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

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2015 Feb 10

PMID 25662011

Citations 359

Authors

Rachel J Perry

Joao-Paulo G Camporez

Romy Kursawe

Paul M Titchenell

Dongyan Zhang

Curtis J Perry

Michael J Jurczak

Abulizi Abudukadier

Myoung Sook Han

Xian-Man Zhang

Hai-Bin Ruan

Xiaoyong Yang

Sonia Caprio

Susan M Kaech

Hei Sook Sul

Morris J Birnbaum

Roger J Davis

Gary W Cline

Kitt Falk Petersen

Gerald I Shulman

Affiliations

Soon will be listed here.

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.

Citing Articles

Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting.

Kumar G, Wang R, Sharma A, David N, Amorim T, Sinden D Nat Commun. 2025; 16(1):1330.

PMID: 39900947 PMC: 11790841. DOI: 10.1038/s41467-025-56613-3.

Role of transforming growth factor-β1 in regulating adipocyte progenitors.

Phuong N, Bilal M, Nawaz A, Anh L, Memoona , Aslam M Sci Rep. 2025; 15(1):941.

PMID: 39824986 PMC: 11748614. DOI: 10.1038/s41598-024-81917-7.

Relationship of Interleukin 6 with Hepatic Steatosis and Liver Fibrosis in Rheumatoid Arthritis at a Rheumatology Care Center in Cartagena, Colombia.

Perez-Mingan G, Sierra-Merlano R, Yepes I, Vergara M, Ortiz M, Pena B Genes (Basel). 2025; 15(12.

PMID: 39766906 PMC: 11675702. DOI: 10.3390/genes15121639.

Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations.

Hemalatha A, Li Z, Gonzalez D, Matte-Martone C, Tai K, Lathrop E Nat Cell Biol. 2025; 27(2):218-231.

PMID: 39762578 PMC: 11821535. DOI: 10.1038/s41556-024-01574-w.

Select Endocrine Disorders and Exosomes in Early PDAC Diagnosis.

Wlodarczyk B, Durko L, Walczak K, Talar-Wojnarowska R, Malecka-Wojciesko E Int J Mol Sci. 2024; 25(22).

PMID: 39596226 PMC: 11594802. DOI: 10.3390/ijms252212159.

References

Kursawe R, Eszlinger M, Narayan D, Liu T, Bazuine M, Cali A . Cellularity and adipogenic profile of the abdominal subcutaneous adipose tissue from obese adolescents: association with insulin resistance and hepatic steatosis. Diabetes. 2010; 59(9):2288-96. PMC: 2927952. DOI: 10.2337/db10-0113. View

Fernandez-Real J, Vayreda M, Richart C, Gutierrez C, Broch M, Vendrell J . Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab. 2001; 86(3):1154-9. DOI: 10.1210/jcem.86.3.7305. View

Glund S, Deshmukh A, Long Y, Moller T, Koistinen H, Caidahl K . Interleukin-6 directly increases glucose metabolism in resting human skeletal muscle. Diabetes. 2007; 56(6):1630-7. DOI: 10.2337/db06-1733. View

Kahn S, Cooper M, Del Prato S . Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2013; 383(9922):1068-83. PMC: 4226760. DOI: 10.1016/S0140-6736(13)62154-6. View

Lutticken C, Wegenka U, Yuan J, Buschmann J, Schindler C, Ziemiecki A . Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science. 1994; 263(5143):89-92. DOI: 10.1126/science.8272872. View

Boyle J, Thompson T, Gregg E, Barker L, Williamson D . Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010; 8:29. PMC: 2984379. DOI: 10.1186/1478-7954-8-29. View

Lewis G, Zinman B, Groenewoud Y, Vranic M, Giacca A . Hepatic glucose production is regulated both by direct hepatic and extrahepatic effects of insulin in humans. Diabetes. 1996; 45(4):454-62. DOI: 10.2337/diab.45.4.454. View

Yuen D, Dwyer R, Matthews V, Zhang L, Drew B, Neill B . Interleukin-6 attenuates insulin-mediated increases in endothelial cell signaling but augments skeletal muscle insulin action via differential effects on tumor necrosis factor-alpha expression. Diabetes. 2009; 58(5):1086-95. PMC: 2671037. DOI: 10.2337/db08-0775. View

Straub R, Hense H, Andus T, Scholmerich J, Riegger G, Schunkert H . Hormone replacement therapy and interrelation between serum interleukin-6 and body mass index in postmenopausal women: a population-based study. J Clin Endocrinol Metab. 2000; 85(3):1340-4. DOI: 10.1210/jcem.85.3.6355. View

10.

Pilkis S, GRANNER D . Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annu Rev Physiol. 1992; 54:885-909. DOI: 10.1146/annurev.ph.54.030192.004321. View

11.

Chisholm A, Allan E, Titheradge M . Regulation of mitochondrial pyruvate carboxylation in isolated hepatocytes by acute insulin treatment. Biochem J. 1983; 214(2):451-8. PMC: 1152266. DOI: 10.1042/bj2140451. View

12.

Schwartz M, Seeley R, Tschop M, Woods S, Morton G, Myers M . Cooperation between brain and islet in glucose homeostasis and diabetes. Nature. 2013; 503(7474):59-66. PMC: 3983910. DOI: 10.1038/nature12709. View

13.

Jordan S, Konner A, Bruning J . Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis. Cell Mol Life Sci. 2010; 67(19):3255-73. PMC: 2933848. DOI: 10.1007/s00018-010-0414-7. View

14.

Mohamed-Ali V, Goodrick S, Rawesh A, Katz D, Miles J, Yudkin J . Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997; 82(12):4196-200. DOI: 10.1210/jcem.82.12.4450. View

15.

Hepp K . Studies on the mechanism of insulin action: basic concepts and clinical implications. Diabetologia. 1977; 13(3):177-86. DOI: 10.1007/BF01219697. View

16.

Yamaguchi T, Omatsu N, Matsushita S, Osumi T . CGI-58 interacts with perilipin and is localized to lipid droplets. Possible involvement of CGI-58 mislocalization in Chanarin-Dorfman syndrome. J Biol Chem. 2004; 279(29):30490-7. DOI: 10.1074/jbc.M403920200. View

17.

Perry R, Kim T, Zhang X, Lee H, Pesta D, Popov V . Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler. Cell Metab. 2013; 18(5):740-8. PMC: 4104686. DOI: 10.1016/j.cmet.2013.10.004. View

18.

Stahl N, Boulton T, Farruggella T, Ip N, Davis S, Witthuhn B . Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science. 1994; 263(5143):92-5. DOI: 10.1126/science.8272873. View

19.

Olefsky J, Glass C . Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010; 72:219-46. DOI: 10.1146/annurev-physiol-021909-135846. View

20.

Vatner D, Weismann D, Beddow S, Kumashiro N, Erion D, Liao X . Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. Am J Physiol Endocrinol Metab. 2013; 305(1):E89-100. PMC: 3725564. DOI: 10.1152/ajpendo.00573.2012. View