Hepatic Acetyl CoA Links Adipose Tissue Inflammation to Hepatic Insulin Resistance and Type 2 Diabetes

By R. Perry, J. Camporez, R. Kursawe, Paul M. Titchenell, Dongyan Zhang, Curtis J. Perry, M. Jurczak, Abulizi Abudukadier, M. Han, Xian‐Man Zhang and 10 more. Cell, 2015

660 citations recorded by the source corpus.

SUMMARY Impaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase. Insulin’s ability to suppress hepatic acetyl CoA, PC activity, and lipolysis was lost in high-fat-fed rats, a phenomenon reversible by IL-6 neutralization and inducible by IL-6 infusion. Taken together, these data identify WAT-derived hepatic acetyl CoA as the main regulator of HGP by insulin and link it to inflammation-induced hepatic insulin resistance associated with obesity and T2D.

Subfields: Biochemistry, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/71824ff0ac86faf9905e0c1ceb160cf10d8f0da0

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In Biochemistry

1. Gerald I. Shulman
2. V. Samuel
3. S. Friedman
4. R. Loomba
5. R. Medzhitov
6. M. Kotas

In Epidemiology

1. V. Samuel
2. Gerald I. Shulman
3. S. Friedman
4. R. Loomba
5. Haiming Cao
6. Y. Saiman
7. J. Puche
8. J. Bonner

In Physiology

1. V. Samuel
2. Gerald I. Shulman
3. C. Choi
4. Shin-Hae Lee
5. Shi-Young Park
6. S. Friedman
7. Haiming Cao
8. Ralph DeFronzo

Citations in the corpus

• Cellular and Molecular Mechanisms of Metformin Action (2020, background): “Hepatic gluconeogenesis is also indirectly regulated by glycerol delivery to the liver by WAT lipolysis, which contributes about 20% to 30% of hepatic gluconeogenesis (94, 100, 105).”
• Insulin Resistance: From Mechanisms to Therapeutic Strategies (2021, background): “In addition to inhibiting gluconeogenic gene expressions, insulin suppresses hepatic gluconeogenesis by inhibiting adipocyte lipolysis, which reduces levels of gluconeogenesis substrates in liver [17].”
• The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. (2016, background): “First, lipolysis increases fatty acid delivery to the liver, leading to increased hepatic acetyl-CoA content, which activates PC activity and PC flux (17, 18).”
• Molecular Mechanisms Linking Oxidative Stress and Diabetes Mellitus (2020, background): “Therefore, ameliorating these inflammatory processes may be a therapeutic option for the management of diabetes [105, 115, 116].”
• Mechanisms and disease consequences of nonalcoholic fatty liver disease (2021, background): “showed that insulin suppression of WAT lipolysis, which occurs within a few minutes, results in immediate reductions in hepatic acetyl-coenzyme A (CoA) content, an allosteric activator of pyruvate carboxylase (PC), which, in turn, reduces PC activity and PC flux (Perry et al., 2015).”