Pancreatic β-Cell Dysfunction in Diet-Induced Obese Mice: Roles of AMP-Kinase, Protein Kinase Cε, Mitochondrial and Cholesterol Metabolism, and Alterations in Gene Expression
| Autor: | Camille Attané, Robert Sladek, Julien Lamontagne, S.R. Murthy Madiraju, Erik Joly, Roxane Lussier, Kezhuo Zhang, Anfal Al-Mass, Marc Prentki, Marie-Line Peyot, Émilie Pepin, Neil B. Ruderman |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Physiology medicine.medical_treatment Gene Expression lcsh:Medicine Mitochondrion Biochemistry Fats Mice Endocrinology 0302 clinical medicine Insulin-Secreting Cells Insulin Secretion Medicine and Health Sciences Insulin Post-Translational Modification Phosphorylation Inner mitochondrial membrane lcsh:Science Beta oxidation Energy-Producing Organelles Cells Cultured Membrane Potential Mitochondrial 2. Zero hunger Multidisciplinary Organic Compounds Monosaccharides Lipids Mitochondria Chemistry Cholesterol Physical Sciences Cellular Structures and Organelles Research Article medicine.medical_specialty endocrine system Carbohydrates Adenylate kinase 030209 endocrinology & metabolism Protein Kinase C-epsilon Bioenergetics Biology 03 medical and health sciences Oxygen Consumption Internal medicine Genetics medicine Animals Lipolysis Obesity Protein kinase A Nutrition Endocrine Physiology Gene Expression Profiling Organic Chemistry Adenylate Kinase lcsh:R Chemical Compounds Biology and Life Sciences Proteins Cell Biology Diet Disease Models Animal Glucose 030104 developmental biology Gene Expression Regulation lcsh:Q Transcriptome Diet-induced obese |
| Zdroj: | PLoS ONE, Vol 11, Iss 4, p e0153017 (2016) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Diet induced obese (DIO) mice can be stratified according to their weight gain in response to high fat diet as low responders (LDR) and high responders (HDR). This allows the study of β-cell failure and the transitions to prediabetes (LDR) and early diabetes (HDR). C57BL/6N mice were fed for 8 weeks with a normal chow diet (ND) or a high fat diet and stratified as LDR and HDR. Freshly isolated islets from ND, LDR and HDR mice were studied ex-vivo for mitochondrial metabolism, AMPK activity and signalling, the expression and activity of key enzymes of energy metabolism, cholesterol synthesis, and mRNA profiling. Severely compromised glucose-induced insulin secretion in HDR islets, as compared to ND and LDR islets, was associated with suppressed AMP-kinase activity. HDR islets also showed reduced acetyl-CoA carboxylase activity and enhanced activity of 3-hydroxy-3-methylglutaryl-CoA reductase, which led respectively to elevated fatty acid oxidation and increased cholesterol biosynthesis. HDR islets also displayed mitochondrial membrane hyperpolarization and reduced ATP turnover in the presence of elevated glucose. Expression of protein kinase Cε, which reduces both lipolysis and production of signals for insulin secretion, was elevated in DIO islets. Genes whose expression increased or decreased by more than 1.2-fold were minor between LDR and ND islets (17 differentially expressed), but were prominent between HDR and ND islets (1508 differentially expressed). In HDR islets, particularly affected genes were related to cell cycle and proliferation, AMPK signaling, mitochondrial metabolism and cholesterol metabolism. In conclusion, chronically reduced AMPK activity, mitochondrial dysfunction, elevated cholesterol biosynthesis in islets, and substantial alterations in gene expression accompany β-cell failure in HDR islets. The β-cell compensation process in the prediabetic state (LDR) is largely independent of transcriptional adaptive changes, whereas the transition to early diabetes (HDR) is associated with major alterations in gene expression. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|