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.
Highlights
Metabolic disorders are associated with chronic inflammation
Identification of PGC-1␣-regulated Hepatic Inflammatory Genes—To explore the role of PGC-1␣ in hepatic regulation of inflammatory genes, mouse primary hepatocytes were transduced with PGC-1␣ adenovirus (PGC-1␣-Ad) or GFP control adenovirus (GFP-Ad), and gene expression was analyzed by microarray
We showed that PPAR␣ is involved in induction of interleukin 1 receptor antagonist (IL1Rn) and IL15R␣ by PGC-1␣
Summary
Metabolic disorders are associated with chronic inflammation. Results: Energy-sensing factor PGC-1␣ regulates cytokine expression in hepatocytes. We hypothesized that energy-sensitive coactivator peroxisome proliferator-activated receptor ␥ coactivator 1-␣ (PGC-1␣) and AMP-activated protein kinase (AMPK) may modulate inflammatory gene expression in liver. Overexpression of PGC-1␣ and induction of PGC-1␣ by fasting, physical exercise, glucagon, or cAMP was associated with increased IL1Rn mRNA and protein expression in hepatocytes. AMPK alter inflammatory gene expression in liver and integrate energy homeostasis and inflammation. The transcriptional coactivator peroxisome proliferator-activated receptor ␥ coactivator 1-␣ (PGC-1␣) is a major regulator of hepatic energy metabolism. Because PGC-1␣ is involved in signaling by numerous nuclear receptors, we hypothesized that PGC-1␣ could be among the key factors integrating regulation of energy homeostasis and inflammatory responses. The results presented here suggest that PGC-1␣ alters inflammatory gene expression in liver and links regulation of energy homeostasis and inflammation. We provide evidence that IL1Rn and IL15R␣ are regulated by another key energy sensor, AMP-activated protein kinase (AMPK)
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