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

• Published in: Cell Vol. 160; no. 4; pp. 745 - 758
• Main Authors: Perry, Rachel J., Camporez, João-Paulo G., Kursawe, Romy, Titchenell, Paul M., Zhang, Dongyan, Perry, Curtis J., Jurczak, Michael J., Abudukadier, Abulizi, Han, Myoung Sook, Zhang, Xian-Man, Ruan, Hai-Bin, Yang, Xiaoyong, Caprio, Sonia, Kaech, Susan M., Sul, Hei Sook, Birnbaum, Morris J., Davis, Roger J., Cline, Gary W., Petersen, Kitt Falk, Shulman, Gerald I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2015
• Subjects: acetyl coenzyme A; Acetyl Coenzyme A - metabolism; Adipose Tissue, White - chemistry; Adolescent; Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; glucose; Glucose - metabolism; Humans; Hyperglycemia; inflammation; insulin; Insulin Resistance; interleukin-6; Interleukin-6 - analysis; Lipolysis; Liver - metabolism; Male; metabolomics; Mice; neutralization; noninsulin-dependent diabetes mellitus; obesity; Obesity - metabolism; Panniculitis - metabolism; pathogenesis; pyruvate carboxylase; rats; Rats, Sprague-Dawley; triacylglycerol lipase; white adipose tissue
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2015.01.012

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. [Display omitted] •Insulin inhibits gluconeogenesis by suppressing lipolysis and hepatic acetyl CoA•Hyperglycemia associated with HFD is due to increased WAT-derived hepatic acetyl CoA•ATGL KOs are protected from HFD-induced insulin resistance due to decreased lipolysis•mφJNK KOs are protected from HFD-induced insulin resistance due to decreased lipolysis Metabolic abnormalities associated with a high-fat diet are found to be driven by increased hepatic acetyl CoA levels, which are shown to be a consequence of white adipose tissue inflammation and inappropriately increased lipolysis.