A Novel Model of Diabetic Complications: Adipocyte Mitochondrial Dysfunction Triggers Massive β-Cell Hyperplasia
| Autor: | Thomas S. Morley, Clair Crewe, Yu An, Ruth Gordillo, Joshua A. Johnson, Alexandra L. Ghaben, Ricardo J. Samms, Nolwenn Joffin, Toshiharu Onodera, Philipp E. Scherer, Christine M. Kusminski, William L. Holland, Andrew C. Adams |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Growth Differentiation Factor 15 FGF21 Adipose Tissue White Endocrinology Diabetes and Metabolism Adipose tissue Mice Transgenic 030209 endocrinology & metabolism Mitochondrion Mitochondrial Proteins Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Insulin resistance Insulin-Secreting Cells Adipocyte Internal medicine Glucose Intolerance Adipocytes Internal Medicine Animals Medicine Obesity Hyperplasia Adiponectin business.industry MITOCHONDRIAL FERRITIN Type 2 Diabetes Mellitus medicine.disease Mitochondria Fibroblast Growth Factors Metabolism 030104 developmental biology Endocrinology chemistry Ferritins Glucose Clamp Technique Insulin Resistance Energy Metabolism Reactive Oxygen Species business |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db19-0327 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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