Fatty acid binding protein 4 (FABP4) is a leaderless lipid carrier protein primarily expressed by adipocytes and macrophages that not only functions intracellularly but is also secreted. The secretion is mediated via unconventional mechanism(s), and in a variety of species, metabolic dysfunction is correlated with elevated circulating FABP4 levels. In diabetic animals, neutralizing antibodies targeting serum FABP4 increase insulin sensitivity and attenuate hepatic glucose output, suggesting the functional importance of circulating FABP4. Using animal and cell-based models, we show that FABP4 is secreted from white, but not brown, adipose tissue in response to lipolytic stimulation in a sirtuin-1 (SIRT1)-dependent manner via a mechanism that requires some, but not all, autophagic components. Silencing of early autophagic genes such as Ulk1/2, Fip200, or Beclin-1 or chemical inhibition of ULK1/2 or VPS34 attenuated secretion, while Atg5 knockdown potentiated FABP4 release. Genetic knockout of Sirt1 diminished secretion, and serum FABP4 levels were undetectable in Sirt1 knockout mice. In addition, blocking SIRT1 by EX527 attenuated secretion while activating SIRT1 by resveratrol-potentiated secretion. These studies suggest that FABP4 secretion from adipocytes is regulated by SIRT1 and requires early autophagic components.
Bibliographical noteFunding Information:
Acknowledgments. The authors thank the members of the Bernlohr laboratory for helpful suggestions. PIK-III (VPS34 inhibitor) was generously provided by Dr. Leon O. Murphy, Novartis Institutes for BioMedical Research, Ulk1/2−/− MEFs were kindly provided by Dr. M. Kundu, St. Jude Children’s Research Hospital (Memphis, TN), and Becn1−/− MEFs were provided by Dr. Zhenyu Yue, Icahn School of Medicine at Mount Sinai (New York, NY) to D.-H.K. Funding. This work was supported by National Institutes of Health grant DK-053189 and the Minnesota Agricultural Experiment Station (MN 70-015) to D.A.B. and National Institute on Aging grant AG-055452, National Institute of Diabetes and Digestive and Kidney Diseases grants DK-108790 and DK-114401, and the American Diabetes Association (1-16-IBS-203) to D.G.M. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. A.J., A.V.H., and D.A.B. developed hypotheses, carried out experiments, interpreted results, and wrote the manuscript. E.K.B. carried out experiments and interpreted results. M.W.M. developed molecular reagents, interpreted results, and edited the manuscript. S.-I.I. and D.G.M. developed hypotheses, interpreted results, and edited the manuscript. D.-H.K. developed hypotheses, interpreted results, and edited manuscript. D.A.B. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, 9–13 June 2017.
This work was supported by National Institutes of Health grant DK-053189 and the Minnesota Agricultural Experiment Station (MN 70-015) to D.A.B. and National Institute on Aging grant AG-055452, National Institute of Diabetes and Digestive and Kidney Diseases grants DK-108790 and DK-114401, and the American Diabetes Association (1-16-IBS-203) to D.G.M
© 2019 by the American Diabetes Association.