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A futile metabolic cycle activated in adipocytes by antidiabetic agents

Nature Medicine volume 8, pages 1122–1128 (2002)Cite this article

Abstract

Thiazolidinediones (TZDs) are effective therapies for type 2 diabetes, which has reached epidemic proportions in industrialized societies. TZD treatment reduces circulating free fatty acids (FFAs), which oppose insulin actions in skeletal muscle and other insulin target tissues. Here we report that TZDs, acting as ligands for the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ, markedly induce adipocyte glycerol kinase (GyK) gene expression. This is surprising, as standard textbooks indicate that adipocytes lack GyK and thereby avoid futile cycles of triglyceride breakdown and resynthesis from glycerol and FFAs. By inducing GyK, TZDs markedly stimulate glycerol incorporation into triglyceride and reduce FFA secretion from adipocytes. The 'futile' fuel cycle resulting from expression of GyK in adipocytes is thus a novel mechanism contributing to reduced FFA levels and perhaps insulin sensitization by antidiabetic therapies.

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Figure 1: TZDs increase GyK expression in adipocytes.
Figure 2: Ciglitazone induces GyK expression in ob/ob mice, lean mice, rats and human primary adipocytes.
Figure 3: Rosiglitazone robustly increases glycerol incorporation into TG in adipocytes.
Figure 4: Rosiglitazone treatment markedly diminishes fatty-acid release from adipocytes, as does GyK overexpression.
Figure 5: Model for the effects of TZD treatment on physiology of lipid storage and mobilization in adipocytes.

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Acknowledgements

We thank H. Camp and D. Owens for the gift of PD068235; T. Willson for GW7845; W. Yin for help with the GyK assay; Y. Qi and R. Ahima for assistance with animal experiments; and M. Birnbaum for helpful discussions and critical reading of the manuscript. This work was supported by NIH grant DK49780 (to M.A.L.).

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Authors and Affiliations

  1. Division of Endocrinology, Departments of Medicine, Diabetes, and Metabolism, Genetics, and Pharmacology, and The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Hong-Ping Guan, Yong Li, Claire M. Steppan & Mitchell A. Lazar

  2. Departments of Pharmacology and Cancer Biology, Sarah Stedman Center for Nutritional Studies and Duke Program in Diabetes Research, Duke University Medical Center, Durham, North Carolina, USA

    Mette Valentin Jensen & Christopher B. Newgard

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  1. Hong-Ping Guan
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Correspondence to Mitchell A. Lazar.

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M.A.L received unrestricted research support from GlaxoSmithKline.

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Guan, HP., Li, Y., Jensen, M. et al. A futile metabolic cycle activated in adipocytes by antidiabetic agents. Nat Med 8, 1122–1128 (2002). https://doi.org/10.1038/nm780

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