ACC2 Deletion Enhances IMCL Reduction Along With Acetyl-CoA Metabolism and Improves Insulin Sensitivity in Male Mice
| Autor: | Kumi Hashimoto, Atsuyuki Shimazaki, Isamu Nanchi, Hirohide Nambu, Hideo Yukioka, Hiroyuki Takagi, Yuto Kashiwagi, Tatsuya Ikehara |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Blood Glucose
Male 0301 basic medicine medicine.medical_specialty Muscle Fibers Skeletal Carbohydrate metabolism Diet High-Fat Mice 03 medical and health sciences Endocrinology Insulin resistance Acetyl Coenzyme A Internal medicine medicine Animals Glycolysis Muscle Skeletal Acetylcarnitine Mice Knockout chemistry.chemical_classification Fatty Acids Fatty acid Skeletal muscle Metabolism Lipid Metabolism medicine.disease Citric acid cycle Glucose 030104 developmental biology medicine.anatomical_structure chemistry Insulin Resistance Oxidation-Reduction Acetyl-CoA Carboxylase medicine.drug |
| Zdroj: | Endocrinology. 159:3007-3019 |
| ISSN: | 1945-7170 |
| DOI: | 10.1210/en.2018-00338 |
| Popis: | Intramyocellular lipid (IMCL) accumulation in skeletal muscle greatly contributes to lipid-induced insulin resistance. Because acetyl-coenzyme A (CoA) carboxylase (ACC) 2 negatively modulates mitochondrial fatty acid oxidation (FAO) in skeletal muscle, ACC2 inhibition is expected to reduce IMCL via elevation of FAO and to attenuate insulin resistance. However, the concept of substrate competition suggests that enhanced FAO results in reduced glucose use because of an excessive acetyl-CoA pool in mitochondria. To identify how ACC2-regulated FAO affects IMCL accumulation and glucose metabolism, we generated ACC2 knockout (ACC2-/-) mice and investigated skeletal muscle metabolites associated with fatty acid and glucose metabolism, as well as whole-body glucose metabolism. ACC2-/- mice displayed higher capacity of glucose disposal at the whole-body levels. In skeletal muscle, ACC2-/- mice exhibited enhanced acylcarnitine formation and reduced IMCL levels without alteration in glycolytic intermediate levels. Notably, these changes were accompanied by decreased acetyl-CoA content and enhanced mitochondrial pathways related to acetyl-CoA metabolism, such as the acetylcarnitine production and tricarboxylic acid cycle. Furthermore, ACC2-/- mice exhibited lower levels of IMCL and acetyl-CoA even under HFD conditions and showed protection against HFD-induced insulin resistance. Our findings suggest that ACC2 deletion leads to IMCL reduction without suppressing glucose use via an elevation in acetyl-CoA metabolism even under HFD conditions and offer new mechanistic insight into the therapeutic potential of ACC2 inhibition on insulin resistance. |
| Databáze: | OpenAIRE |
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