ACC2 Deletion Enhances IMCL Reduction Along With Acetyl-CoA Metabolism and Improves Insulin Sensitivity in Male Mice

Abstract

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.

Interleukin 1 Receptor 1 Knockout and Maternal High Fat Diet Exposure Induces Sex-Specific Effects on Adipose Tissue Adipogenic and Inflammatory Gene Expression in Adult Mouse Offspring

“…There is also a decrease in Acacb, which encodes the protein ACC2, a rate limiting step in fatty acid uptake and oxidation in the mitochondria, in female IL1R1 −/− groups irrespective of maternal diet. Depletion of this protein improves overall metabolic health in mice fed a HFD (Takagi et al, 2018). Furthermore, there was a decrease in expression of Acsl1, which encodes a protein which mediates the conversion of long-chain fatty acids to fatty acyl-CoA esters producing important substrates for mitochondrial fatty acid biosynthesis, in IL1R1 −/− groups irrespective of genotype.…”

Full transcriptome analysis of gene expression in liver of mice in a comparative study of quercetin efficiency on two obesity models

“…Повышенная экспрессия гена Acacb (ацетил-коэнзим А карбоксилаза бета), рассматриваемого в качестве регулируемого AMPK (cAMP-activated protein kinase) промотера липогенеза и фактора, препятствующего митохондриальному β-окислению жирных кислот [25,26], отмечалась у db/db-мышей, получавших Q, в то время как ответ этого гена у мышей C57Bl/6J был противоположным. Малонил-КоА, генерируемый ацетил-КоА-карбоксилазами, является ключевым метаболитом в синтезе жирных кислот.…”

A Novel Acetyl-CoA Carboxylase 2 Selective Inhibitor Improves Whole-Body Insulin Resistance and Hyperglycemia in Diabetic Mice through Target-Dependent Pathways

“…BKS.Cg-1Lepr db /1Lepr db /Jcl (db/db) mice and their nondiabetic controls (db/m) were obtained from CLEA Japan (Tokyo, Japan). ACC2 knockout mice and wild-type mice were generated as previously described (Takagi et al, 2018). All studies were performed using male animals.…”

“…2000; Brownsey et al, 2006;Wakil and Abu-Elheiga, 2009). Though whole-body deletion of ACC1 in mice is embryonic lethal (Abu-Elheiga et al, 2005), deletion of ACC2 in mice has been reported to decrease lipid accumulation by enhancing FAO in skeletal muscle and improve whole-body insulin resistance (Choi et al, 2007;Takagi et al, 2018). Pharmacological selective inhibition of ACC2 is thus currently regarded as a hopeful avenue for the therapy of insulin resistance.…”

“…These results indicate that A-908292 could interfere with ACC2-independent metabolic pathways that have an impact on glucose homeostasis. In particular, its remarkable effect on triglyceride levels may be possibly attributed to the structure-based off-target action, considering the fact that genetic knockout of ACC2 did not show reduced triglyceride levels in high-fat diet-induced diabetic models (Choi et al, 2007;Takagi et al, 2018).…”