RT Journal Article SR Electronic T1 A Novel Acetyl-CoA Carboxylase 2 Selective Inhibitor Improves Whole-Body Insulin Resistance and Hyperglycemia in Diabetic Mice through Target-Dependent Pathways JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 256 OP 263 DO 10.1124/jpet.119.263590 VO 372 IS 3 A1 Hiroyuki Takagi A1 Keiichi Tanimoto A1 Atsuyuki Shimazaki A1 Yutaka Tonomura A1 Sotaro Momosaki A1 Shingo Sakamoto A1 Kohji Abe A1 Mitsuru Notoya A1 Hideo Yukioka YR 2020 UL http://jpet.aspetjournals.org/content/372/3/256.abstract AB Excess intramyocellular lipid (IMCL) deposition in skeletal muscle is closely associated with insulin resistance. Pharmacological inhibition of acetyl-CoA carboxylase (ACC) 2 offers a promising approach to treat insulin resistance through stimulation of mitochondrial fatty acid oxidation (FAO) and reduction of IMCL deposition. Previously reported experimental ACC2 inhibitors exhibited plasma glucose–lowering effects in diabetic rodents. However, their antidiabetic action may be potentially biased by off-target effects on triglyceride metabolism or by neurologic side effects. In this study, we investigated a safety profile, target dependency of its action, and antidiabetic efficacy of compound 2e, a novel olefin derivative potent ACC2 selective inhibitor. Four-day administration of suprapharmacological dose of compound 2e did not exhibit any obvious side effects in Sprague-Dawley rats. In db/db mice, single administration of compound 2e led to significantly elevated FAO and reduced IMCL deposition in skeletal muscle. In ACC2 knockout mice, treatment with pharmacological doses of compound 2e did not reduce plasma triglyceride levels, whereas A-908292, a previously reported ACC2 inhibitor, caused a significant triglyceride reduction, showing that compound 2e was devoid of off-target triglyceride-lowering activity. Chronic treatment of db/db mice with compound 2e improved hyperglycemia but did not decrease plasma triglyceride levels. Additionally, compound 2e showed significant improvements of whole-body insulin resistance in the clamp study and insulin tolerance test. Collectively, compound 2e demonstrated a good safety profile and significant antidiabetic effects through inhibition of ACC2-dependent pathways. These findings provide further evidence that selective inhibition of ACC2 is an attractive strategy against insulin resistance and type 2 diabetes.SIGNIFICANCE STATEMENT This study shows that pharmacological inhibition of acetyl-CoA carboxylase (ACC) 2 leads to significant improvements in whole-body glucose homeostasis, independently of off-target metabolic pathways and toxicity, which were observed in previously reported ACC2 inhibitors. These findings support the concept that ACC2-selective inhibitors will be a novel remedy for treatment of type 2 diabetes.