Liver triglyceride accumulation associated with insulin resistance is partially mediated by elevated de novo lipogenesis (DNL); thus, limiting this pathway is a promising therapeutic strategy for NAFLD. Targeted suppression of acetyl-CoA carboxylase (ACC) activity depletes malonyl-CoA resulting in lower DNL and a simultaneous increase in fat oxidation due to activation of CPT-1. Recently developed ACC1/2 liver specific double KO mice (LDKO) are protected from hepatic steatosis and closely recapitulate pharmacological inhibition of ACC1/2 in humans with NAFLD. However, hepatic ACC inhibition causes surprising elevations in circulating triglyceride and glucose concentrations. LDKO mice had worsened glucose tolerance, which was most consequential during a HFD and especially prominent during fasting. Glucose labeling from 2H2O and [U-13C3] lactate was higher in LDKO hepatocytes, an effect that was dependent on the availability of long chain fatty acids, suggesting that loss of malonyl-CoA and activation of CPT-1 promote gluconeogenesis (GNG). Ketogenesis was increased in LDKO hepatocytes and showed limited response to insulin. Acetyl-CoA was elevated in the fed state, as previously reported, but was normal during fasting when hyperglycemia was most prominent. LDKO mice exhibited massive accumulation of liver citrate and a high fasted hepatic energy charge, which are both known to activate GNG. Hence, despite improved hepatic lipid profile and insulin sensitivity, LDKO liver activates GNG. The resulting hyperinsulinemia partially ameliorates the glycemia phenotype, but may also induce hepatomegaly through canonical signaling pathways and effects on energy status. Thus, activation of fat oxidation in liver lowers lipid accumulation, but has downstream metabolic effects on energetically dependent pathways, such as GNG, that may promote elevated glucose levels in contexts of reduced insulin action, such as fasting and diet induced obesity.


S. Deja: None. J.A. Fletcher: None. B. Kucejova: None. X. Fu: None. C. Kim: None. J. Browning: None. J.D. Horton: Board Member; Self; Pfizer Inc. Consultant; Self; Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Stock/Shareholder; Self; Catabasis Pharmaceuticals. Other Relationship; Self; Regeneron Pharmaceuticals, Sanofi. S.C. Burgess: None.


National Institutes of Health (R01DK078184, P41EB015908); Robert A. Welch Foundation (I-1804)

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