@article{ca6703b55ef946918b4df8bca5f07913,
title = "A novel model of diabetic complications: Adipocyte mitochondrial dysfunction triggers massive β-cell hyperplasia",
abstract = "Obesity-associated type 2 diabetes mellitus (T2DM) entails insulin resistance and loss of β-cell mass. Adipose tissue mitochondrial dysfunction is emerging as a key component in the etiology of T2DM. Identifying approaches to preserve mitochondrial function, adipose tissue integrity, and β-cell mass during obesity is a major challenge. Mitochondrial ferritin (FtMT) is a mitochondrial matrix protein that chelates iron. We sought to determine whether perturbation of adipocyte mitochondria influences energy metabolism during obesity. We used an adipocyte-specific doxycycline-inducible mouse model of FtMT overexpression (FtMT-Adip mice). During a dietary challenge, FtMT-Adip mice are leaner but exhibit glucose intolerance, low adiponectin levels, increased reactive oxygen species damage, and elevated GDF15 and FGF21 levels, indicating metabolically dysfunctional fat. Paradoxically, despite harboring highly dysfunctional fat, transgenic mice display massive β-cell hyperplasia, reflecting a beneficial mitochondria-induced fat-to-pancreas interorgan signaling axis. This identifies the unique and critical impact that adipocyte mitochondrial dysfunction has on increasing β-cell mass during obesity-related insulin resistance.",
author = "Kusminski, {Christine M.} and Ghaben, {Alexandra L.} and Morley, {Thomas S.} and Samms, {Ricardo J.} and Adams, {Andrew C.} and Yu An and Johnson, {Joshua A.} and Nolwenn Joffin and Toshiharu Onodera and Clair Crewe and Holland, {William L.} and Ruth Gordillo and Scherer, {Philipp E.}",
note = "Funding Information: Acknowledgments. The authors kindly thank J. Song and S. Connell (Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX) for technical assistance in addition to the rest of the Scherer laboratory for helpful discussions. The authors also thank R. Hammer and The University of Texas Southwestern Medical Center Transgenic Core Facility for the generation of mouse models as well as the Metabolic Core Facility. The authors also thank L. Jackson of the Iron and Heme Core Facility at the University of Utah for additional confirmatory iron and heme measurements and G. Milne and S. Sanchez (Eicosanoid Core Laboratory, Vanderbilt University Medical Center, Nashville, TN) for F2-isoprostane measurements. Floxed FGF21-KO mice were kindly provided by the D. Mangelsdorf and S. Kliewer laboratory (Department of Pharmacology, The University of Texas South-western Medical Center, Dallas, TX). mCAT mice were kindly provided by Dr. Peter Rabinovitch (Department of Pathology, University of Washington). Funding. The authors were supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grants R01-DK-55758, R01-DK-099110, and P01-DK-088761 (to P.E.S.). Duality of Interest. R.J.S. and A.C.A. are affiliated with Eli Lilly Research Laboratories. This does not alter the authors{\textquoteright} adherence to Diabetes policies on sharing data and materials. No other potential conflicts of interest relevant to this article were reported. Author Contributions. C.M.K. conducted all experiments and wrote the manuscript, except the portions indicated below. A.L.G. and T.S.M. performed and analyzed the triolein experiments. R.J.S. and A.C.A. performed the FGF21 measurements. Y.A. and J.A.J. assisted in the ROS measurements. J.A.J. and W.L.H. performed the 2-DG and clamp experiments. N.J. and C.C. assisted in mouse experiments. R.G. performed the ceramide and sphingolipid experiments. P.E.S. was involved in experimental design, experiments, data analysis and interpretation, and in writing the manuscript. All authors approved the final version of the manuscript. P.E.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: {\textcopyright} 2019 by the American Diabetes Association.",
year = "2020",
month = mar,
day = "1",
doi = "10.2337/db19-0327",
language = "English (US)",
volume = "69",
pages = "313--330",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "3",
}