Abstract
Obesity and insulin resistance are associated with chronic, low grade inflammation. Moreover, regulation of energy metabolism and immunity are highly integrated. We hypothesized that energy-sensitive coactivator peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and AMP-activated protein kinase (AMPK) may modulate inflammatory gene expression in liver. Microarray analysis revealed that PGC-1α up-regulated expression of several cytokines and cytokine receptors, including interleukin 15 receptor α (IL15Rα) and, even more importantly, anti-inflammatory interleukin 1 receptor antagonist (IL1Rn). Overexpression of PGC-1α and induction of PGC-1α by fasting, physical exercise, glucagon, or cAMP was associated with increased IL1Rn mRNA and protein expression in hepatocytes. Knockdown of PGC-1α by siRNA down-regulated cAMP-induced expression of IL1Rn in mouse hepatocytes. Furthermore, knockdown of peroxisome proliferator-activated receptor α (PPARα) attenuated IL1Rn induction by PGC-1α. Overexpression of PGC-1α, at least partially through IL1Rn, suppressed interleukin 1β-induced expression of acute phase proteins, C-reactive protein, and haptoglobin. Fasting and exercise also induced IL15Rα expression, whereas glucagon and cAMP resulted in reduction in IL15Rα mRNA levels. Finally, AMPK activator metformin and adenoviral overexpression of AMPK up-regulated IL1Rn and down-regulated IL15Rα in primary hepatocytes. We conclude that PGC-1α and AMPK alter inflammatory gene expression in liver and thus integrate energy homeostasis and inflammation. Induction of IL1Rn by PGC-1α and AMPK may be involved in the beneficial effects of exercise and caloric restriction and putative anti-inflammatory effects of metformin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism*
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Animals
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C-Reactive Protein / biosynthesis
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C-Reactive Protein / genetics
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Caloric Restriction
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Cells, Cultured
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Energy Metabolism*
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Enzyme Activators / pharmacology
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Fasting / metabolism
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Gene Knockdown Techniques
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Haptoglobins / biosynthesis
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Haptoglobins / genetics
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Hepatocytes / metabolism
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Hepatocytes / pathology
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Hypoglycemic Agents / pharmacology
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Inflammation Mediators / metabolism*
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Insulin Resistance / genetics
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Interleukin 1 Receptor Antagonist Protein / biosynthesis*
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Interleukin 1 Receptor Antagonist Protein / genetics
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Liver / metabolism*
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Liver / pathology
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Male
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Metformin / pharmacology
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Mice
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Mice, Inbred DBA
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Obesity / genetics
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Obesity / metabolism
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Obesity / therapy
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PPAR alpha / genetics
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PPAR alpha / metabolism
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Physical Conditioning, Animal
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Rats
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Receptors, Interleukin-15 / biosynthesis
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Receptors, Interleukin-15 / genetics
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Enzyme Activators
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Haptoglobins
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Hypoglycemic Agents
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Il15ra protein, mouse
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Il1rn protein, mouse
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Inflammation Mediators
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Interleukin 1 Receptor Antagonist Protein
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PPAR alpha
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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Ppargc1a protein, rat
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RNA-Binding Proteins
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Receptors, Interleukin-15
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Trans-Activators
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Transcription Factors
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C-Reactive Protein
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Metformin
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AMP-Activated Protein Kinases