Hormonal
Inhibition of Acetyl-CoA Carboxylase 2 (ACC2) reduces malonyl-CoA levels, thereby removing inhibition on CPT1, which increases fatty acid oxidation, reduces intracellular lipid accumulation, and improves insulin sensitivity in muscle and liver.
Targeting the ACC2 enzyme to lower malonyl-CoA levels appears to be a highly effective strategy for improving insulin sensitivity and reducing liver fat. By preventing the inhibition of fat transport into mitochondria (via CPT1), the body can burn fat more efficiently, which in turn lowers the toxic lipid byproducts that cause insulin resistance. This suggests that therapies aimed at ACC2 inhibition could treat obesity and type 2 diabetes by restoring the body's ability to burn fat.
Because ACC1 is the predominant isoform in liver and adipose tissue, the malonyl-CoA levels in both tissues of the WT mutant mice and the Acc2 mutant mice were similar. In heart and soleus muscle, where ACC2 is highly expressed, the levels of malonyl-CoA in Acc2 mutant mice were 10- and 30-fold lower, respectively, than in the WT mice tissues. Fatty acid oxidation rates in the Acc2 mutant mice were significantly higher than in the WT mice, suggesting that only ACC2-produced malonyl-CoA is involved in the regulation of fatty acid oxidation.
Why this rating
Evidence is derived from multiple knockout mouse studies and antisense oligonucleotide trials showing consistent reversal of insulin resistance and steatosis.
Source
Fatty acid metabolism: target for metabolic syndrome
Salih J. Wakil et al. · Journal of Lipid Research · 2008
DOI 10.1194/jlr.r800079-jlr200
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