title: Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.
abstract: 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.
authors: Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA; Department of Internal Medicine, Yale University, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA.
authors: Rachel J
authors: RJ
authors: Perry
authors: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA.
authors: João-Paulo G
authors: JG
authors: Camporez
authors: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA.
authors: Romy
authors: R
authors: Kursawe
authors: The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Paul M
authors: PM
authors: Titchenell
authors: Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA.
authors: Dongyan
authors: D
authors: Zhang
authors: Department of Immunobiology, Yale University, New Haven, CT 06520, USA.
authors: Curtis J
authors: CJ
authors: Perry
authors: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA.
authors: Michael J
authors: MJ
authors: Jurczak
authors: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA.
authors: Abulizi
authors: A
authors: Abudukadier
authors: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors: Myoung Sook
authors: MS
authors: Han
authors: Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA.
authors: Xian-Man
authors: XM
authors: Zhang
authors: Department of Comparative Medicine, Yale University, New Haven, CT 06520, USA.
authors: Hai-Bin
authors: HB
authors: Ruan
authors: Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA; Department of Comparative Medicine, Yale University, New Haven, CT 06520, USA.
authors: Xiaoyong
authors: X
authors: Yang
authors: Department of Pediatrics, Yale University, New Haven, CT 06520, USA.
authors: Sonia
authors: S
authors: Caprio
authors: Department of Immunobiology, Yale University, New Haven, CT 06520, USA.
authors: Susan M
authors: SM
authors: Kaech
authors: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors: Hei Sook
authors: HS
authors: Sul
authors: The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Morris J
authors: MJ
authors: Birnbaum
authors: Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors: Roger J
authors: RJ
authors: Davis
authors: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA.
authors: Gary W
authors: GW
authors: Cline
authors: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA.
authors: Kitt Falk
authors: KF
authors: Petersen
authors: Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA; Department of Internal Medicine, Yale University, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA. Electronic address: gerald.shulman@yale.edu.
authors: Gerald I
authors: GI
authors: Shulman
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000737:chemistry; D000293:Adolescent; D000818:Animals; D003924:Diabetes Mellitus, Type 2; D059305:Diet, High-Fat; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000032:analysis; D008066:Lipolysis; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D009765:Obesity / Q000378:metabolism; D015434:Panniculitis / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
chemical_list: D015850:Interleukin-6; D000105:Acetyl Coenzyme A; D005947:Glucose