacking malonyl CoA decarboxylase which are resistant to the development of HFD-induced insulin resistance. CONCLUSION: the activation of myocardial p70s6k and PKCα is closely associated with cardiac insulin resistance in which the accumulation of intra-myocardial DAG could be responsible.
AIMS: the molecular processes leading to cardiac insulin resistance induced via a high-fat diet (HFD) remain unclear. We examined the changes in cardiac insulin sensitivity and the potential mechanism(s) involved following HFD in mice. METHODS AND RESULTS: C57BL/6 mice were fed either a low-fat diet (LFD, 4% kcal fat) or a HFD (60% kcal fat) for 3 or 10 weeks. Insulin-stimulated glucose oxidation in isolated working hearts was decreased at 10 weeks of HFD compared with mice on LFD (249 ± 19 to 399 ± 46 vs. 551 ± 97 to 1464 ± 243 nmol/g dry wt/min; P < 0.05). The accumulation of myocardial diacylglycerol (DAG; 479 ± 174 vs. 266 ± 29 micromol/g wet wt; P < 0.05), but not long-chain acyl CoA, ceramide, or triacylglycerol, correlated with the development of insulin resistance. The accumulation of DAG occurred concomitantly with an increase in glycerol phosphate acyltransferase activity, a decrease in DAG acyltransferase activity, as well as an increase in the translocation of protein kinase C-α (PKCα) and phosphorylation of p70s6k. Neither HFD-induced accumulation of cardiac DAG nor up-regulation of phosphorylated p70s6k occurred in mice lacking malonyl CoA decarboxylase which are resistant to the development of HFD-induced insulin resistance. CONCLUSION: the activation of myocardial p70s6k and PKCα is closely associated with cardiac insulin resistance in which the accumulation of intra-myocardialDAG could be responsible.
Authors: E Liepinsh; M Makrecka-Kuka; J Kuka; R Vilskersts; E Makarova; H Cirule; E Loza; D Lola; S Grinberga; O Pugovics; I Kalvins; M Dambrova Journal: Br J Pharmacol Date: 2015-01-12 Impact factor: 8.739
Authors: Miranda M Y Sung; Debby P Y Koonen; Carrie-Lynn M Soltys; René L Jacobs; Maria Febbraio; Jason R B Dyck Journal: J Mol Med (Berl) Date: 2011-03-10 Impact factor: 4.599
Authors: Vincent G Demarco; David A Ford; Erik J Henriksen; Annayya R Aroor; Megan S Johnson; Javad Habibi; Lixin Ma; Ming Yang; Carolyn J Albert; John W Lally; Caleb A Ford; Mujalin Prasannarong; Melvin R Hayden; Adam T Whaley-Connell; James R Sowers Journal: Endocrinology Date: 2012-11-09 Impact factor: 4.736
Authors: Osama Abo Alrob; Sowndramalingam Sankaralingam; Cary Ma; Cory S Wagg; Natasha Fillmore; Jagdip S Jaswal; Michael N Sack; Richard Lehner; Mahesh P Gupta; Evangelos D Michelakis; Raj S Padwal; David E Johnstone; Arya M Sharma; Gary D Lopaschuk Journal: Cardiovasc Res Date: 2014-06-25 Impact factor: 10.787