A novel model of diabetic complications: Adipocyte mitochondrial dysfunction triggers massive β-cell hyperplasia

Christine M. Kusminski, Alexandra L. Ghaben, Thomas S. Morley, Ricardo J. Samms, Andrew C. Adams, Yu An, Joshua A. Johnson, Nolwenn Joffin, Toshiharu Onodera, Clair Crewe, William L Holland, Ruth Gordillo, Philipp E. Scherer

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)313-330
Number of pages18
JournalDiabetes
Volume69
Issue number3
DOIs
StatePublished - Mar 1 2020

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Kusminski, C. M., Ghaben, A. L., Morley, T. S., Samms, R. J., Adams, A. C., An, Y., Johnson, J. A., Joffin, N., Onodera, T., Crewe, C., Holland, W. L., Gordillo, R., & Scherer, P. E. (2020). A novel model of diabetic complications: Adipocyte mitochondrial dysfunction triggers massive β-cell hyperplasia. Diabetes, 69(3), 313-330. https://doi.org/10.2337/db19-0327